Hyperparathyroidism in Emergency Medicine 

Updated: Oct 13, 2021
Author: Philip N Salen, MD; Chief Editor: Erik D Schraga, MD 


Practice Essentials

Primary hyperparathyroidism is one of the most common causes of hypercalcemia and should be considered in the differential of any individual presenting with an elevated calcium level.[1]  Primary hyperparathyroidism (PHPT), hypersecretion of parathormone (parathyroid hormone: PTH) from the parathyroid glands, results in persistent hypercalcemia and usually hypercalciuria.[2]   Rarely, PHPT manifests as a component of genetically transmitted endocrine diseases, specifically multiple endocrine neoplasia syndromes. PHPT causes symptoms in multiple organ systems throughout the body via its impact on calcium homeostasis. The most recognizable symptoms are renal and skeletal complications: nephrolithiasis, nephrocalcinosis, osteitis fibrosa cystica, and osteoporosis.[2]  PHPT also manifests more subtly with nonspecific symptoms in other organ systems including: cardiovascular, gastrointestinal, rheumatic, and neuropsychiatric. Untreated PHPT can lead to irreversible changes including skeletal deformations and renal insufficiency.


The parathyroid glands regulate serum calcium and phosphorus levels by the secretion of parathyroid hormone (PTH), which elevates serum calcium levels while depressing serum phosphorus levels. The regulation of PTH secretion occurs through a negative feedback loop in which calcium-sensing receptors on the membranes of parathyroid cells trigger decreased PTH production as serum calcium concentrations rise.

Primary hyperparathyroidism (PHPT), which accounts for most hyperparathyroidism cases, results from excessive release of PTH and manifests as hypercalcemia.[3] Patients with hypercalcemia who have normal renal function and no malignancy must be suspected of having primary hyperparathyroidism and must be evaluated for hyperparathyroidism.

Hyperparathyroidism is often incidentally discovered during routine laboratory testing when hypercalcemia is noted. For 80% of patients with hyperparathyroidism, the symptoms of hyperparathyroid induced hypercalcemia are mild or are not notable at the time of discovery. Management of asymptomatic PHPT patients is not clear-cut because routine laboratory tests have not been predictive of development of overt manifestations of the disease. Conversely, patients with overtly symptomatic hyperparathyroidism (eg, those with urinary tract stones, bone pain, cognitive abnormalities) and those with marked hypercalcemia (calcium levels >10.2 mg/dL) should be referred for consideration for parathyroidectomy.[4]


PHPT is usually the result of a single benign adenoma; a minority of patients have hyperplasia of all 4 parathyroid glands. Parathyroid carcinoma manifests rarely, less than 0.5%, as a cause of hyperparathyroidism.

Asymptomatic PHPT manifests with serum calcium concentrations only slightly elevated to within 1 mg/dL above the upper limit of the reference range. Within the setting of asymptomatic PHPT, the parathyroid hormone (PTH) level is typically 1.5-2 times the upper limit of the reference range. Hypophosphatemia and hyperchloremia are typically seen only in patients who are highly symptomatic patients and have advanced hyperparathyroidism.

Hypercalciuria, more than 300 mg daily of urinary calcium excretion, is observed in a significant subset of PHPT patients (30%). The most frequent complication of symptomatic PHPT is nephrolithiasis, which occurs in about 20% of patients.[5]  PHPT also can decrease glomerular filtration rates, inducing chronic kidney disease.

When hyperparathyroidism manifests with hyperplasia in all 4 glands, familial-genetic syndromes should be contemplated as causal within the differential diagnosis. Syndromes to be considered include type I and type II multiple endocrine neoplasia (MEN) or, less commonly, familial hypocalciuric hypercalcemia and hyperparathyroidism–jaw tumor syndrome. Radiation therapy to the head and neck increases the risk of development of parathyroid tumors.

Secondary hyperparathyroidism occurs when the parathyroid glands become hyperplastic after long-term hyperstimulation and release of PTH. In secondary hyperparathyroidism, elevated PTH levels do not result in hypercalcemia. Secondary hyperparathyroidism has been attributed to a physiologic response to the hypocalcemia present in those with chronic renal failure (CRF). However, hypocalcemia is not an absolute requirement for the development of secondary hyperparathyroidism in CRF. Nearly all patients on maintenance dialysis will develop secondary hyperparathyroidism regardless of their calcium level.[6] Calcium homeostasis becomes an issue of concern because of accelerated vascular calcifications seen in patients on dialysis.

