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Endocrinology and Metabolism Diabetes Mellitus Type 1 Diabetes Mellitus Diagnosis Type 1 diabetes is characterizedby aB cell destructive process that may eventually lead to absolute insulin deficiency. The onset of type 1 diabetes is ffpically abrupt and severe and may be associated with a precipitating event, such as infection, pregnancy, or MI. Look for fatigue, polyuria, polydipsia, blurring of vision, weight loss, and dehydration. More than 90'X, of cases of type l diabetes are autoimmune (type 1A). Measuring antibodies to GAD65 and IA-2 is recommended for initial confirmation. Approximately 20'l. of patients with type 1 diabetes develop other organ-specific autoimmune diseases, such as celiac disease, Graves disease, hypothyroidism, Addison disease, pernicious anemia, and vitiligo. Treatment Patients with type 1 diabetes are treated with intensive insulin therapy, which includes intermediate acting or long-acting insulin for basal coverage and preprandial analogue or regular insulin injections throughout the day. Intensive insulin therapy can also include continuous subcutaneous insulin infusion with an insulin pump and meal time boluses. Basal insulin dose accounts fbr 50% of the total daily dose of insulin; the remaining insulin is divided to cover the preprandial doses. Examples of basal insulin options: . Insulin glargine, insulin detemir, or insulin degludec: A single 10 prur dose controls nocturnal plasma glucose levels and glucose levels between meals. It also counters the early morning rise in glucose level ("dawn phenomenon") caused by hepatic gluconeogenesis. . Isophane (NPH) intermediate acting insulin: This insulin can be used in the morning and evening to provide basal plasma insulin levels and to suppress hepatic gluconeogenesis. Examples of short acting preprandial insulin options

. Insulin glargine, insulin detemir, or insulin degludec: A single 10 prur dose controls nocturnal plasma glucose levels and glucose levels between meals. It also counters the early morning rise in glucose level ("dawn phenomenon") caused by hepatic gluconeogenesis. . Isophane (NPH) intermediate acting insulin: This insulin can be used in the morning and evening to provide basal plasma insulin levels and to suppress hepatic gluconeogenesis. Examples of short acting preprandial insulin options o Insulin aspart, insulin glulisine, and insulin lispro: rapid acting insulin given 5 to 15 minutes befbre meals to modulate the postprandial rise in glucose level. . Regular insulin: given 30 minutes before meals to prevent postprandial elevations in blood glucose. Correctional insulin is the use of additional analogue or regular insulin beyond the usual dose to treat preprandial glucose that is not at target. For example, a correction for type 1 diabetes may be an additional 1 U of insulin lbr every 50 mg/dl that the glucose level is above the preprandial target. Insulin pumps: Subcutaneous infusion of rapid-acting insulin is delivered continuously for basal insulin requirements and given in intermittent boluses for prandial needs. 47

Endocrinology and Metabolism STtrDY ?ABLE: Adjusting lnsulin Dose in Diabetes Mellitus Condition Cause Fasting hyperglycemia Not enough basal insulin Prelunch hyperglycemia Not enough rapid-acting insulin at breakfast or not enough morning NPH insulin Predinner hyperglycemia Not enough rapid-acting insulin at lunch or not enough morning NPH insulin Bedtime hyperglycemia Not enough rapid-acting insulin at dinner Fasting or nocturnal hypoglycemia Too much basal insulin Prelunch hypoglycemia Too much rapid-acting insulin at breakfast or too much morning NPH insulin Predinner or bedtime hypoglycemia Too much rapid-acting insulin at lunch or dinner or too much morning NPH Hypoglycemia unawareness describes the presence of severely lo\ / plasma glucose levels that occur without warning symptoms lbllowed by sudden loss or impairment of consciousness. Treat immediately with rapid acting carbohydrates or a glucagon injection followed by food. Lowering the insulin dose and allowing the average plasma glucose level to increase for several weeks may restore sensitivity to hypoglycemia. Type 2 Diabetes Mellitus Diagnosis Type 2 diabetes is characterized by a combination of insulin resistance and a p-cell secretory defect. With time, progressive p-cell dysfunction can develop, leading to absolute insulin deficiency. Because symptoms may be subtle, the time to diagnosis may be delayed. Consequently, approximately 2O"l' of patients with type 2 diabetes have microvascular complications of the disease at presentation; an even higher percentage may have CAD or periph eral vascular disease. Most patients with type 2 diabetes are obese or at least have abdominal obesity. Characteristic findings of long standing diabetes include: o polyuria, polyphagia, and polydipsia o retinal microaneurysms, dot-and-blot hemorrhages, macular edema . symmetric sensory "stocking-glove" peripheral neuropathy . cardiovascular and kidney disease Screening forType 2 Diabetes The USPSTF recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults aged 35 to 70 years who are overweight or obese.

o polyuria, polyphagia, and polydipsia o retinal microaneurysms, dot-and-blot hemorrhages, macular edema . symmetric sensory "stocking-glove" peripheral neuropathy . cardiovascular and kidney disease Screening forType 2 Diabetes The USPSTF recommends screening for abnormal blood glucose as part of cardiovascular risk assessment in adults aged 35 to 70 years who are overweight or obese. The ADA recommends screening overweight adults (BMI >25 >23 in Asian Americans) with at least one additional risk factor and all patients >45 years. Additional risk factors include: o lirst degree relative with diabetes . high risk race/ethnicity (Black, Hispanic/Latino, American Indian, Asian, Native Hawaiian/Pacific lslander) o history of gestational diabetes mellitus . history of CVD . physical inactivity . hypertension o HDL cholesterol level <35 mg/dl and/or triglyceride level >250 mg/dl . PCOS o prediabetes on previous testing 48

Endocrinology and Metabolism Screen using the following tests: fasting plasma glucose, 2-hour postprandial glucose during an OGTT, or hemoglobin A,". lf two separate tests are done simultaneously and both are abnormal, diagnose diabetes. If only one olthe two tests is abnormal, repeat the abnormal test. DO]II,T BE TRICKED o A random plasma glucose level >200 mg/dl with hyperglycemic symptoms is diagnostic of diabetes and does not warrant repeat measurement. STUDY TABLE: Diagnosis and Classification of Type 2 Diabetes Mellitus Diagnosis Fasting Glucose Random Glucose 2-Hour Glucose Hemoglobin Ar. during OGTT lncreased risk for 100-125 mg/dl 140-199 mg/dL 140-199 mg/dL 5.7"/"-6.4"/" diabetes (prediabetes) Diabetes >-126 mg/dl >200 mg/dLwith >200 mg/dL >-6.5"/" symptoms Treatment Intensive lifestyle modification (diet, exercise, weight loss) is appropriate for all patients with prediabetes or type 2 diahetes. Medication, such as metformin. reduces the risk of diabetes in patients with prediabetes, although not as effectively as lifestyle interventions. Bariatric procedures should be considered in patients with obesi[2. Blood glucose monitoring includes self monitoring of blood glucose, hemoglobin A,", or continuous glucose monitoring. o Use sell monitoring of blood glucose for patients taking multiple daily injection insulin therapy or continuous subcutane ous insulin infusion therapy. o Obtain postprandial blood glucose levels in patients with at goal preprandial readings but with hemoglobin A," not at goal. . Obtain overnight blood glucose monitoring to detect hypoglycemia or dawn phenomenon. Although guidelines vary a reasonable individualized goal tbr most patients is a hemoglobin Ar. of 7'l. to 8'/.. Goals are adjusted based on patient age and health status.

