Parathyroid Disorders PDF - AAFP 2013

Parathyroid Disorders THOMAS C. MICHELS, MD, MPH, Madigan Army Medical Center, Tacoma, Washington KEVIN M. KELLY, MD, MBA, Carl R. Darnall Army Community Hospital, Fort Hood, Texas Disorders of the parathyroid glands most commonly present with abnormalities of serum calcium. Patients with primary h...

Parathyroid Disorders THOMAS C. MICHELS, MD, MPH, Madigan Army Medical Center, Tacoma, Washington KEVIN M. KELLY, MD, MBA, Carl R. Darnall Army Community Hospital, Fort Hood, Texas Disorders of the parathyroid glands most commonly present with abnormalities of serum calcium. Patients with primary hyperparathyroidism, the most common cause of hypercalcemia in outpatients, are often asymptomatic or may have bone disease, nephrolithiasis, or neuromuscular symptoms. Patients with chronic kidney disease may develop secondary hyperparathyroidism with resultant chronic kidney disease-mineral and bone disorder. Hypo- parathyroidism most often occurs after neck surgery; it can also be caused by autoimmune destruction of the glands and other less common problems. Evaluation of patients with abnormal serum calcium levels includes a history and physical examination; repeat measurement of serum calcium level; and measurement of creatinine, magne- sium, vitamin D, and parathyroid hormone levels. The treatment for symptomatic primary hyperparathyroidism is parathyroidectomy. Management of asymptomatic primary hyperparathyroidism includes monitoring symptoms; serum calcium and creatinine levels; and bone mineral density. Patients with hypoparathyroidism require close monitoring and vitamin D (e.g., calcitriol) replacement. (Am Fam Physician. 2013;88(4):249-257. Copyright © 2013 American Academy of Family Physicians.) T CME This clinical content he four parathyroid glands, located 84-amino acid peptide. PTH increases serum conforms to AAFP criteria posterior to the thyroid gland, reg- calcium levels through direct action on bone for continuing medical education (CME). See CME ulate calcium homeostasis through and the kidneys. It stimulates osteoclasts to Quiz on page 227. release of parathyroid hormone resorb bone and mobilize calcium into the Author disclosure: No rel- (PTH). Because most parathyroid disorders blood. In the kidneys, PTH acts to reduce evant financial affiliations. present with abnormalities of serum cal- calcium clearance and stimulates synthesis cium, they commonly appear in differential of 1,25-dihydroxyvitamin D, which stimu- diagnoses. Therefore, understanding the lates calcium absorption in the gastrointes- presentation and principles of evaluation of tinal tract (Figure 1).1,2 In their normal state, parathyroid disorders is important in pri- the glands function to keep serum calcium mary care. levels within a consistent and tightly con- trolled range. The glands synthesize and Pathophysiology store the PTH, allowing it to respond within The parathyroid glands respond to low serum minutes of hypocalcemia. Sustained hypo- calcium levels by releasing PTH, which is an calcemia leads to cellular replication and SORT: KEY RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating References Patients with primary hyperparathyroidism and symptoms or signs should C 25, 26 undergo surgical removal of their parathyroid gland(s). Patients with primary hyperparathyroidism who do not undergo C 15, 26 parathyroidectomy should have serum calcium and creatinine levels measured annually, and three-site (i.e., hip, spine, and forearm) bone density measurement every one to two years. Family members of a patient with multiple endocrine neoplasia type 2 C 10, 21 should be tested for the patient’s specific genetic mutation. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi- dence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort. Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright © 2013 American Academy of Family Physicians. For the private, August 15, 2013 use of Volume 88, Number user of the4Web site. All other rights reserved. www.aafp.org/afp Americanand/orFamily requests. 