Additional risk factors for the development of secondary hyperparathyroidism include phosphorus retention, intrinsic parathyroid gland abnormalities, diminished serum calcitriol levels, and resistance to PTH by skeletal tissue. Rickets and malabsorption syndromes are rarer causes of secondary hyperparathyroidism.

With long-term parathyroid hyperstimulation, the glands function autonomously and produce high levels of PTH even after correction of chronic hypocalcemia. Tertiary hyperparathyroidism refers to hypercalcemia caused by autonomous parathyroid function after long-term hyperstimulation.


Causes include the following:

  • A single parathyroid adenoma is the underlying pathology of PHPT in 85% of cases.

  • Diffuse hyperplasia of all parathyroid glands occurs in approximately 15% of cases. More than half of multiple parathyroid gland involvement cases are part of multiple endocrine neoplasia syndromes.

  • Parathyroid carcinoma is an uncommon cause of PHPT.

  • Secondary hyperparathyroidism is a frequent complication of chronic renal failure.[7]  Secondary hyperparathyroidism occurs when the parathyroid glands are chronically stimulated to release PTH. Hypocalcemia, hyperphosphatemia, and depressed 1.25 vitamin D (calcitriol) levels are the main triggers for the development of secondary hyperparathyroidism in chronic renal failure, malabsorption syndromes, and rickets.[8]

  • Tertiary hyperparathyroidism results when long-standing secondary hyperparathyroidism progresses to autonomous hypersecretion of PTH even after correction of chronic hypocalcemia.

  • External radiation to the head, neck, and chest regions is associated with an increased likelihood of developing parathyroid tumors. Parathyroid adenomas manifesting after radiation exposure are usually hyperfunctioning and often manifest as symptomatic PHPT.[9]  Patients with radiation-induced hyperparathyroidism are also more likely to have coexistent nodular goiter and thyroid gland carcinoma than patients with spontaneous hyperparathyroidism.[10]



Primary hyperparathyroidism is a common endocrine disease that affects nearly 1 in 500 women and 1 in 2000 men per year, most often in the fifth, sixth, and seventh decades of life.[5]

Sex- and age-related demographics

Most individuals with PHPT, asymptomatic and symptomatic, are postmenopausal women.[1]  The incidence of affected women reaches 21 per 1000 in women older than the age of 50.[2]  Asymptomatic PHPT is a disease that affects mainly women in their middle years. Women with PHPT outnumber men by approximately 3:1.[11]  

Although hyperparathyroidism can manifest at any age, PHPT occurrence rises markedly in persons older than 40 years. The disease manifests most commonly within the first decade after onset of menopause. 




The prognosis is excellent for patients after successful parathyroidectomy.

Asymptomatic patients who do not have indications for surgery have an excellent prognosis. Significant bone loss and other symptoms may be absent for years in subsequent follow-up visits.

The skeletal status of individuals with primary hyperparathyroidism plays an important role in management decisions. Surgical intervention is often recommended for patients with primary hyperparathyroidism and low bone mineral density, based on data from observational studies that demonstrate increases in bone mineral density after surgical treatment.[12]

The prognosis of secondary hyperparathyroidism is related to the underlying advanced chronic renal failure and resultant chronic hypocalcemia.


Most patients, who are predominantly middle aged or elderly, present with mild elevations of serum calcium and are not overtly symptomatic. Usually, the rate of progression of PHPT is slow, and monitoring these patients and medically managing the disease is usually safe.

All patients with biochemically confirmed, symptomatic PHPT should be referred for surgical parathyroidectomy. In symptomatic patients, there is evidence that after parathyroidectomy, cognitive function improves, bone density improves, fracture rate declines, and the incidence of ureteral colic declines. Furthermore, cardiovascular disease and premature death also appear to decrease after parathyroidectomy in symptomatic patients.[13]  Complication rates and symptom relief are similar in younger and older patients who undergo surgery.[1]

Of note, many "supposedly asymptomatic" patients do not realize that their hyperparathyroid symptoms are a manifestation of their PHPT until after these symptoms diminish or disappear following parathyroidectomy.[14]


When the diagnosis of hyperparathyroidism is delayed, patients are more likely to present with complications or sequelae of their disease. Recurrent nephrolithiasis with consequent ureteral colic results from hyperparathyroidism induced hypercalciuria. Hyperparathyroid induced osteoporosis increases the risk of fractures compared to the general population.[2]  Brown tumor, a musculoskeletal complication of hyperparathyroidism, is a focal bone lesion caused by increased osteoclastic activity and fibroblast proliferation encountered in primary and, more rarely, in secondary hyperparathyroidism.[7]  Rheumatologic diseases such as gout and pseudogout have been associated with hyperparathyroidism induced alterations in calcium homeostasis.[15] The risk of pancreatitis is approximately 10 times higher in PHPT patients than in the general population.[2] Another gastrointestinal manifestation of PHPT is its association with chronic autoimmune atrophic gastritis. PHPT is associated with a higher incidence of arterial hypertension and an increased risk of overall cardiovascular mortality.[2]

Maternal hyperparathyroidism can lead to profound hypocalcemia and tetany, coma, and death in newborns in a syndrome known as neonatal severe hyperparathyroidism.

