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Am Fam Physician. 2022;105(3):289-298

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Parathyroid disorders are most often identified incidentally by abnormalities in serum calcium levels when screening for renal or bone disease or other conditions. Parathyroid hormone, which is released by the parathyroid glands primarily in response to low calcium levels, stimulates osteoclastic bone resorption and serum calcium elevation, reduces renal calcium clearance, and stimulates intestinal calcium absorption through synthesis of 1,25-dihydroxyvitamin D. Primary hyperparathyroidism, in which calcium levels are elevated without appropriate suppression of parathyroid hormone levels, is the most common cause of hypercalcemia and is often managed surgically. Indications for parathyroidectomy in primary hyperparathyroidism include presence of symptoms, age 50 years or younger, serum calcium level more than 1 mg per dL above the upper limit of normal, osteoporosis, creatinine clearance less than 60 mL per minute per 1.73 m2, nephrolithiasis, nephrocalcinosis, and hypercalciuria. Secondary hyperparathyroidism is caused by alterations in calcium, phosphate, and vitamin D regulation that result in elevated parathyroid hormone levels. It most commonly occurs with chronic kidney disease and vitamin D deficiency, and less commonly with gastrointestinal conditions that impair calcium absorption. Secondary hyperparathyroidism can be managed with calcium and vitamin D replacement and reduction of high phosphate levels. There is limited evidence for the use of calcimimetics and vitamin D analogues for persistently elevated parathyroid hormone levels. Hypoparathyroidism, which is most commonly caused by iatrogenic surgical destruction of the parathyroid glands, is less common and results in hypocalcemia. Multiple endocrine neoplasia types 1 and 2A are rare familial syndromes that can result in primary hyperparathyroidism and warrant genetic testing of family members, whereas parathyroid cancer is a rare finding in patients with hyperparathyroidism.

The parathyroid glands typically lie adjacent to the thyroid gland, although they are occasionally located in the superior mediastinum.1 Parathyroid glands regulate serum calcium in response to abnormal levels. When the extracellular calcium-sensing receptor (CASR) on parathyroid cells detects low serum calcium levels, one or more of the parathyroid glands release parathyroid hormone (PTH), an 84–amino acid peptide.1 PTH stimulates osteoclasts to resorb bone and mobilize calcium into the blood, reduces renal calcium clearance, and stimulates intestinal calcium absorption through synthesis of 1,25-dihydroxyvitamin D (Figure 1).2 Conversely, high calcium levels drive PTH suppression, with hypermagnesemia and 1,25-dihydroxyvitamin D also inhibiting the production and release of PTH. Parathyroid disorders can be primary or secondary.

Clinical recommendationEvidence ratingComments
Initial evaluation of hypercalcemia to identify primary hyperparathyroidism should include symptom assessment; measurements of serum total or ionized calcium, albumin, parathyroid hormone, serum creatinine, 25-hydroxyvitamin D, and 24-hour urinary calcium and creatinine; and dual-energy x-ray absorptiometry.13,16 CConsensus guidelines and expert opinion
In patients with primary hyperparathyroidism, parathyroidectomy is indicated for those with symptoms, significant renal impairment, osteoporosis, or serum calcium level more than 1 mg per dL (0.25 mmol per L) above the upper limit of normal.15,16 CConsensus guidelines with cohort studies consistently showing improvement in bone mineral density, fractures, and kidney stones
In the evaluation of secondary hyperparathyroidism, bone density measurement should be obtained in patients with chronic kidney disease–bone mineral disorder.8 CConsensus guidelines and consistent cohort studies showing bone density measurement accurately predicts fracture risk
Serum phosphate and calcium levels should be monitored with the goal of avoiding severe hyperphosphatemia or hypercalcemia in patients with chronic kidney disease stages 3a to 5.8 CConsensus guidelines with cohort studies showing increased mortality with higher calcium and phosphate levels but an absence of evidence of benefit from pharmacologic interventions to lower levels
Genetic screening and laboratory monitoring are recommended for first-degree relatives of people with hyperparathyroidism due to multiple endocrine neoplasia type 1 or 2.3133 CConsensus guidelines and expert opinion

Initial Approach to Calcium Abnormalities

Parathyroid disorders are most often identified incidentally by abnormalities in serum calcium levels when screening for renal or bone disease or other conditions.1,3 Once a calcium abnormality has been identified, the evaluation should include a systematic search for signs and symptoms associated with abnormal calcium levels (Table 1).1,2,46 A history should include dietary intake of calcium and phosphorus, medications that increase serum calcium levels (Table 21,2,46), supplements that contain calcium, and family history of endocrine disorders. A patient history of conditions such as fractures, pancreatitis, and nephrolithiasis may indicate or contribute to abnormal calcium levels.