249 Physician ◆ noncommercial one individual Contact [email protected] for copyright questions permission  Parathyroid Disorders increased mass of the glands. Calcium and 1,25-dihydroxyvitamin D provide negative feedback at the parathyroid glands to inhibit PTH release. One normal gland is sufficient for adequate secretion of PTH to maintain normal calcium levels.1,3,4 Parathyroid disorders most commonly present with serum calcium abnormalities. Decreased Rarely, patients can present with a neck mass serum calcium or for evaluation of a family history of para- thyroid or related disorders. The estimated incidence of primary hyperparathyroidism is approximately 25 cases per 100,000 persons Increased serum calcium per year in outpatients of Western countries,5-7 with a prevalence of one to four per 1,000 per- Parathyroid sons.8 Hypoparathyroidism most commonly glands occurs after inadvertent damage or removal of parathyroid glands during neck surgery; Bone estimates for the occurrence of this surgical complication range from 0.5% to 6.6%, with higher rates after repeat neck surgery.1,9 Mul- Parathyroid hormone tiple endocrine neoplasia type 1 (MEN-1) and type 2 (MEN-2), which often include parathy- Kidney roid neoplasia, each occur in about two per Increased bone 100,000 persons per year.10 Parathyroid can- resorption cer is rare, with an incidence of approximately four per 10 million persons per year.11 Hyperparathyroidism Increased calcium reabsorption PRIMARY Primary hyperparathyroidism, the most common cause of hypercalcemia in outpa- Intestine tients, is often discovered incidentally dur- 25-hydroxyvitamin D to ing evaluation of serum electrolyte levels. 1,25-dihydroxyvitamin D Before the easily available measurement of Increased calcium absorption in the serum calcium levels, patients presented with gastrointestinal tract a spectrum of symptoms (Table 1).4,12,13 Most ILLUSTRATION BY DAVID KLEMM Negative feedback/ patients today are asymptomatic, with neph- decreased activity rolithiasis occurring in up to 15% of patients, Positive feedback/ bone disease (formerly osteitis fibrosa cys- stimulation tica) occurring in 2% of patients, and neu- romuscular symptoms occurring rarely.3,14,15 Figure 1. Control of mineral metabolism by parathyroid hormone Although marked symptoms are uncommon (PTH). Calcium-sensing receptors of parathyroid cells respond to in Western countries, it is important to be serum calcium level and change with increased release (hypocal- aware that subtle and nonspecific symptoms cemia) or suppression (hypercalcemia) of PTH. PTH stimulates bone may be present.14-16 Other causes of hypercal- resorption, which increases serum calcium and phosphorus. In the cemia are listed in Table 2.3,5,8,17,18 kidney, PTH stimulates reabsorption of calcium and promotes phos- phorus excretion. PTH also helps convert 25-hydroxyvitamin D to Overall, 85% of patients with primary 1,25-dihydroxyvitamin D in the kidneys, which then increases intesti- hyperparathyroidism have a single adenoma. nal transport of calcium and phosphorus. Risk factors for primary hyperparathyroid- Information from references 1 and 2. ism include a history of neck radiation, age 250 American Family Physician www.aafp.org/afp Volume 88, Number 4 ◆ August 15, 2013  Table 1. Symptoms Associated with Hypercalcemia Organ system Most common symptoms and possible diagnoses older than 50 years, and female sex; women Cardiovascular Angina, dyspnea, palpitations, syncope are twice as likely as men to develop pri- Possible diagnoses: diastolic dysfunction, dysrhythmias, hypertension, left ventricular hypertrophy, vascular mary hyperparathyroidism. Multiglandu- calcification lar hyperplasia accounts for 10% to 15% of patients with primary hyperparathyroid- Gastrointestinal Anorexia, constipation, epigastric pain, nausea, vomiting ism, and carcinoma accounts for 1% or less. Possible diagnoses: pancreatitis, peptic ulcer disease There are also uncommon familial causes, Neuromuscular Anxiety, confusion, depression, fatigue, forgetfulness, such as MEN-1 and MEN-2A; persons with impaired vision, insomnia, lethargy, weakness these conditions may have parathyroid ade- Possible diagnoses: corneal calcification, delirium, mild nomas or asymmetric hyperplasia.8,19 cognitive impairment SECONDARY Renal Polydipsia, polyuria, renal colic Possible diagnoses: nephrocalcinosis, nephrolithiasis, Secondary hyperparathyroidism most com- nephrogenic diabetes insipidus monly occurs because of decreased levels of 1,25-dihydroxyvitamin D, hyperphospha- Skeletal Arthralgia, bone pain, fractures temia, and hypocalcemia in the setting of