Nocturia and polyuria may result from the effects of elevated calcium levels on the renal tubule. Approximately 20% of patients with hyperparathyroidism have nephrolithiasis.

CNS disturbances, coma, and death may result from markedly elevated serum calcium levels when left untreated.

Skeletal sequelae, osteoporosis or pathologic fractures, may occur.

Cardiovascular complications, such as heart failure, valvular or vascular calcifications, may occur.

Surgical complications

Surgical complications include the following:

  • Hypoparathyroidism

  • Recurrent laryngeal nerve damage

  • Hemorrhage

  • Infection

  • Unsuccessful surgery

    • Persistent or recurrent disease occurs in a low percentage of individuals who undergo surgery for primary hyperparathyroidism.[16]

    • Persistent primary hyperparathyroidism is defined as the presence of elevated serum calcium levels and PTH levels documented within 6 months of the initial operation. The most common cause of persistent primary hyperparathyroidism is the presence of a missed parathyroid adenoma, which is usually in an ectopic location in this setting. Less commonly, persistent disease may be secondary to inadequate resection of unappreciated multigland disease.[16]

Patient Education

Educate patients about prescribed medications. Educate patients regarding the importance of periodic laboratory and radiologic testing.

Information for patients

Hyperparathyroidism is a disease of the 4 parathyroid glands that are next to the thyroid gland in the neck. The parathyroid glands release a hormone called parathormone (parathyroid hormone) that is important for maintaining the normal calcium levels in the body. Primary hyperparathyroidism, the most common kind of hyperparathyroidism, occurs when too much parathormone is released from one or more of the parathyroid glands and is most commonly caused when one of the four parathyroid glands grows abnormally large. Secondary hyperparathyroidism occurs when the parathyroid glands respond to a stimulus within the body to release too much parathormone. Hyperparathyroidism causes high levels of calcium in the blood. The most common symptoms of hyperparathyroid induced hypercalcemia are kidney stones, which can cause flank pain, and weak bones, which can break more easily. Other symptoms of hyperparathyroidism are feeling weak, tired, and depressed.

Hyperparathyroidism is diagnosed by checking the blood for high levels of calcium and parathormone.

Many patients with primary hyperparathyroidism have mild forms of the disease, do not have symptoms, and do not need treatment. Some patients with symptoms of weak bones or kidney stones need to have their parathyroid glands surgically removed.




Most patients with PHPT are asymptomatic or minimally symptomatic. At time of diagnosis, PHPT patients' symptoms and signs are subtle and the diagnosis is made fortuitously as part of the work-up of hypercalcemia.[14] Because manifestations of hyperparathyroidism are subtle, the disease may run an occult course for years prior to detection. Symptomatic hyperparathyroidism is characterized by vague, nonspecific symptoms including generalized weakness, fatigue, poor concentration, and depression.

When a patient has symptoms secondary to PHPT induced hypercalcemia, classically, PHPT targets the kidney and the skeleton.[17]  A helpful mnemonic, "painful bones, renal stones, abdominal groans, and psychic moans," can be used to recall the typical symptoms of hypercalcemia. Painful bones are the result of abnormal bone remodeling due to overproduction of PTH. Nephrolithiasis occurs secondary to hyperparathyroid disease–induced hypercalcemia and resultant hypercalciuria. Abdominal groans refers to hypercalcemia-induced ileus. Psychic moans or depression may occur in the presence of persistently elevated serum calcium levels.

As many as 75% of patients who eventually undergo surgical treatment for PHPT present initially with recurrent ureteral colic. Patients with PHPT not only have a greater risk of renal stone disease, but this risk persists for 10 years postparathyroidectomy.[18]

Some PHPT patients suffer from easy fatigability, asthenia, a sense of generalized weakness, or mild cognitive impairment. Proximal muscle weakness may occur, typically affecting the lower limbs more than the upper limbs. Chondrocalcinosis and pseudogout are other potential complications of hyperparathyroidism.

Rarely, symptomatic PHPT may abruptly worsen and cause severe hypercalcemic complications such as profound dehydration, delirium, or coma; this is referred to as hypercalcemic parathyroid crisis.