o Use sell monitoring of blood glucose for patients taking multiple daily injection insulin therapy or continuous subcutane ous insulin infusion therapy. o Obtain postprandial blood glucose levels in patients with at goal preprandial readings but with hemoglobin A," not at goal. . Obtain overnight blood glucose monitoring to detect hypoglycemia or dawn phenomenon. Although guidelines vary a reasonable individualized goal tbr most patients is a hemoglobin Ar. of 7'l. to 8'/.. Goals are adjusted based on patient age and health status. DO]II,T BE TRICKED o If a patient is nonadherent with multiple insulin injections, adherence is unlikely to increase because a pump is prescribed. . Hemoglobin A,. will be falsely low in patients with hemolytic anemia, patients taking erythropoietin, or patients with kidney injury. Pharmacologic Therapy for Type 2 Diabetes Mellitus o Metformin is the recommended first line oral agent for newly diagnosed type 2 diabetes. o Hemoglobin A," should be assessed every 3 months with adjustments to therapy until the glycemic target is achieved and every 6 months if at goal. . If not at goal, next preflerred therapy is an SGlif2 inhibitor or a GLP-I receptor agonist for patients at risk for or with established ASCVD or with established kidney disease, and an SGLI2 inhibitor for HR . [n most patients who need the greater glucose lowering effect of an injectable medication, GLP 1 receptor agonists are prelerred to insulin. . If weight loss is a desired effect, GLP 1 receptor agonists and SGLT2 inhibitors are the best choices. 49

Endocrinology and Metabolism Mellitus STUDY IABLE: Pharmacologic Ag ents Used to Lower Blood Glucose Levels in Type 2 Diabetes Drug Weight ASCVD HF Kidney Benefit Neutral Possible benefit Neutral Neutral Metformin SGLT2 inhibitors Loss Benefit (empagliflozin, Benefit (empagliflozin, Benefit (empaglif lozin, canagliflozin) canagliflozin, dapagliflozin) canagliflozi n, dapag liflozin) Loss Benefit (dulaglutide, Neutral Benefit (dulaglutide, GLP-1 receptor agonists liraglutide, semaglutide) liraglutide, semaglutide) DPP-4 inhibitors Neutral Neutral Possible risk, saxagliptin Neutral Th iazolid ined iones Gain Possible benefit, Risk Neutral pioglitazone Seco nd-gene ration Gain Neutra I Neutra I Neutral Gain Neutral Neutral Neutral Screening recommendations for chronic complications of diabetes: Patients with type 1 and type 2 diabetes should be screened regularly for diabetic complications, including: . retinopathy (comprehensive eye examination) t nephropathy (albumin to-creatinine ratio) o neuropathy (10 g monofilament, 128 Hz tuning fork, pedal pulses, and ankle reflex) o CVD (BP and fasting lipid profile measurements) Screening for complications in patients with type 1 diabetes should begin at 5 years after diagnosis and should be performed annually thereafter. Screening for complications in patients with type 2 diabetes should begin at the time of diagnosis and be performed annually thereafter.

. retinopathy (comprehensive eye examination) t nephropathy (albumin to-creatinine ratio) o neuropathy (10 g monofilament, 128 Hz tuning fork, pedal pulses, and ankle reflex) o CVD (BP and fasting lipid profile measurements) Screening for complications in patients with type 1 diabetes should begin at 5 years after diagnosis and should be performed annually thereafter. Screening for complications in patients with type 2 diabetes should begin at the time of diagnosis and be performed annually thereafter. STUDY TABLE: Treatment of Diabetes Complications Condition Goal or lndication Treatment Hypertension BP goal <130/80 mm Hg (ACC/AHA All first-line antihypertensive drug classes hypertension guideline) BP goal <140/90 mm Hg (ADA guideline) ACE inhibitor or ARB in patients with albuminuria Diabetes and average Age >40 years, diabetes, and a 1 O-year Moderate intensity statin cardiovascular risk ASCVD risk <7.5% (ACC/AHA guideline) Diabetes and increased CAD, peripheral vascular disease, or ASCVD High-intensity statin cardiovascular risk risk >7.5% (AHA/ACC guideline) Age 40-75 years, diabetes, and a calculated Moderate- to high-intensity statin 1 0-year risk of a cardiovascular event >1 0% (USPSTF recommendation)

STUDY TABLE: Treatment of Diabetes Complications Condition Goal or lndication Treatment Hypertension BP goal <130/80 mm Hg (ACC/AHA All first-line antihypertensive drug classes hypertension guideline) BP goal <140/90 mm Hg (ADA guideline) ACE inhibitor or ARB in patients with albuminuria Diabetes and average Age >40 years, diabetes, and a 1 O-year Moderate intensity statin cardiovascular risk ASCVD risk <7.5% (ACC/AHA guideline) Diabetes and increased CAD, peripheral vascular disease, or ASCVD High-intensity statin cardiovascular risk risk >7.5% (AHA/ACC guideline) Age 40-75 years, diabetes, and a calculated Moderate- to high-intensity statin 1 0-year risk of a cardiovascular event >1 0% (USPSTF recommendation) ADA and ACC/AHA recommendation SGLT2 inhibitor or GLP-1 receptor agonist Diabetic kidney disease Urine albumin excretion >30 mg/g ACE inhibitor or ARB, SGLT2 inhibitor, GLP-1 receptor agonist Diabetic retinopathy Proliferative and nonproliferative retinopathy Excellent blood glucose and BP control; smoking cessation Panretinal laser photocoagulation for PDR and severe NPDR lntraocular injections of bevacizumab or ranibizumab for severe NPDR and PDR or macular edema Diabetic peripheral Numbness, tingling, burning, heaviness, Amitri ptyline, venlafaxine, duloxetine, paroxetine, neu ropathy pain, or sensitivity in stocking-glove pregabalin, gabapentin, valproate, or capsaicin cream distribution Sexual dysfunction Erectile dys{unction Oral phosphodiesterase inhibitor (sildenafil, vardenafil, tadalafil) Gastroparesis Early satiety, nausea and vomiting Small feedings; metoclopramide or erythromycin Diabetic foot Ulcer or osteomyelitis See lnfectious Disease, Diabetic Foot Infections NPDR = nonproliferatlve diabetic retinopathy; PDR = proliferative dratt'etic retinopathy.