Possible diagnoses: bone disease, insufficiency chronic kidney disease. Other causes include fractures, osteomalacia, osteoporosis vitamin D deficiency secondary to low Information from references 4, 12, and 13. dietary intake, lack of sun exposure, mal- absorption, liver disease, and other chronic illness.20 In some patients with advanced renal failure, hypercalcemia is due to progres- Table 2. Causes of Hypercalcemia sion from appropriate parathyroid hyper- plasia to autonomous overproduction of Parathyroid hormone–dependent PTH, a disorder termed tertiary hyperpara- Primary hyperparathyroidism thyroidism.12,20 Familial hypocalciuric hypercalcemia Patients with normocalcemic hyper- Lithium-associated parathyroidism may present with low bone Tertiary hyperparathyroidism density, osteoporosis, or a fragility fracture. Genetic disorders (e.g., multiple endocrine neoplasia type 1 or type 2A, familial hyperparathyroidism) Many of these patients will probably evolve into having hyperparathyroidism, although Parathyroid hormone–independent the exact natural history is not known. It is Renal failure, acute or chronic* important to exclude vitamin D deficiency Neoplasms and chronic kidney disease before making Parathyroid hormone–related protein dependent this diagnosis.8,15 Osteolytic metastases and multiple myeloma Other humoral syndromes EVALUATION Excess vitamin D Primary hyperparathyroidism is diagnosed Ingested or topical vitamin D analogues when the serum calcium level is elevated, Granulomatous disease with an increased or inappropriately normal Williams syndrome serum PTH level. An algorithm for the evalu- Other endocrine diseases: thyrotoxicosis, adrenal insufficiency ation of patients with suggestive symptoms Drugs: vitamin A intoxication, milk-alkali syndrome, thiazide diuretics, theophylline or asymptomatic hypercalcemia is shown Other: immobilization, Jansen disease in Figure 2.2,4,8,10,21-23 Hypercalcemia should be verified, and vitamin D levels should be NOTE: Causes are listed in order of clinical importance. measured and determined to be adequate *—Renal failure is typically associated with hypocalcemia unless patients with acute before parathyroid disorder is considered.18 kidney injury have concomitant rhabdomyolysis, and unless patients with chronic In patients with hypercalcemia, the PTH kidney disease develop tertiary hyperparathyroidism. level distinguishes PTH-mediated from non– Information from references 3, 5, 8, 17, and 18. PTH-mediated hypercalcemia. A physical August 15, 2013 ◆ Volume 88, Number 4 www.aafp.org/afp American Family Physician 251  Evaluation of Hypercalcemia Symptoms* Incidental laboratory finding Hypercalcemia Serum albumin, ionized calcium, corrected calcium levels† Verified hypercalcemia Immediate treatment if severe‡ Elevated PTHrp level Obtain history and perform physical History and physical examination§ examination if not done Measure vitamin D||, magnesium, Perform common laboratory testing creatinine, PTH levels (e.g., complete blood count, liver profile); chest radiography; mammography; abdominal and chest computed tomography; serum/urine immunoelectrophoresis; Specific cause PTH level normal or high (PTH- PTH level low (< 20 bone scan identified, such dependent hypercalcemia) pg per mL [20 ng per as chronic kidney L]; PTH-independent disease-mineral and hypercalcemia) bone disorder¶, Elevated 1,25-dihydroxyvitamin D Calcium/creatinine ratio with medications** level 24-hour urine collection Chest radiography (e.g., lymphoma, Measure PTHrp, sarcoid) 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D levels Elevated ratio Low ratio ( > 0.01) (≤ 0.01) Elevated 25-hydroxyvitamin D level Check medications, including vitamins and herbal medications (e.g., vitamin Primary hyperparathyroidism Familial D toxicity) Risk factors for multiple endocrine hypocalciuric neoplasia, carcinoma?