In the modern era, even though most patients present with “asymptomatic” PHPT, careful questioning and examination can often elucidate subtle neurocognitive and psychiatric complaints.[11]

Physical Examination

In developed countries, most patients with hyperparathyroidism have no specific physical findings. Patients may present with nonspecific symptoms such as fatigue, mild depression, or cognitive impairment. While it is important to exclude neck masses in patients with suspected hyperparathyroidism, parathyroid adenomas and carcinomas are rarely palpable. Band keratopathy, the deposition of calcium phosphate in the exposed regions of the cornea that is detected by a slit-lamp examination, is an exceedingly rare hyperparathyroidism manifestation and only occurs with very high serum calcium and phosphate levels, which is rare in PHPT.[15]

In developing nations where biochemical screening is not widely available, patients can develop and present with more severe physical examination findings because they present with more advanced cases of hyperparathyroidism. Advanced, initial presentation of hyperparathyroidism include: brown tumors of the maxilla, sphenoid, sinus, and occipital bone; nephrocalcinosis, neuropsychiatric disturbances. The brown tumor is an unusual presentation of fibrous osteitis that represents a serious complication of renal osteodystrophy, affecting predominantly the hands, feet, skull, and facial bones.[7]  Neuropsychiatric disturbances vary and can include lethargy, decreased cognitive and social function, depressed mood, psychosis, and coma when there is severe hypercalcemia.[15]

Physical examination findings

There are no sine qua non physical examination findings that corroborate the diagnosis of hyperparathyroidism without confirmatory laboratory evidence.

Central nervous system manifestations of PHPT are neuropsychiatric or neurocognitive. Symptomatic PHPT patients frequently display clinical signs of mental depression, poor general health, low energy levels, decreased ability to complete daily tasks at home or at work, decreased social interaction, and pain, particularly in the legs.[14]  If hyperparathyroid induced hypercalcemia levels are high enough, which is rare, patients can manifest hypercalcemia-induced delirium.

PHPT may have cardiovascular sequelae as well. There is evidence that PHPT is associated with hypertension, left ventricular hypertrophy, vascular calcifications and stiffness, and even myocardial events.[19]  Even very mild PHPT, with a mean serum calcium in the range of 10.6 mg/dL, can increase aortic valve calcification area, increase aortic and carotid stiffness, and increase vascular wall thickness, all of which are preclinical predictors of deleterious cardiovascular outcomes.[11]

Musculoskeletal system manifestations of hyperparathyroidism typically manifest as skeletal demineralization.

Overt bone disease, including subperiosteal bone resorption and osteitis fibrosa cystica, is a serious but rare manifestation of hyperparathyroidism. Osteitis fibrosa cystica, cystic bone lesions ("brown tumors") of bones, and periosteal bone resorption were commonly seen in typical PHPT historically, which rarely manifests now with improved laboratory screening techniques for PHPT and hypercalcemia along with curative therapy.[11]

Both men and women with PHPT are more likely to have low bone density, osteopenia/osteoporosis, and increased fracture risk, out of proportion to their relative risk secondary to their age and gender.[19]  Surgical correction of PHPT results in reduction in bone turnover and significant improvements in bone mineral density.[20]

Other manifestations of hyperparathyroidism are chondrocalcinosis, pseudogout, and easily fatigued musculature, particularly the proximal muscle groups.

Gastrointestinal manifestations of hyperparathyroidism are pancreatitis, pancreatic calcification, and peptic ulcer disease.

Renal manifestations of PHPT include recurrent calcium nephrolithiasis, nephrocalcinosis, and impaired renal function.[18]




Diagnostic Considerations

Hyperparathyroidism is the most common cause of hypercalcemia in the outpatient setting.[21]  

Thiazide diuretics and lithium can alter calcium homeostasis.  Thiazide diuretics cause mild hypercalcemia by reducing urinary calcium excretion. If hypercalcemia persists after stopping the thiazide diuretic, PHPT is likely. Patients on long-term lithium therapy uncommonly develop hypercalcemia secondary to lithium decreasing the parathyroid gland’s sensitivity to calcium, and resulting in increases in serum levels of calcium and PTH.[15]

Differential Diagnoses



Approach Considerations

Patients with mild pHPT are often identified during routine laboratory evaluation or when undergoing workup for bone loss. As such, they tend to be postmenopausal women who are at risk for osteoporosis that undergo BMD studies and calciotropic hormone measurements for evaluation.[21]  With the advent of multichannel autoanalyzer testing of PTH, increasing neck imaging studies, and calcium measurements taken for screening and bone health evaluation, patients with biochemically mild profiles are frequently identified. Among the increasing numbers of patients diagnosed with PHPT, subsets of patients are now more frequently identified with biochemically mild PHPT, who are either normocalcemic with elevated PTH or hypercalcemic with an inappropriately normal or high-normal PTH.[21]

Laboratory Studies

The biochemical hallmarks of PHPT include elevated serum calcium levels in the presence of elevated or inappropriately normal levels of PTH. All nonparathyroid causes of hypercalcemia are associated with PTH levels that are suppressed. Malignancy-associated hypercalcemia is a disorder to consider primarily in the differential diagnosis of PHPT, and will be excluded with a low PTH level.[11]

Elevated PTH levels in the setting of hypercalcemia establish the diagnosis of hyperparathyroidism. The normal range for the PTH-intact assay is 10-65 pg/mL. The introduction of an immunoradiometric assay for PTH that detects only the fully intact PTH molecule has improved diagnostic accuracy of PTH determination.[22]

The threshold value for serum calcium, above which parathyroidectomy is indicated, is persistent elevation more than 1 mg/dL (0.25 mM/liter) above the upper limits of normal.[23]

The most common alternative cause of hypercalcemia in older individuals, hypercalcemia of malignancy, is associated with suppressed PTH levels.

Although measuring the concentration of ionized calcium rather than the total calcium concentration provides added accuracy, one may alternatively use the total serum calcium concentration corrected for the patient's albumin concentration. This can be achieved by adding 0.8 per dL to the total serum calcium value for every 1 g/dL below a serum albumin concentration of 4 g/dL. Those with secondary hyperparathyroidism and associated chronic renal failure are especially prone to hypoalbuminemia, which makes this correction of particular importance for that population.

Levels of 25-hydroxyvitamin D should be assessed in all patients suspected of having PHPT, and vitamin D deficiency should be cautiously corrected at the time it is detected.[23]

It is important to monitor renal function, both at the time of diagnosis and during follow-up of hyperparathyroid patients.[23] Urinary calcium excretion may be elevated in patients with symptomatic PHPT and predisposes to ureteral colic.

Increased bone turnover may be reflected in elevated levels of markers of bone formation, alkaline phosphatase, and bone resorption, urinary pyridinoline, though these tests do not aid in diagnosis of PHPT.

Lithium and thiazide diuretics induce changes in parathyroid function that can potentially mimic PHPT. To evaluate whether these medications are causing hypercalcemia, they can be withdrawn for 3 months, if medically safe, and the patient’s calcium and PTH can be retested. Usually, drug withdrawal does not alter biochemical results and the medications, excluded as causal, can be reinstituted.[11]

Expedited determination of PTH levels in the intraoperative setting with rapid laboratory assays has been used during parathyroid excisions. Because of the short half-life of PTH (< 5 min), intraoperative measurement is recommended by the National Academy of Clinical Biochemistry Guidelines.[24] Intraoperative use of the PTH assay provides quantitative confirmation when all hyperfunctioning parathyroid tissue has been excised. A decrease in the PTH concentration of more than 50% from the baseline level 5-10 minutes after excision of all suspected hyperfunctioning parathyroid tissue suggests the absence of any residual hyperfunctioning tissue. The advent of intraoperative PTH testing has reduced the postoperative failure rate of initial parathyroidectomy surgery from 6% to 1.5%[25] and has decreased the need for performing frozen sections.[26]

Imaging Studies

Positive imaging studies are not necessary for the confirmation of a diagnosis of PHPT. Moreover, negative imaging study results do not exclude the diagnosis of primary hyperthyroidism. Parathyroid imaging studies have the potential for false-positive or false-negative findings that can be misleading. Therefore, biochemical confirmation of the diagnosis of PHPT should always precede parathyroid imaging studies.[13]

Preoperative imaging in the setting of PHPT is designed to assist the surgeon in identifying the anatomic localization of abnormally functioning or enlarged parathyroid glands. The noninvasive imaging modalities commonly used in patients with PHPT include technetium-99m (99m Tc) sestamibi imaging, ultrasonography, CT scanning, and MRI.[13]

Ultrasonography and99m Tc sestamibi scanning have the advantages of being widely available and relatively inexpensive compared with other noninvasive modalities. The most sensitive and reliable technique is99m Tc sestamibi tomographic reprojection nuclear scanning because of its ability to produce a 3-dimensional image that can be used for visual reference by the surgeon intraoperatively.[27]  In sestamibi scanning, the dual isotope technique in which an I-123NaI or99m Tc sestamibi image of the thyroid is subtracted from a99m Tc sestamibi image is commonly used.[16]  Sestamibi scintigraphy has the advantage of being able to screen the entire mediastinal and cervical regions.

High-resolution real-time cervical ultrasonography using a 10-MHz transducer results in true positive findings in 50-60% of patients who undergo evaluation for persistent or recurrent primary hyperparathyroidism. Using ultrasonography, hyperfunctioning parathyroid tissue has a characteristic sonolucent signal that is distinct from thyroid. The most helpful ultrasonography results reveal parathyroid tissue in one of the normal cervical locations adjacent to the thyroid gland.[16]  Ultrasonography may be useful but is operator-dependent.[27]

Plain-film radiography has limited diagnostic value, especially in the early stages of the disease. Normal findings do not rule out hyperparathyroidism. Distinct radiographic abnormalities are uncommon and typically are only found with overt, symptomatic disease. The findings include subperiosteal resorption that is best seen at the radial sides of the phalanges, distal phalangeal tufts, and distal clavicles. However, in most older patients, no specific radiologic manifestations are observed, and routine skeletal radiography is not recommended.

Bone-density measurements based on dual energy x-ray absorptiometry (DXA) at the hip and spine should be obtained in individuals with PHPT, regardless of age.[1] Recommended management of primary hyperparathyroidism includes surgical intervention be undertaken if the bone mineral density T-score at any of 3 sites (lumbar spine, proximal femur, or forearm) is less than -2.5 standard deviation.[12]

Cystic bone lesions called brown tumors are seen only in severely symptomatic patients with long standing disease. Soft tissue calcification may be apparent in the joints, kidneys, and lungs using conventional radiography and may be more readily evident on bone scans.

CT scanning of the spine provides reproducible quantitative estimates of spinal bone density. Serial measurements can provide an early indication of whether or not progressive osteopenia is present.


If malignancy is suspected, percutaneous needle biopsy may be performed for aspiration cytology and tissue PTH determination.



Approach Considerations

Definitive therapy for symptomatic and asymptomatic PHPT is parathyroidectomy. Parathyroid induced hypercalcemic crisis is managed by volume repletion, administration of loop diuretics once the patient is euvolemic, and bisphosphonate therapy to further decrease bone resorption.[15]  

Prehospital Care

Only in the most severe acute manifestation of hyperparathyroidism, hypercalcemia-induced delirium, does management need to begin in the prehospital setting. In such cases, prehospital care should focus on the stabilization of airway, breathing, and circulation. In the field and the emergency department, hydration is the principal primary therapy directed at hypercalcemia.

Emergency Department Care

The emergency department (ED) management of hyperparathyroidism is focused on the treatment of hypercalcemia. Specifically, the goal of treatment is to reduce the calcium level to below 11.5 mg/dL; most patients have resolution of hypercalcemia-induced symptoms when calcium levels are below this level.

  • Intravenous administration of isotonic saline is the first and most vital step in the management of severe hypercalcemia.[28] Severe hypercalcemia is nearly always accompanied by severe dehydration. When the depleted intravascular volume is restored to the reference range, the serum calcium concentration declines by the degree to which dehydration raised it. Subsequent hydration serves to enhance renal excretion of excess calcium.

  • Hypercalcemia symptoms are mild in most asymptomatic patients with hyperparathyroidism and may be controlled with gentle hydration with normal saline.

  • In patients presenting with severe alterations of mental status or other life-threatening complications from profound hypercalcemia, fluid resuscitation with normal saline, immediate institution of bisphosphonate therapy — with or without calcitonin, depending on the severity of the symptoms — is the standard of management for hypercalcemia.[28]

  • Loop diuretics may facilitate the urinary excretion of calcium and may prevent the volume overload that may accompany the administration of large volumes of saline. However, furosemide does not consistently normalize calcium levels quickly, even at markedly higher doses than those routinely prescribed.[28] Patients with hypercalcemia may be destabilized further by fluid and electrolyte disturbances caused by aggressive diuresis and, as such, should have serial chemistry panels performed for monitoring. Initiation of loop diuretics should only occur after rehydration has taken place.

  • In postmenopausal women with mild hyperparathyroidism, estrogen therapy has been advocated because it may inhibit demineralization of the skeleton and may reduce blood calcium levels.

  • Parathyroidectomy is the only definitive treatment for severe hyperparathyroidism.

  • Successful parathyroidectomy induces normocalcemia in 95-98% of patients with hyperparathyroidism, and 82% of patients have symptomatic improvement. Patients with osteoporosis and hyperparathyroidism experience a prompt and sustained increase in their bone mineral density after successful parathyroidectomy.

  • Although few studies related to the incidence of postparathyroidectomy fractures are available,[29] bone mineral density in the femoral neck rises by 6% after 1 year and rises by 14% after 10 years.[27]

  • Although some controversy surrounds indications for surgery, current National Institutes of Health guidelines for curative, surgical intervention indications are defined by the measurable objective criteria listed below. Approximately 20% of patients with PHPT meet the following criteria:[30]

    • Patients with overt clinical manifestations of disease

    • Age younger than 50 years

    • Serum calcium concentration more than 1 mg/dL above upper limit of reference range

    • Urinary calcium excretion of more than 400 mg/d

    • Low or declining bone mineral density

    • Uncertain prospect for successful medical monitoring

    • Patient requests surgery

    • Poor or uncertain follow-up

    • Coexistent disease that may confound or contribute to disease progression

    • Reduction in creatinine clearance of 30% or more

    • Reduction of bone mineral density greater than 2.5 standard deviations below the reference range for bone density in terms of age, gender, and race (T score < 2.5)

  • Of note, many patients tolerate mild hyperparathyroidism well without operative treatment. Roughly 75% of asymptomatic patients who present with mild hypercalcemia did well over a 10-year period without significant loss of cortical bone, progressive hypercalcemia, or excessive urinary calcium excretion. Because no factors (other than the ones listed above) predict which patients with mild disease will experience disease progression, all asymptomatic patients, who are not operated on, must have serum calcium levels periodically monitored.[27] Asymptomatic patients who were not deemed candidates for surgery had the following features: a serum calcium level less than 1 mg/dL (0.25 mmol/L) above the upper limits of normal, no history of kidney stones or fractures, a creatinine clearance that was within 30% of age- and sex-matched controls, 24-h urine calcium level less than 400 mg/24 h (0.1 mmol/kg per day), and the absence of osteoporosis by bone density T-score.[19]

  • Because of the improvements in radiopharmaceutical screening and the availability of the intraoperative, rapid parathyroid hormone (PTH) assay, minimally invasive parathyroidectomies under local anesthesia are now performed; patients are discharged several hours postoperatively. This technique has altered the management and the surgical indications for hyperparathyroid in some patients. For example, symptomatic elderly patients with comorbid disease who were previously denied surgery because of risks related to anesthesia and bilateral neck dissection are now potential candidates for minimally invasive parathyroidectomy. Furthermore, in centers in which limited parathyroidectomy is available, asymptomatic patients with moderate hypercalcemia (0.4-0.9 mg/dL above normal) can be considered for earlier parathyroidectomy before severe bone loss or kidney damage occurs.[27]


All patients with biochemically confirmed PHPT who have specific symptoms or signs of their disease should undergo surgical treatment.[23]

Surgical consultation is necessary for patients with severe hypercalcemia due to hyperparathyroidism who meet current National Institute of Health guidelines for curative surgical intervention. Surgery remains the only curative option in asymptomatic, as in symptomatic disease.[11]

New techniques for identifying and operating on hyperactive parathyroid glands have improved the success rate of parathyroidectomy, as measured by a return to normocalcemia in 98% of patients, and have also simplified the operation from a bilateral neck operation under general anesthesia to a simpler outpatient procedure.

The new parathyroidectomy technique involves performing the procedure through a small incision under local anesthesia with limited, target-specific dissection. Excision of the hyperfunctioning gland is confirmed in the operating room by a quantitative decrease in the plasma PTH level, ensuring that all hypersecreting tissue has been removed. The failure rate of this minimally invasive procedure is low, approximately 1.5%.[27]

  • When normal glands are found in association with one enlarged adenomatous gland, excision of the single adenoma usually leads to a cure or eliminates symptoms.

  • The surgical approach usually entails removal of a single enlarged gland; however, all glands must be examined in some way to eliminate the possibility that more than one gland is abnormal. Multiglandular disease, identified by quantitative biochemical frozen section, is present in 5% of patients with primary hyperparathyroidism and must be recognized and treated at the time of operation to ensure operative success.[27]

  • In patients with multiple gland hyperplasia, total parathyroidectomy is performed with immediate transplantation of a portion of a removed minced parathyroid gland into the muscles of the forearm; even if parathyroid gland hyperfunction recurs, surgical excision is easier from the ectopic site in the arm.

  • A decline in serum calcium level occurs within 24 hours of successful surgery. Additionally, serum PTH levels fall within minutes of a successful parathyroidectomy. Intraoperative measurement of PTH can be useful in locating obscure glands through differential venous sampling, measuring increased hormone secretion after massage of specific areas, and correctly identifying the excision of abnormal parathyroid tissue when it is not easily recognized.[27]

  • Serum ionized calcium and/or total calcium have to be monitored regularly, eg, every 6 to 12 hours for the first day post-operatively or until the patient’s calcium level is stable.[8]

  • Usually, blood calcium levels fall to low reference range values for 3-5 days until the remaining parathyroid tissue resumes hormone secretion. Severe postoperative hypocalcemia is likely only if osteitis fibrosa cystica is present or if injury to all the normal parathyroid glands occurs during surgery.

  • To maintain the calcium levels within the normal range, many patients will need intravenous calcium substitution soon after parathyroidectomy. Oral calcium supplements can be instituted as soon as the patient is able to swallow, and the dose is progressively increased as necessary.[8]

Medical Care

In patients with asymptomatic PHPT, medical management designed to target skeletal protection or lower serum calcium might be a suitable option. It can be of value for those with contraindications to, or those who do not wish to have, surgery. Among drugs in the bisphosphonate class, alendronate in particular has been shown to decrease bone turnover and increase BMD in PHPT. Hormone replacement therapy also improved BMD in postmenopausal women with mild PHPT. It is not known whether these treatments also reduce fracture risk.[15]  Patients should be encouraged to engage in physical activity (to decrease bone resorption) and to maintain adequate hydration (to reduce the risk of developing serious hypercalcemia or nephrolithiasis).[15]

Surgical Care

The definitive management and curative therapy for PHPT is surgery. Cure rates for surgical management of PHPT are 95% to 98%.[21] For an asymptomatic PHPT patient, the decision for parathyroid surgery is based upon patient characteristics including age, creatinine clearance, and bone mineral density. Specific indications for parathyroidectomy in the setting of asymptomatic PHPT are: 1. Serum calcium above upper limit of normal 0.25 mmol/L; 2. Creatinine clearance (calculated) reduced to < 60 mL/min; 3. Bone mineral density T score less than -2.5 at any site or previous fragility fracture; 4. Age less than 50 years old.[15]  Minimally invasive parathyroidectomy is the operative intervention of choice by the experienced endocrine surgeon if preoperative imaging localizes a parathyroid adenoma. If the parathyroid glands causing PHPT are not localized preoperatively, bilateral neck exploration is undertaken. The short half-life of PTH allows for intraoperative testing and confirmation that the abnormal gland has been excised.[21]

Complications from surgical management of PHPT are uncommon, 1% to 2%.[21]

Parathyroid hormone levels may be elevated postoperatively in as many as 20-40% of patients. If the serum calcium level remains within the reference range, this elevated state does not usually suggest persistent disease but may indicate a higher risk of recurrence.[31] The recurrence rate after successful parathyroidectomy is approximately 10-15% with long-term follow-up.[32]


Prevention and Long-Term Monitoring


Asymptomatic PHPT patients and patients who are not undergoing surgical excision are advised to remain well hydrated, to avoid immobilization, and to avoid thiazide diuretics, which can increase serum calcium levels. There has been debate regarding the benefits of restrictions in dietary calcium intake.[21]

Long-term monitoring

Recommended surveillance of PHPT patients who do not undergo operative cure is measurement of: serum calcium levels twice yearly, urinary calcium excretion yearly, and bone mineral density measurements yearly.[21]



Medication Summary

There are no drugs currently approved for use specifically in patients with asymptomatic PHPT.[11]

Intravenous hydration with isotonic sodium chloride solution adequately reduces calcium levels in most patients with symptomatic hyperparathyroid-induced hypercalcemia. Restoration of euvolemia with isotonic saline is the mainstay emergency department treatment of hypercalcemia of any cause, including PHPT.

Bisphosphonate and hormone replacement therapy provide skeletal protection in patients with PHPT. Neither of these classes of medications significantly lowers serum calcium or PTH levels. The magnitude of the effects of bisphosphonates and estrogen on bone mineral density in PHPT is comparable to that which occurs after surgical correction of primary hyperparathyroidism.[20] Of the two agents, bisphosphonates are preferred because of the adverse nonskeletal effects of long-term hormone replacement therapy.

Cinacalcet, a calcimimetic, reduces both serum calcium and parathyroid hormone (PTH) levels and raises serum phosphorus. Cinacalcet inhibits parathyroid cell function and reduces PTH secretion by altering the function of parathyroid calcium-sensing receptors, normalizes serum calcium in PHPT, both mild and more severe, for sustained periods.[11] