
Am Fam Physician. 2022;105(3):289-298
Author disclosure: No relevant financial relationships.
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.

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).1,2,4–6 A history should include dietary intake of calcium and phosphorus, medications that increase serum calcium levels (Table 21,2,4–6), 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 system | Hypercalcemia | Hypocalcemia |
---|---|---|
Cardiovascular | Arrhythmias, bradycardia, hypertension, palpitations, prolonged PR interval, shortened QT interval | Arrhythmias, dyspnea, heart failure, hypotension, palpitations, prolonged QT interval, syncope, torsades de pointes |
Gastrointestinal | Abdominal pain, anorexia, constipation, dyspepsia, epigastric pain, nausea, pancreatitis, vomiting | Abdominal pain |
Musculoskeletal | Arthralgias, bone pain, fractures, myalgias | Muscle spasms |
Neurologic | Confusion, delirium, headache, impaired concentration, impaired vision, lethargy, memory loss, sleep disturbance | Acute: Chvostek sign,* circumoral numbness, headache, impaired vision, seizures, tetany, Trousseau sign† Chronic: dementia, parkinsonism |
Psychiatric | Anxiety, depression, emotional instability | Anxiety, depression |
Pulmonary | — | Bronchospasm, laryngospasm, wheezing |
Renal | Polydipsia, 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 21,2,4–6 and Figure 37–11) 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 2.1,2,4–6 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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