†† hypercalcemia Normal PTHrp and vitamin D levels Perform other tests, such as serum Yes No protein electrophoresis; urine protein Gene analysis, other electrophoresis; measurement hormone evaluation of thyroid-stimulating hormone, vitamin A, or cortisol levels Possible causes include immobilization, Localization studies, bone mineral density vitamin A toxicity, milk-alkali syndrome measurement, renal ultrasonography‡‡ *—See Table 1. related hypercalcemia is typically mild and may take two weeks to †—Ideal laboratory testing should be performed with the patient fasting resolve. For a review of the effects of lithium, see: Saunders BD, Saun- and with minimal venous occlusion. Corrected serum calcium = mea- ders EF, Gauger PG. Lithium therapy and hyperparathyroidism: an evi- sured serum calcium + 0.8(4 – measured serum albumin); calcium is dence-based assessment. World J Surg. 2009;33(11):2314-2323. Vitamin measured in mg per dL, and albumin is measured in g per dL. D deficiency (25-hydroxyvitamin D level < 20 ng per mL) and hypomag- ‡—Management of parathyroid crisis or severe hypercalcemia (calcium nesemia should be corrected. level > 14 mg per dL [3.50 mmol per L]) includes volume repletion with ††—Risk factors for multiple endocrine neoplasia are positive family his- normal saline (usually 2 to 4 L per day) and bisphosphonates (usually tory, prior pancreatic or pituitary tumor in the index patient, multiple or intravenous pamidronate). Calcitonin and other agents can be used, but recurrent parathyroid tumors, male sex, and younger age. Patients with they are not first-line therapy. parathyroid carcinoma usually present with symptoms from marked hyper- §—See Table 3. calcemia and very high PTH levels; these patients may have a neck mass. ||—Vitamin D deficiency: 25-hydroxyvitamin D level < 20 ng per mL (50 ‡‡—Choice of localization studies is institution-specific; sestamibi scans nmol per L). and ultrasonography are most commonly used. Renal imaging with plain ¶—Includes renal osteodystrophy and other disorders of mineralization. radiography or ultrasonography is indicated only when nephrolithiasis is suspected. **—Most commonly thiazide diuretics and lithium. Thiazide diuretic– Figure 2. Algorithm for evaluating patients with hypercalcemia. (PTH = parathyroid hormone; PTHrp: parathyroid hormone–related peptide.) Information from references 2, 4, 8, 10, and 21 through 23.  Parathyroid Disorders examination is important to identify subtle features con- In one study, 15% of asymptomatic patients developed sistent with hyperparathyroidism and to assist in the dif- an indication for surgery over an average of 4.7 years.6 ferential diagnosis (Table 3).1,4,8,24 Asymptomatic persons with primary hyperpara- Other tests listed in Figure 2 should identify patients thyroidism and osteoporosis or osteopenia are candi- with primary hyperparathyroidism.2,4,8,10,21-23 Familial dates for parathyroidectomy because bone density and hypocalciuric hypercalcemia results from an inactivat- fracture risk improve after surgery. Bone density, but ing mutation of the calcium-sensing receptor gene, and not fracture risk, has also been shown to improve after patients with this disorder require a higher level of calcium to suppress PTH secretion; they may present with high calcium lev- Table 3. Physical Examination Findings in Persons with els, normal or elevated PTH levels, and low Parathyroid Disorders urinary calcium secretion.8 Referral to an endocrinologist (or other specialist if an eti- System Finding Possible cause(s) ology for hypercalcemia other than primary hyperparathyroidism is found) is often indi- Abdominal Flank pain, tenderness Nephrolithiasis from hypercalcemia cated after this stepwise evaluation. Epigastric pain, Pancreatitis from INDICATIONS FOR SURGERY tenderness hypercalcemia, or causing hypocalcemia Patients with primary hyperparathyroidism and symptoms or signs should undergo surgi- Cardiovascular Hypotension Hypocalcemia cal removal of their parathyroid gland(s).25,26 Hypertension Hypercalcemia In some patients, medical comorbidities may Irregular heartbeat Dysthymia from hypo- or hypercalcemia preclude surgery, and controlling hypercal- Rales, edema, third Congestive heart failure cemia alone may be the goal. In this situa- heart sound or systolic or diastolic tion, the calcimimetic cinacalcet (Sensipar) dysfunction from hypo- effectively lowers serum calcium levels, but or hypercalcemia does not affect bone density.27,28 Age alone Dermatologic Dry, puffy skin Hypocalcemia should not preclude parathyroidectomy.29 Dry, brittle hair Hypocalcemia The role of surgery in patients with asymp- Candidiasis Polyglandular autoimmune tomatic primary hyperparathyroidism is not syndrome with as clear. Younger patients and patients at risk hypoparathyroidism of progression