ADA and ACC/AHA recommendation SGLT2 inhibitor or GLP-1 receptor agonist Diabetic kidney disease Urine albumin excretion >30 mg/g ACE inhibitor or ARB, SGLT2 inhibitor, GLP-1 receptor agonist Diabetic retinopathy Proliferative and nonproliferative retinopathy Excellent blood glucose and BP control; smoking cessation Panretinal laser photocoagulation for PDR and severe NPDR lntraocular injections of bevacizumab or ranibizumab for severe NPDR and PDR or macular edema Diabetic peripheral Numbness, tingling, burning, heaviness, Amitri ptyline, venlafaxine, duloxetine, paroxetine, neu ropathy pain, or sensitivity in stocking-glove pregabalin, gabapentin, valproate, or capsaicin cream distribution Sexual dysfunction Erectile dys{unction Oral phosphodiesterase inhibitor (sildenafil, vardenafil, tadalafil) Gastroparesis Early satiety, nausea and vomiting Small feedings; metoclopramide or erythromycin Diabetic foot Ulcer or osteomyelitis See lnfectious Disease, Diabetic Foot Infections NPDR = nonproliferatlve diabetic retinopathy; PDR = proliferative dratt'etic retinopathy. 50

Endocrinology and Metabolism Prollferative Diabetit Retinopathy: A network of new vessels (neovasculariza- llonproliferatiue Diabetic Retlnopathy: Dot-and,blot hemonhages and clus, tion) is shown protruding from the optic nerve. ters of hard, yellowish exudates are characteristic of nonproliferative diabetic reti nopathy. DOil'T BETRICKED o Do not treat diabetic mononeuropathy (e.g., third nerve palsy); symptoms resolve spontaneously TESTYOURSETF A 29-year-old woman with a 1O-year history of type 1 diabetes has nocturnal hypoglycemia. Her insulin schedule includes 24 U NPH insulin/lO U regular insulin before breakfast and 14 U NPH insulin/IO U regular insulin before dinner. Her hemoglobin Ar" is 7.2%.'Nhat change should be made to her insulin regimen? ANSWER: For management, three answers are possible: Delay the NPH insulin until bedtime, Iower the evening NPH dose, or (an even better choice) stop the NPH insulin and substitute insulin glargine, detemir, or degludec at bedtime. Hyperglycemic Hyperosmolar Syndrome and Diabetic Ketoacidosis Diagnosis : Hyperglycemic hyperosmolar syndrome (HHS) occurs with extrerne hyperglycemia (>600 mg/dl) in older patients with type 2 diabetes mellitus, no or low serum levels of ketones, and a relatively normal arterial pH and bicarbonate level. ; ! The major manifestations of DKA are hyperglycemia, ketosis, and hypovolemia. Laboratory findings include a plasma glucose level >250 mg/dl, arterial blood pH <7.30, bicarbonate level <15 mEq/L, increased I b l I anion gap, and positive serum ketone levels. Evaluate patients with either HHS or DKA for underlying precipitants such as medication nonadherence, infection, and MI and confounding medications (atypical antipsychotics, glucocorticoids). Eug$cemic DKA can occur in patients taking SGLI2 t inhibitors. t t L L I 51 I L I

Endocrinology and Metabolism Begin the evaluation of all patients with fasting hypoglycemia with screening for surreptitious use of an oral hypoglycemia agent, such as a sulfonylurea or insulin. gastrinomas that MEN1 can present as hyperparathyroidism, pituitary neoplasms, or pancreatic NETs' Pancreatic NETs include can cause PUD and insulinomas that can cause hypoglycemia. DON'T BETRICKED e Do not use home glucometers to document hypoglycemia, because they may be inaccurate' . Asymptomatic hypoglycemia with a plasma glucose level <6o mg/dl is often found after fasting in patients without underlying disease and does not require evaluation. Treatment Treat acute hypoglycemia with oral carbohydrates, IV glucose, or glucagon. For management of postprandial hypoglycemia associated with previous gastrectomy or gastric bypass surgery choose small mixed meals containing protein, fat, and high-fiber complex carbohydrates. TESTYOUNSETF A previously healthy 2S-year-old female registered nurse is found unconscious on the ward where she works. Her plasma glucose level is 28 mg/dl. She regains consciousness following IV glucose administration. Serum insulin level is 42 mU/L (normal, 2 20 mU lL) , and serum C-peptide level is 7.2 ng/ml (normal, 0.9-4.0 ng/ml). ANSWER: For diagnosis, select factitious hypoglycemia. For management, choose screening for surreptitious ingestion of hypogly cemic agents such as sulfonylureas. Pituitary Hormone Deficiency Diagnosis Panhypopituitarism is a condition in which adequate production of all anterior pituitary hormones is lacking, usually because of a large tumor (see Pituitary Adenomas following), apoplexy, necrosis, autoimmune disorder, or complications of pituitary surgery. Pituitary apoplery results from sudden pituitary hemorrhage or infarction and is often associated with sudden headache, visual change, ophthalmoplegia, and altered mental status. Postpartum pituitary necrosis (Sheehan syndrome) is caused by silent pituitary infarction; is usually associated with obstetric hemorrhage and hypotension; and most commonly presents with amenorrhea, a postpartum inability to lactate, and fatigue.

Pituitary apoplery results from sudden pituitary hemorrhage or infarction and is often associated with sudden headache, visual change, ophthalmoplegia, and altered mental status. Postpartum pituitary necrosis (Sheehan syndrome) is caused by silent pituitary infarction; is usually associated with obstetric hemorrhage and hypotension; and most commonly presents with amenorrhea, a postpartum inability to lactate, and fatigue. Lymphocytic hypophysitis causes hypopituitarism and, possibly, symptoms of a mass lesion. Most cases of lymphocy'tic hypo physitis occur during or after pregnancy but may be the result of cancer immunotherapy with checkpoint inhibitors. The posterior pituitary releases vasopressin and ory.tocin directly into the systemic circulation. Deficiencies of these hormones can occur independent of anterior pituitary dysfunction. Look for symptoms of panhypopituitarism: . fatigue, nausea, vomiting, weight loss, or abdominal pain (ACTH deflciency) . cold intolerance, weight gain, or constipation (TSH deficiency) r visual fleld diagram showing bitemporal loss of vision (mass effect on the optic chiasm) o amenorrhea, loss of libido, or erectile dysfunction (FSH/LH deficiency) . loss of muscle mass (GH deficiency) 54

Endocrinology and Metabolism L R Visual tield Defects: Bitemporal quadrant visual field defeits secondary to a pituitary mass. Pituitary adenomas become symptomatic by two different mechanisms: o mass effect causing hypopituitarism (anterior hormone deficiencies more common than posterior), headaches, visual disturbance/visual field defects, and cranial nerve dysfunction . endocrine hyperfunction caused by excess secretion by the tumor (most commonly prolactinomas) DOil'T BE TRICKED . The pituitary gland is enlarged diffusely in untreated primary hypothyroidism and during normal pregnancies. Testing Most incidentally noted pituitary masses in asymptomatic patients are benign, nonfunctional pituitary adenomas. o Obtain dedicated pituitary MRI. . Assess possible pituitary hypersecretion (measure prolactin and IGF 1) Screen patients lor hypopituitarism with pituitary tumors regardless of symptoms with measurement of: . FSH. LH o cortisol . TSH, T+ o total testosterone (men) DOil'T BE TRICKED . A menstrual history can assess for hypogonadotropic hypogonadism in premenopausal women. . Testing for Cushing disease is not necessary in the absence of symptoms.

o Obtain dedicated pituitary MRI. . Assess possible pituitary hypersecretion (measure prolactin and IGF 1) Screen patients lor hypopituitarism with pituitary tumors regardless of symptoms with measurement of: . FSH. LH o cortisol . TSH, T+ o total testosterone (men) DOil'T BE TRICKED . A menstrual history can assess for hypogonadotropic hypogonadism in premenopausal women. . Testing for Cushing disease is not necessary in the absence of symptoms. Sf UDY TABLE: Diagnosis of Pituitary Adenomas lf you see this... Think this.. Order this... Galactorrhea, amenorrhea Prolactinoma Serum prolactin level Enlargement of hands, feet, nose, lips, or Acromegaly Serum IGF-1 tongue; increased spacing ofteeth OGTT (fails to suppress GH) Proximal muscle weakness, facial rounding, Cushing disease 24-Hour urine cortisol excretion, centripetal obesity, purple striae, diabetes dexamethasone suppression test, or late-night mellitus, and hypertension salivary cortisol level (elevated), serum ACTH level (elevated or inappropriately "normal") Goiter and hyperthyroidism TSH-secreting adenoma (rare) TSH normal or elevated; increased Ta 55

Endocrinology and Metabolism DON'T BE TRICKED . Psychotropic agents, tricyclic antidepressants, antiseizure medications, metoclopramide and domperidone, calcium channel blockers, methyldopa, opioids, and protease inhibitors can cause hyperprolactinemia. . The prolactin level influenced by drugs and other nonprolactinoma conditions is usually <150 ng/ml. o Obtain a pregnancy test in all women with hyperprolactinemia. . Obtain a serum TSH level in all patients with hyperprolactinemia (hypothyroidism can cause hyperprolactinemia). I I Treatment t Choose observation for women with microprolactinoma and normal menses or for patients with nonfunctioning pituitary I L microadenomas. Prolactinoma: A discrete area of hypolucency (arow) is seen in an otherwise nor- Choose a dopamine agonist (cabergoline preferred to bromocrip I mal-sized pituitary gland of homogeneous density. tine) for symptomatic prolactinoma. I t Choose surgery for adenomas secreting GH, ACTH, or TSH; for adenomas associated with mass effect, visual field defects, or t hypopituitarism; and for prolactinomas unresponsive to dopamine agonists. i I TESTYOURSETT A 32-year old woman has a 4 mm hypointense area in the pituitary gland discovered incidentally on an MRI. Medical history includ- i. ing menstrual function, and physical examination are normal. The serum prolactin level and thyroid function tests are normal. ANSWER: For diagnosis, choose an incidental nonfunctioning pituitary adenoma. For management, repeat the MRI in 1year. Diabetes lnsipidus Diagnosis DI is characterized by an inability to concentrate urine because ofinsufficient arginine vasopressin (AVP, ADH) release (central I DI) or activity (nephrogenic DI). Symptoms and signs of central DI are polydipsia; polyuria; nocturia; and, depending on mass effect of a pituitary tumor, visual field deficits. Testing Measure the plasma glucose level to rule out diabetes mellitus and the serum calcium level to rule out hypercalcemia as causes of polyuria. L

DI) or activity (nephrogenic DI). Symptoms and signs of central DI are polydipsia; polyuria; nocturia; and, depending on mass effect of a pituitary tumor, visual field deficits. Testing Measure the plasma glucose level to rule out diabetes mellitus and the serum calcium level to rule out hypercalcemia as causes of polyuria. L An inappropriately low urine osmolality in the setting of an elevated serum osmolality and hypernatremia in a patient with polyuria is diagnostic. A water deprivation test can be performed when the diagnosis is uncertain. Following water deprivation, an elevated serum osmolality or hypernatremia with inappropriately dilute urine is diagnostic. 57

Endocrinology and Metabolism Evaluating the response to desmopressin can help differentiate central from nephrogenic DI. If the desmopressin challenge test is positive (urine concentrates, indicating central DI), order an MRI of the pituitary gland. If the test is negative (urine does not concentrate, indicating nephrogenic DI), order kidney ultrasonography. Treatment Central DI is treated with desmopressin. TE TYOURSETF A previously healthy 27-year old woman has a 1-month history of polydipsia and polyuria. Her plasma urine output is 4 L/d, urine osmolality is 95 mOsm/kg HrO, and simultaneous serum osmolality is >295 mOsm/kg HrO. Serum glucose and calcium are nor- mal. Urine osmolality increases to >800 mOsm/kg HrO after desmopressin. ANSWER: For diagnosis, choose central DI. Empty Sella Syndrome Diagnosis Empty sella is diagnosed when the normal pituitary gland is not visualized or is excessively small on MRI. Causes include: . increased CSF entering and enlarging the sella . tumor o previous pituitary surgery radiation, or infarction Testing In asymptomatic persons, obtain cortisol, TSH, and free (or total) To measurements. Hypefthyroidism Diagnosis The term thyrotoxicosis encompasses any cause of thyroid hormone excess. HAperthAroidism is thyrotoxicosis caused by excessive endogenous thyroid hormone production. Look for symptoms of thyrotoxicosis: o nervousness, emotional lability . increased sweating, heat intolerance o palpitations . increased defecation . weight loss o menstrual irregularity Look for signs of thyrotoxicosis: . tachycardia . lidlag 58

Endocrinology and Metabolism o fine tremor . muscle wasting, proximal muscle weakness ' hyperreflexia The most common causes of hyperthyroidism are Graves disease and toxic adenoma(s)' Physical examination findings specific for Graves disease include goiter, ophthalmopathy (proptosis, chemosis, and extraocular muscle palsy), and pretibial mlxedema. Older adult patients with hyperthyroidism may present with depression, AE, and HF. Thyrotoxicosis occurs in destructive thyroiditis because thyroid damage results in release of preformed thyroid hormone into the circulation. Thyroid storm is the development of life-threatening hyperthyroidism associated with cardiac decompensation, fever, delirium, and psychosis. It may occur following surgery infection, or administration of an acute iodine Ioad (contrast agents) and may also develop in patients with untreated Graves disease. Thyroid storm is a clinical diagnosis; no level of thyroid hormone ele vation is diagnostic. Testing Order serum TSH and free T, levels to make the diagnosis of thyrotoxicosis. If TSH is suppressed but T. is normal, order free T, to diagnose T, toxicosis (rare). Thyroglobulin levels can be elevated in hyperthyroidism and thyroiditis. Intake of exogenous thyroid hormone suppresses thyroglobulin levels, which makes its measurement useful (when low) in patients with thyrotoxicosis caused by surrepti- tious use of thyroid hormone. An elevated serum ESR supports thyroiditis, whereas TSH-receptor antibodies and thyroid stimulating immunoglobulins are associated with Graves disease. However, antibodies need not be checked routinely in the evaluation ofhyperthyroidism unless the diagnosis is unclear. STUDY TABLET lnterpreting Thyroid Function Tests in Hyperthyroidism lf you see this... Choose this... J TSH, t free Ta Primary hyperthyroidism J TSH, t T3, normal free Ta Primary hyperthyroidism with T3 toxicosis J TSH, normal T3 and free To, without symptoms Subclinical hyperthyroidism H, 'l T3, I free Ta Secondary hyperthyroidism from a pituitary tumor (central hyperthyroidism, very [' rare)

STUDY TABLET lnterpreting Thyroid Function Tests in Hyperthyroidism lf you see this... Choose this... J TSH, t free Ta Primary hyperthyroidism J TSH, t T3, normal free Ta Primary hyperthyroidism with T3 toxicosis J TSH, normal T3 and free To, without symptoms Subclinical hyperthyroidism H, 'l T3, I free Ta Secondary hyperthyroidism from a pituitary tumor (central hyperthyroidism, very [' rare) lmaging STUDY TABLE: Radioactive lodine Uptake and Scan lnterpretation Result Diagnosis Diffuse homogeneous increased uptake Graves disease Patchy areas of increased uptake Toxic multinodular goiter Focal increased uptake with decreased uptake in the rest ofthe Solitary adenoma gland Decreased or no uptake lodine load (lV contrast or amiodarone) Thyroiditis (silent, subacute, postpartum, or amiodarone induced) Surreptitious ingestion of excessive thyroid hormone 59

Endocrinology and Metabolism Nonthyroidal illness s5mdrome occurs in patients who are acutely ill with a nonthyroidal illness. Testing reveals low or normal free To and suppressed TSH (initially), followed by elevated TSH (recovery phase). Normalization of thyroid function tests occurs 4 to 8 weeks after recovery. DON'T BE TRICKED . Thyroid scan and radioactive iodine uptake tests are not used to make the diagnosis of hypothyroidism. STUDY TABLE: lnterpreting Thyroid Function Tests in Hypothyroidism lf you see this... Choose this... 1TSH, J free Ta Primary hypothyroidism 'l TSH, normalTa Subclinical hypothyroidism J TSH, J free Ta Secondary (central) hypothyroidism; consider hypopituitarism Treatment Levothyroxine is used to treat hypothyroidism. Treatment of subclinical hypothyroidism is controversial. Most guidelines support these treatment indications for subclinical hypothyroidism (TSH >10 pU/mL): o symptomatic . pregnant or planning to become pregnant o possibly age <30 years Levothyroxine should be taken on an empty stomach 60 minutes before consuming breakfast or coffee. Recall that celiac dis- ease, calcium and iron supplements, and PPIs can decrease levothyroxine absorption; medications affecting absorption should be taken at least 4 hours apart from levothyroxine. DOil'T BE IRICKED r No treatment is required for nonthyroidal illness syndrome. . Check thyroid function tests frequently during pregnancy in women with a known diagnosis of hypothyroidism taking thyroxine, because maternal thyroxine demand increases by 30% to 50%. STUDY TABLE: Levothyroxine Treatment of Hypothyroidism Condition Treatment Age <60 years Begin full-dose levothyroxine (about 100 pgld) Age >60 years Begin levothyroxine at 25-50 pg/d lncrease by 25 pg every 6 weeks untilTSH level is 1.0-2.5 pU/mL Heart disease Begin levothyroxine at 1 2.5-25 1tg/ d lncrease by 12.5-25 pg every 6 weeks untilTSH level is 1 .0-2.5 pU/mL Thyroid Nodules Diagnosis Thyroid nodules are common and are often found incidentally on physical examination or imaging tests.

STUDY TABLE: Levothyroxine Treatment of Hypothyroidism Condition Treatment Age <60 years Begin full-dose levothyroxine (about 100 pgld) Age >60 years Begin levothyroxine at 25-50 pg/d lncrease by 25 pg every 6 weeks untilTSH level is 1.0-2.5 pU/mL Heart disease Begin levothyroxine at 1 2.5-25 1tg/ d lncrease by 12.5-25 pg every 6 weeks untilTSH level is 1 .0-2.5 pU/mL Thyroid Nodules Diagnosis Thyroid nodules are common and are often found incidentally on physical examination or imaging tests. Look for risk factors for thyroid cancer, including family history of thyroid malignancy, personal history of radiation therapy to the head and neck, or other radiation exposure in childhood. 52

Endocrinology and Metabolism lmaging and Testing When a nodule is discovered, assess thyroid function with a serum TSH level. . Low TSH -+ obtain radioisotope scan scintigraphy to confirm the diagnosis of autonomously functioning thyroid adenoma and to rule out additional nonfunctioning nodules. . Normal or high TSH + obtain ultrasonography. Thyroid nodule characteristics and size on ultrasound determine the need for FNAB' FNAB is not recommended for subcenti meter nodules unless associated with symptoms, pathologic lymphadenopathy, extrathyroidal extension, history of childhood radiation exposure, or family thyroid cancer syndrome. FNAB is indicated for: . al1 thyroid nodules >1 cm with suspicious sonographic features and a normal TSH level . nodules <1 cm in patients with risk factors for thyroid can cer or suspicious ultrasound characteristics In patients with multinodular goiter, the risk for malignancy is the same for multiple nodules as it is for a solitary nodule; there- fore, evaluation and management are identical. Evaluate patients with multinodular goiter for compressive symptoms: . dysphagia . hoarseness . dyspnea (tracheal compression from substernal goiter) Consider evaluation with barium swallow direct vocal cord visu- alization, spirometry with flow volume loops, and/or chest CT as needed. Thyroid l{odule: A hyperfunctioning nodule is shown on the lateral aspect of the left thyroid lobe on thyroid scan. DON'T BE TRICKED . Serum thyroglobulin measurement is not helpful in distinguishing benign from malignant thyroid nodules. . Calcitonin measurement is considered only in patients with hypercalcemia or a family history of thyroid cancer or MEN2. Treatment Observation: Follow benign nodules with periodic ultrasonography. Malignancy must be ruled out when a nodule increases in size or if a nodule develops concerning ultrasound characteristics. Radioactive iodine or surgery: Treat hyperfunctioning solitary thyroid nodules with radioactive iodine ablation or hemithyroidectomy. Surgery is indicated for patients with: o continued nodule growth despite normal initial FNAB results . nondiagnostic results on repeat FNAB . malignant cytologz . large multinodular goiters with compressive symptoms 53

Endocrinology and Metabolism DOil'T BE TRICKED r Do not prescribe T4-suppression therapy for benign thyroid nodules. TESTYOURSELF An 18-year old man has a 2-cm solid right sided thyroid nodule. The serum TSH level is 1.4 pU/mL. ANSWER: For management, choose FNAB. Hypercortisolism (Cushing Syndrome) Diagnosis Cushing syndrome results from excess glucocorticoid. The most common cause of Cushing syndrome is the use of systemic, topical, intra-articular, or inhaled glucocorticoids. Doses of prednisone (or equivalent) >t0 to 20 mg/d can cause hypothalamic-pituitary adrenal axis suppression after >3 weeks of consecutive use. Endogenous causes ofCushing syndrome can be ACTH dependent or independent. ACTH-dependent causes of Cushing syndrome are defined by ACTH levels elevated or inappropriately "normal" in relation to the cortisol level: . ACTH-secreting pituitary adenomas (Cushing disease) . ACTH-secreting carcinomas and carcinoid tumors ACTH-independent causes of Cushing syndrome are defined by low or "normal" ACTH levels in relation to the cortisol level: . adrenal adenomas . adrenal carcinomas Clinical findings highly specific for Cushing syndrome include: . proximal muscle weakness . facial plethora . supraclavicular or dorsocervical ("buffalo hump") fat pads . wide (>t cm) violaceous striae Testing First line diagnostic studies include: o 1-mg overnight dexamethasone suppression test (failure to suppress serum cortisol to <3 pg/dl) o 24 hour urine cortisol level (elevated) . late night salivary cortisol level (elevated) If the cortisol level is elevated (or not suppressible), obtain an ACTH level to differentiate ACTH-dependent from ACTH- independent hypercortisolism. 64

Endocrinology and Metabolism STUDY TABLE; Evaluation of Hypercortisolism lf you see this... Do this.. Morning ACTH elevated Pituitary MRI or CT Morning ACTH suppressed or normal Adrenal CT DON'T BE TRIGKED . Evaluation for Cushing syndrome should be limited to patients with a significant clinical suspicion of disease, including specific signs of Cushing syndrome or an adrenal mass. . False-positive results (failure to suppress cortisol) with the 1-mg dexamethasone suppression test are common owing to alcohol use, obesity, and psychological disorders. Treatment Surgical resection is the definitive treatment for benign and malignant cortisol-secreting adrenal tumors. Bisphosphonates are the treatment of choice for low bone density caused by hypercortisolism. TEST YOURSELF A 43 year-old woman has diabetes mellitus; hypertension; hir- sutism; and wide, purple abdominal striae. The serum cortisol level is 26 ytgldL after administration ofll mg of dexamethasone. The serum ACTH level is 50 pglml. ANSWER: For diagnosis, choose pituitary tumor. For testing, select pituitary gland MRL Adrenal lncidentaloma Cushing Syndrome: Wide purple striae characteristic of Cushing syndrome. Diagnosis An adrenal incidentaloma is a mass >1 cm that is discovered incidentallv. Testing The two goals of evaluation are to determine if an adenoma is functioning and if it is malignant. Treatment Surgery is recommended for adrenal masses >4 cm in diameter or functioning tumors. 65

Endocrinology and Metabolism lncidentally Noted Adrenal Mass" Benign CT lmaging lndeterminate CT Suspicious CT lmaging Phenotypeb lmaging Phenotypeb Phenotypeb o Size <4 cm o Size >4 cm o Density s10 HUb . Density >10 HUb o Contrast washout . Contrast washout >50% (10 min)b s50% (10 min)b Test for Hormone Excess"

Benign CT lmaging lndeterminate CT Suspicious CT lmaging Phenotypeb lmaging Phenotypeb Phenotypeb o Size <4 cm o Size >4 cm o Density s10 HUb . Density >10 HUb o Contrast washout . Contrast washout >50% (10 min)b s50% (10 min)b Test for Hormone Excess" All patients lndications for Adrenalectomy Cortisol . Suspicious imaging . Test: LDST . GroMh >20% plus >5 mm Catecholamines increase in diameter on o Test: plasma or urine repeat imaging metanephrines or urine . Unilateral adrenal tumor with catecholaminesd clinically significant hormone excess

All patients lndications for Adrenalectomy Cortisol . Suspicious imaging . Test: LDST . GroMh >20% plus >5 mm Catecholamines increase in diameter on o Test: plasma or urine repeat imaging metanephrines or urine . Unilateral adrenal tumor with catecholaminesd clinically significant hormone excess Select patients Aldosterone o Who: HTN or J K' . TESI: PRA/PAC Androgens o Who: lf suspected" . Test: DHEAS, testosterone, androstenedione No Functioning adrenal tumor Yes

Select patients Aldosterone o Who: HTN or J K' . TESI: PRA/PAC Androgens o Who: lf suspected" . Test: DHEAS, testosterone, androstenedione No Functioning adrenal tumor Yes Benign CT lmaging phenotype lndeterminate CT lmaging Phenotype Consider Adrenalectomy o NFAT: No repeat testing or imaging lmmediate MRl, immediate adrenalectomy, MACE or repeat imaging (CT or MRI) in 6 to 12 months . Benign CT imaging phenotype . Screen for diabetes, hypertension, and osteoporosis . No repeat imaging

Benign CT lmaging phenotype lndeterminate CT lmaging Phenotype Consider Adrenalectomy o NFAT: No repeat testing or imaging lmmediate MRl, immediate adrenalectomy, MACE or repeat imaging (CT or MRI) in 6 to 12 months . Benign CT imaging phenotype . Screen for diabetes, hypertension, and osteoporosis . No repeat imaging Algorithm for the Initial Diagnonic Evaluation and Follow-up of an Incidentally l{oted Adrenal Mass: HTN = hypertension; HU = Hounsfield units; K = potassium; LDSI= low-dose (1-mg) dexamethasone suppression test; MACE = mild autonomous cortisol excess; NFAT= nonfunctioning adrenal tumor; PAC = plasma aldosterone concen- tration; PRA= plasma renin activity. Endo(inol. 2016;175:G1-34. IPMID; 27390021] doi:10.1 530iEJE.16.0467 pheochromoc,,toma is completed. 'Positive screening tests usually require funher biochemical evaluation t0 confirm the diagnosis. dMeasure plasma metanephrines if radiographic appearance is typical for a pheochromocytoma; otherwise measure 24-hour !rine metanephrines and catecholamines. 66

Endocrinology and Metabolism I Hypoadrenalism t t Diagnosis (secondary) I Adrenal insufficiency may be caused by disease of the adrenal glands (primary) or disorders of the pituitary gland ' L I Primary disease (Addison disease) results in loss ofcortisol, aldosterone, and adrenal androgens; secondary insufficiency causes L only cortisol and adrenal androgen deficiencies (aldosterone synthesis is not ACTH dependent) ' I I i Symptoms and Signs L I Characteristic findings include L I . weight loss I I j o fatigue, anorexia, nausea, vomiting, abdominal pain L o orthostatic hypotension I t ' hYPoglYcemia l. . eosinophilia i . hyperpigmentation (primary adrenal insufficiency only) . hyponatremia and hyperkalemia (primary adrenal insufficiency only) o hypercalcemia Causes Autoimmune adrenalitis is the most common cause of primary insufficiency. Glucocorticoid use is the most common cause of secondary insufficiency (hypothalamic-pituitary suppression). Look for patients who recently discontinued glucocorticoid therapy or did not increase their glucocorticoid dose in times of stress. Testing An 8:00 AM semm cortisol <3 pg/dl confirms cortisol deficiency and values >18 pgldl exclude the diagnosis. For patients with unequivocally low cortisol levels, a morning ACTH level can help distinguish between primary and secondary adrenal insufficiency. STUOY TABLE: Evaluation of Hypocortisolism lf you see this... Do this... Morning ACTH elevated Adrenal CT Morning ACTH suppressed or "normal" Pituitary MRI For nondiagnostic cortisol values, select stimulation testing with qmthetic ACTH (cosrrrtropin). A stimulated serum cortisol >18 pg/dl excludes adrenal insufficiency.

STUOY TABLE: Evaluation of Hypocortisolism lf you see this... Do this... Morning ACTH elevated Adrenal CT Morning ACTH suppressed or "normal" Pituitary MRI For nondiagnostic cortisol values, select stimulation testing with qmthetic ACTH (cosrrrtropin). A stimulated serum cortisol >18 pg/dl excludes adrenal insufficiency. DOil'T BE TRICKED . Approximately 50% of patients with autoimmune adrenal insufficiency have other autoimmune endocrine disorders (thyroid disease, type I diabetes, vitiligo), referred to as autoimmune polyglandular syndrome; testing for these disorders is indicated. Treatment If acute adrenal insufficienry is suspected, treat empirically with high-dose (4 mg) dexamethasone and IV saline without waiting for the ACTH and cortisol level results to return from the laboratory. Dexamethasone does not interfere with the serum cortisol assay. 67

Endocrinology and Metabolism Chronic replacement therapy: . oral hydrocortisone ls to 25 mg/d (standard dose) o oral fludrocortisone (primary adrenal insufficiency) . oral hydrocortisone 2 to 10 times standard dose during periods of physiologic stress, including minor surgery . IV hydrocortisone 100 mg followed by 50 mg every 6 h for major stress (major surgery trauma, critical illness, childbirth) o fludrocortisone is not required in primary adrenal insufficiency if the hydrocortisone dose >40 mg/d DON'T BE TRICKED o Do not prescribe dexamethasone for chronic replacement therapy TESTYOURSEIF A 32-year old man with hypothyroidism has a 3-month history of fatigue, weakness, nausea, and a 13.9-kg (30-lb) weight loss. He has orthostatic hypotension and increased pigment in the palmar creases. The serum sodium level is f32 mEq/L and the serum potassium level is 5 mEq/L. ANSWER: For diagnosis, choose autoimmune adrenalitis. Pheochromocytoma Diagnosis Pheochromocytomas are rare tumors arising in the chromaffin cells of the adrenal medulla that secrete biogenic amines (nor epinephrine, epinephrine, or dopamine) or their metabolites. Symptoms and Signs Indications for testing: o adrenergic-type spells (headache, sweating, and tachycardia) o incidentally discovered adrenal mass o resistant hlpertension (>t\Olgo mm Hg) . hypertension with onset <20 years of age . idiopathic cardiomyopathy . hypertensive episode induced by anesthesia, surgery or angiography . familial syndromes that predispose to pheochromocltoma (see following) . family history of pheochromoc,'toma or paraganglioma Pheochromocytoma is associated with MEN2, von Hippel-Lindau disease, and neuroflbromatosis type 1. Testing Twenty-four-hour urine measurements of metanephrines and catecholamines or measurement of plasma metanephrines is preferred. Positive biochemical tests are followed by abdominal and pelvic CT with contrast. 68

Endocrinology and Metabolism lnfertility Diagnosis Infertility is defined as the inability to conceive after I year of intercourse without contraception in women <35 years and after 6 months in women >35 years. Regular menses is correlated with regular ovulation. If oligomenorrhea is present, evaluate like secondary amenorrhea. Consider structural abnormalities and evaluate with pelvic ultrasonography or hysterography. Male partner should be evaluated concurrently. Male Hypogonadism Diagnosis Male hypogonadism is present when sperm or testosterone production is decreased. It can be a primary (testicular) or secondary (typically hypothalamic-pituitary) condition. STUDY TAELET Clinical Features of Male Hypogonadism Specific Features Nonspecific Features Decreased morning and spontaneous erections Decreased mood/energy Decreased libido Decreased muscle strength/bu lklstamina lnfertility Poor sleep Gynecomastia Poor concentration Decreased male-pattern hair growth Causes and Testing Testosterone deficiency is diagnosed with two 8:00 eu total testosterone levels below the reference range. o If the testosterone measurement is equivocal, measure free testosterone. r If the testosterone level is low measure LH, FSH, and prolactin levels. Elevated LH and FSH values indicate primary testicular failure. Some common causes include: o Klinefelter syndrome (check karyotype) . atrophy secondary to mumps orchitis o autoimmunedestruction o previous chemotherapy or pelvic irradiation r hemochromatosis Low or normal LH and FSH levels indicate secondary hypogonadism. Important causes include: . sleep apnea . hyperprolactinemia . hypothalamic or pituitary disorders (hemochromatosis, pituitary/hypothalamic tumor) . use of opioids, anabolic steroids, or glucocorticoids 72

Endocrinology and Metabolism If secondary hypogonadism is confirmed, in addition to measuring prolactin, check iron studies to rule out hemochromatosis and obtain an MRI to evaluate for hypothalamic or pituitary lesions. Men who self-administer anabolic steroids can come to medical attention because of infertility. Physical examination typically reveals acne, muscular hypertrophy, testicular atrophy, and grnecomastia (if the patient is using testosterone). Laboratory data show suppressed LH and FSH levels, variable testosterone levels, and otherwise normal pituitary function. DO]I'T BE TRICKED . Do not measure serum testosterone if a patient is having regular morning erections, has no gynecomastia on examination, and has a normal genital examination. Treatment Testosterone can be administered by multiple routes. Before initiation of testosterone replacement and during therapy, routinely monitor hematocrit and PSA to screen for the development of erythrocytosis and prostate cancer, respectively. DOil'T BE TRICKED . Don't provide testosterone replacement therapy for nonspecific symptoms such as fatigue andweakness in the absence of unequivocal testosterone deflciency. . Testosterone therapy does not treat infertility (impairs spermatogenesis). Gynecomastia Diagnosis Gynecomastia is caused by proliferation ofglandular tissues in the male breast because ofan increase in the ratio ofestrogen to androgen. Diagnosis is confirmed by finding subareolar glandular tissue >0.5 cm in diameter and is usually bilateral. Causes include: o medications (spironolactone, cimetidine, antiandrogens, Sq,-reductase inhibitors, protease inhibitors) . opioid use . cirrhosis, CKD . hlpogonadism, hyperthyroidism . germ cell tumors Testing In patients without an obvious cause, obtain hCG and 8 errr fasting testosterone and estradiol levels. Treatment Treatment can be effective during the early proliferative phase. Testosterone is indicated for confirmed hypogonadism; other wise, choose selective estrogen receptor modulators and aromatase inhibitors. DOil'T BETRICKED o Differentiate gynecomastia from pseudogynecomastia, which is fat deposition typically seen in men with obesity . Obtain mammography for unilateral, nontender, or fixed masses to diagnose breast cancer. 73

Endocrinology and Metabolism DOI{'T BE TRICKED . About 50% of patients with primary hyperparathyroidism have coexisting vitamin D deficiency, and serum and urine calcium levels may be decreased. Select measurement of serum vitamin D levels in all patients with hyperparathyroidism. Hypocalcemia Diagnosis Most cases olhypocalcemia are caused by low serum albumin levels; the ionized calcium concentration is normal. Total calcium declines by 0.8 mg/dl for each 1 g/dl decrement in serum albumin concentration. Symptoms and Signs Look for: o circumoral and acral paresthesias . carpopedal spasm o positive Trousseau sign o positive Chvostek sign Causes Autoimmune hypoparathyroidism (low PTH) occurs as an isolated defect or as part of polyglandular autoimmune syndrome type 1 in association with mucocutaneous candidiasis, adrenal insufficiency, hypogonadism, and malabsorption. Hypo parathyroidism may also occur secondary to surgical excision or vascular injury to the parathyroid glands. In addition to hypoparathyroidism, hypocalcemia associated with elevated PTH may result from o vitamin D deficiency . hypomagnesemia . severe pancreatitis . rhabdomyolysis . kidney injury o tumor lysis syndrome Order calcium, phosphate, magnesium, creatinine, PTH, 25 hydroryvitamin D, albumin, and/or ionized calcium tests. Order an ECG to evaluate for QT interval prolongation. STUDY TABLE: Differential Diagnosis of Hypocalcemia Diagnosis Key features include hypocalcemia and... Hypoparathyroidism Hyperphosphatemia; low PTH and variable vitamin D levels CKD Hyperphosphatemia; elevated PTH and low 1,25-dihydroxyvitamin D levels Vitamin D de{iciency Hypophosphatemia; bone tenderness or fibromyalgia-like syndrome, weakness, gait difficulty, osteomalacia lmpaired PTH secretion and Magnesium deficiency (small bowel bypass, diarrhea, alcoholism, diuretic therapy) PTH resistance "Hungry bone" syndrome Recent parathyroidectomy 76

Endocrinology and Metabolism . rheumatoid arthritis . medications (excessive thyroid hormone, glucocorticoids, phenobarbital, phenytoin, thiazolidinediones) . multiple myeloma o CKD, chronic liver disease o vitamin D deflciency Testing In the absence of bone fracture, primary osteoporosis is associated with normal laboratory testing. Reasonable tests for the evaluation of secondary osteoporosis include CBC; TSH; calcium, phosphorus, and eGFR; liver chem istry tests; ESR; serum 2S-hydroryvitamin D level (if vitamin D deficiency is suspected); and tTG antibodies (if celiac disease is suspected). Treatment Encourage all patients to: o stop smoking . reduce alcohol intake . begin resistance exercises . supplement calcium and vitamin D intake Indications for antiresorptive therapy: . osteoporosis . osteopenia (if additional high-risk factors are present) r previous fragility fracture o vertebral or hip fracture The FRAX estimates the 10 year probability of hip fracture and major osteoporotic fracture. Antiresorptive treatment is cost effective when the risk of major osteoporotic fracture is >20% or the risk of hip fracture is >3%. Treatment options: . alendronate or risedronate is first-line therapy . denosumab (monoclonal antibody that inhibits osteoclast activation) may be preferred in patients with stage 4 CKD and in those intolerant of or incompletely responding to bisphosphonates Oral bisphosphonates are contraindicated in patients with CKD or esophageal disease. IV zoledronate (once yearly) is an alter- native therapeutic option. DOil'T BETRIGKED . The effects of denosumab are not sustained when treatment is stopped, and bone loss is accelerated. No recommended duration oftherapy is specified. Stopping therapy after 3 years (lV therapy) or 5 years (oral therapy) is reason- able in women who have a stable BMI, have no history of fracture, and are at Iow risk for fracfure. Recommended duration of the drug holiday is unknown. Drugs for osteoporosis have various adverse effects: . Oral bisphosphonate therapy may lead to erosive esophagitis and atypical hip fracture. o IV bisphosphonate therapy and denosumab can lead to osteonecrosis of the jaw. 78

Endocrinology and Metabolism Vitamin D Deficiency Screening The USPSTF concludes that evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D defi- ciency in asymptomatic adults. Diagnosis Prolonged and severe vitamin D deficiency will cause secondary hyperparathyroidism; osteomalacia in adults; and symptoms of bone pain, muscle weakness (including difficulty walking), and fracture. Testing In assessing serum levels of vitamin D, concentrations of 2S-hydroxyvitamin D are the best indicator of vitamin D status The Institute of Medicine has determined that a vitamin D level of >20 ng/ml is sufficient. Treatment The USPSTF concludes that evidence is insufficient to recommend vitamin D and calcium supplementation, alone or combined, for the prevention of fractures in men and premenopausal women. Treatment options for prevention and treatment of vitamin D deficiency vary by indication and underlying disease. Paget Disease Diagnosis Paget disease is a focal disorder of bone remodeling that leads to greatly accelerated rates of bone turnover, disruption of the normal architecture of bone, and sometimes gross deformities of bone (enlargement of the skull, bowing of the femur or tibia). Most patients are asymptomatic, and the disease is suspected when an isolated elevation of alkaline phosphatase is detected in the absence of liver disease. Symptoms and signs include: r bone pain, fractures . cranial nerve compression syndromes, spinal stenosis, nerve root syndromes o high output cardiac failure Testing If the serum alkaline phosphatase (bone) level is elevated in an asymptomatic patient, order a bone scan and follow-up x-rays of areas that localize radionuclide. In symptomatic patients, obtain x-rays of the painful area. X rays will reveal these patho gnomonic pagetic lesions: . focal osteolysis with coarsening of the trabecular pattern o "cotton wool" skull o cortical thickening 80