Organ systemHypercalcemiaHypocalcemia
CardiovascularArrhythmias, bradycardia, hypertension, palpitations, prolonged PR interval, shortened QT intervalArrhythmias, dyspnea, heart failure, hypotension, palpitations, prolonged QT interval, syncope, torsades de pointes
GastrointestinalAbdominal pain, anorexia, constipation, dyspepsia, epigastric pain, nausea, pancreatitis, vomitingAbdominal pain
MusculoskeletalArthralgias, bone pain, fractures, myalgiasMuscle spasms
NeurologicConfusion, delirium, headache, impaired concentration, impaired vision, lethargy, memory loss, sleep disturbanceAcute: Chvostek sign,* circumoral numbness, headache, impaired vision, seizures, tetany, Trousseau sign
Chronic: dementia, parkinsonism
PsychiatricAnxiety, depression, emotional instabilityAnxiety, depression
PulmonaryBronchospasm, laryngospasm, wheezing
RenalPolydipsia, polyuria, renal colic, renal failure
PTH dependent
Genetic disorders: familial hyperparathyroidism, familial hypocalciuric hypercalcemia, hyperparathyroidism–jaw tumor syndrome, multiple endocrine neoplasia
Medications: lithium
Primary hyperparathyroidism
Tertiary hyperparathyroidism*
PTH independent
Cancer: humoral hypercalcemia of malignancy (mediated by PTH-related peptide), osteolytic metastases (e.g., multiple myeloma)
Excess vitamin D
 Endogenous sources: Williams syndrome, granulomatous diseases such as sarcoidosis, tuberculosis, histoplasmosis, or coccidioidomycosis
 Exogenous sources: vitamin D supplements or analogues
Medications: thiazides, theophylline, vitamin A, synthetic PTH (teriparatide [Forteo], abaloparatide [Tymlos]), calcium (milk-alkali syndrome)
Other endocrine disorders: thyrotoxicosis, adrenal insufficiency, pheochromocytoma
Renal failure (acute or chronic)

Initial laboratory testing (Figure 21,2,46 and Figure 3711) can be used to identify potential etiologies of parathyroid disorders that affect calcium levels. Primary hyperparathyroidism and malignancy are the most common causes of hypercalcemia.4 Additional causes are listed in Table 2.1,2,46 Humoral hypercalcemia of malignancy, a paraneoplastic syndrome mediated by PTH-related peptide, should be considered in patients with low PTH levels, rapid onset of symptoms, and other signs and symptoms of malignancy (e.g., weight loss, fatigue, loss of appetite, night sweats). It is most often associated with squamous cell carcinoma and solid tumors of the lung, breast, esophagus, skin, cervix, and kidney.4 Vitamin D deficiency is the most common cause of hypocalcemia.5

Severe symptomatic hypercalcemia (serum calcium level greater than 14 mg per dL [3.50 mmol per L]) should be managed acutely with intravenous fluids, bisphosphonates, calcitonin, denosumab, or dialysis.6 Severe symptomatic hypocalcemia, which can present acutely with carpopedal spasm, tetany, seizures, and a prolonged QT interval, should be managed with intravenous calcium gluconate while the cause is being determined.12

Hyperparathyroidism

PRIMARY

Primary hyperparathyroidism is a common condition and the most common cause of hyperparathyroidism and mild hypercalcemia.1,13 In primary hyperparathyroidism, calcium levels are usually elevated without appropriate suppression of PTH levels, which can be normal or high.13 However, in normocalcemic cases, calcium levels can be normal with elevated PTH levels, which may be encountered incidentally when screening for bone and renal disorders. In nations with readily accessible laboratory services, primary hyperparathyroidism is most often identified in asymptomatic individuals as an incidental finding of hypercalcemia on routine laboratory testing.

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