to symptomatic disease are the best candidates for parathyroidectomy. Neuromuscular Chvostek sign Hypocalcemia Recommendations from the Third Inter- Trousseau sign Hypocalcemia national Workshop on the Management of Emotional instability, Hypo- or hypercalcemia anxiety, depression Asymptomatic Primary Hyperparathyroid- Cognitive dysfunction, Hypo- or hypercalcemia ism include performing parathyroidectomy dementia in asymptomatic persons with primary Lethargy, delirium, Hypercalcemia hyperparathyroidism and any one of the coma following 26 : Muscle weakness Hypercalcemia Serum calcium level greater than 1.0 mg Movement disorders, Hypocalcemia per dL (0.25 mmol per L) above the upper parkinsonism limit of normal Other: head, ears, Neck mass or Granulomatous disease, Creatinine clearance less than 60 mL per eyes, nose, and lymphadenopathy parathyroid cancer, large minute per 1.73 m2 (1 mL per second per m2) throat parathyroid adenoma Bone mineral density T-score of less than –2.5 at any one of three sites (i.e., hip, spine, or Other: Cataract Hypocalcemia ophthalmologic Band keratopathy Hypercalcemia wrist) and/or any previous fragility fracture (z scores should be used in premenopausal women and in men younger than 50 years) Information from references 1, 4, 8, and 24. Age younger than 50 years August 15, 2013 ◆ Volume 88, Number 4 www.aafp.org/afp American Family Physician 253 Parathyroid Disorders disorder; full discussion of these guidelines Table 4. Causes of Hypoparathyroidism is beyond the scope of this article and is available from this referenced source.34 Mechanism Comment Hypoparathyroidism Destruction of parathyroid tissue Hypoparathyroidism most commonly Postsurgical Most common form of hypoparathyroidism occurs after inadvertent damage or removal Postradiation Rare complication of parathyroid glands during neck surgery. Autoimmune May be associated with other endocrine insufficiencies It can occur years after neck surgery.1 Most Metastatic infiltration Case reports head and neck surgeons carefully track this Heavy metal deposition Iron deposition in 10% of persons with complication with intra- and postoperative thalassemia monitoring of calcium and PTH levels.31 Autoimmune parathyroid destruction, either Reversible impairment in parathyroid hormone secretion or action isolated or as part of a multiple endocrine Hypomagnesemia Chronic illness, drugs, acidosis deficiency syndrome, is another important Hypermagnesemia Tocolytic therapy, magnesium supplementation cause of hypoparathyroidism. Rarely, there Resistance to parathyroid hormone action is tissue resistance to the actions of PTH, Pseudohypoparathyroidism — which results in a picture of hypoparathy- Genetic disorders of parathyroid hormone synthesis roidism but with elevated PTH levels. This is termed pseudohypoparathyroidism, and it NOTE: Causes are listed in order of clinical importance. is a genetically heterogeneous condition.1,24 Information from references 1, 3, and 24. These and other causes of hypoparathyroid- ism are listed in Table 4.1,3,24 Most patients with hypoparathyroidism bisphosphonate therapy and hormone therapy in these present with hypocalcemia. Figure 3 is an algorithm for patients.27 The relationship between neurocognitive evaluating patients with symptomatic or incidentally function and primary hyperparathyroidism is somewhat discovered hypocalcemia.1-4,24 In some patients, such controversial, but some studies show improvement in as those with acute pancreatitis, sepsis, or other criti- neurocognitive function after parathyroidectomy.16,27,30,31 cal illness, the cause of hypocalcemia is apparent, and Other reviews conclude that surgery and medical man- treatment without full evaluation is warranted. Table 5 agement improve bone density; however, there were no lists causes of hypocalcemia based on clinical clues.1,24 differences in quality of life.32,33 Symptoms associated with hypocalcemia depend on If patients with primary hyperparathyroidism do the severity, duration, and rate of development; com- not undergo parathyroidectomy, they should be closely mon symptoms are listed in Table 6.1,3,24 Physical find- monitored for the development of symptoms or other ings are listed in Table 3.1,4,8,24 It is important to ensure indications for surgery. These patients should have repletion to normal levels of vitamin D and magnesium serum calcium and creatinine levels measured annually, in these patients. Serum levels of PTH, phosphorus, and three-site (i.e., hip, spine, and forearm) bone density 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D measurement every one to two years (PTH has a cata- can help differentiate between disorders causing hypo- bolic effect on cortical bone, and this change may only calcemia (Table 7).22 be evident in the distal forearm).15,26 Figure 3 provides brief recommendations for the The management of secondary hyperparathyroidism immediate treatment of severe hypocalcemia1-4,24 ; a in chronic kidney disease usually involves consultation detailed discussion is beyond the scope of this article. with a nephrologist. Protein restriction and calcium Long-term management of hypoparathyroidism should supplementation have been shown to decrease the devel- include at least initial involvement of an endocrinolo- opment of this complication, with a reduction in death gist. Vitamin D analogues are essential (e.g., calcitriol from renal causes. Vitamin D supplements and calcimi- [Rocaltrol]), and thiazide diuretics and dietary modifi- metics, which inhibit PTH secretion, have been shown to cation are typically used as well. PTH therapy has been improve biochemical markers (without patient-oriented studied, but data are limited and PTH preparations are outcomes). There are several evidence-based reviews not approved by the U.S. Food and Drug Administration for managing chronic kidney disease-mineral and bone for this purpose.1,35 254 American Family Physician www.aafp.org/afp Volume 88, Number 4 ◆ August 15, 2013  Parathyroid Disorders Evaluation of Hypocalcemia Symptoms* Laboratory evaluation done for other reasons Hypocalcemia Serum magnesium, albumin, ionized calcium, corrected calcium levels† Correct hypo- or hypermagnesemia Verified hypocalcemia Immediate treatment Serum phosphorus, creatinine, Patient and family history, if symptomatic‡ PTH, 25-hydroxyvitamin D levels§ physical examination|| Suspect underlying cause¶ Elevated creatinine level PTH level elevated PTH level normal or low Chronic kidney disease- Calcium/creatinine ratio with mineral and bone disorder** 24-hour urine collection Phosphorus level low or Phosphorus level high lower limit of normal or upper limit of normal Low vitamin D level Low High Pseudohypo- Calcium-sensing Hypoparathyroidism Vitamin D deficiency parathyroidism receptor abnormality *—See Table 6. infusion (10 g of calcium gluconate in 1 L of dextrose 5% at 1 to 3 mg †—Ideal laboratory testing should be performed with the patient fasting per kg per hour). and with minimal venous occlusion. Corrected serum calcium = mea- §—See Table 7. sured serum calcium + 0.8(4 – measured serum albumin); calcium is ||—See Table 3. measured in mg per dL, and albumin is measured in g per dL. ¶—See Table 5. ‡—Calcium gluconate, 1 to 2 g intravenously slowly over 10 minutes, **—Includes renal osteodystrophy and other disorders of mineralization. with clinical and electrocardiographic monitoring, followed by slow Figure 3. Algorithm for evaluating patients with hypocalcemia. (PTH = parathyroid hormone.) Information from references 1 through 4, and 24. Other Parathyroid Disorders medullary thyroid carcinoma, pheochromocytoma, and Some patients present to their physician after a family parathyroid tumors. The issue of screening family mem- member has been diagnosed with MEN. MEN-1 includes bers for MEN-1 is controversial because presymptomatic neoplasias of the parathyroid, pancreas, pituitary, and detection has not been shown to reduce morbidity or adrenal glands. MEN-2 includes neoplasias of the thy- mortality. Because hyperparathyroidism is common in roid, adrenal, and parathyroid glands. MEN-2A involves persons with MEN-1 (80% to 100%), it is reasonable to August 15, 2013 ◆ Volume 88, Number 4 www.aafp.org/afp American Family Physician 255 Parathyroid Disorders screen with measurement of serum calcium Table 5. Causes of Hypocalcemia Based on Clinical Clues levels alone. Others advocate screening with measurement of calcium and PTH levels Cause Result annually, starting at eight years of age.19 A discussion with the affected patient and fam- Acute illness: pancreatitis, Secondary hyperparathyroidism from low tumor lysis, severe illness circulating calcium levels ily about screening is warranted. In a family Autoimmune disease Autoimmune parathyroid gland destruction with a history of MEN-2, a sample from one Family history of Genetic defects in calcium-sensing receptor patient already affected should be tested to hypocalcemia or parathyroid hormone secretion determine the specific genetic mutation for Limited ultraviolet light Vitamin D deficiency that family. When a mutation is found, all exposure or poor dietary persons of unknown status in that family intake should then be definitively genotyped.10,21 Malabsorption syndrome Vitamin D deficiency Rarely, patients with parathyroid disor- Neck surgery Low or absent parathyroid hormone with ders may present with a neck mass, either parathyroid gland removal self-reported or as an incidental finding on Renal disease Secondary hyperparathyroidism examination. Parathyroid cancer, hyperpla- Information from references 1 and 24. sia, adenomas, and cysts could all present in this way. Other neck tumors, including primary or metastatic cancers, are more common than parathyroid causes. Ultra- Table 6. Symptoms Associated with Hypocalcemia sonography, computed tomography, and biopsy are typically required to determine Organ system Most common symptoms and possible diagnoses the diagnosis.36 Data Sources: We searched the Cochrane Database Cardiovascular Dyspnea, edema, palpitations, syncope of Systematic Reviews, Clinical Evidence, the National Possible diagnoses: dysrhythmia, prolonged corrected Guidelines Clearinghouse, the Agency for Healthcare QT interval, systolic dysfunction Research and Quality Evidence Reports, Essential Neurologic Headache, impaired vision, neuropsychiatric symptoms Evidence Plus, as well as Ovid and PubMed using the keywords parathyroid, hyperparathyroidism, hypopara- Possible diagnoses: premature cataracts, pseudotumor thyroidism, hypercalcemia, hypocalcemia, and multiple cerebri endocrine neoplasia. The search included meta-analyses, Neuromuscular Circumoral numbness and paresthesias; cramping, randomized controlled trials, clinical trials, and reviews. muscle twitching, spasms; seizures Search dates: June 5 through December 22, 2011. Possible diagnosis: carpopedal spasm The opinions and assertions contained herein are the private views of the authors and are not to be construed Information from references 1, 3, and 24. as official or as reflecting the views of the U.S. Army Medical Department or the U.S. Army. Table 7. Laboratory Evaluation of Hypocalcemia Level Condition Parathyroid hormone Phosphorus 25-hydroxyvitamin D 1,25-dihydroxyvitamin D Hypoparathyroidism Low Elevated Normal Normal or low Calcium-sensing receptor Normal or low Elevated Normal Normal activating mutation Parathyroid hormone resistance Elevated Elevated Normal Normal (pseudohypoparathyroidism) Vitamin D deficiency Elevated Low or normal Low Normal or elevated Chronic kidney disease Elevated Elevated Normal Low Information from reference 22. 256 American Family Physician www.aafp.org/afp Volume 88, Number 4 ◆ August 15, 2013  Parathyroid Disorders 16. Mikhail N. Clinical significance of vitamin D deficiency in primary hyper- The Authors parathyroidism, and safety of vitamin D therapy. South Med J. 2011; 104(1):29-33. THOMAS C. MICHELS, MD, MPH, is a faculty member in the Madigan Fam- 17. Eastell R, Arnold A, Brandi ML, et al. Diagnosis of asymptomatic primary ily Medicine Residency Program in the Department of Family Medicine at hyperparathyroidism: proceedings of the third international workshop. Madigan Army Medical Center in Tacoma, Wash. J Clin Endocrinol Metab. 2009;94(2):340-350. KEVIN M. KELLY, MD, MBA, is the director of the Darnall Family Medi- 18. Sharma B, Misicko NE, Hitchcock K, Neher JO. Clinical inquiries. How cine Residency Program at Carl R. Darnall Army Community Hospital, Fort should you evaluate elevated calcium in an asymptomatic patient? J Fam Hood, Tex. At the time this article was written, he was the faculty develop- Pract. 2008;57(4):267-269. ment fellow with the Madigan Family Medicine Residency Program in the 19. Malone JP, Srivastava A, Khardori R. Hyperparathyroidism and multiple Department of Family Medicine at Madigan Army Medical Center. endocrine neoplasia. Otolaryngol Clin North Am. 2004;37(4):715-736, viii. 20. Ahmad R, Hammond JM. 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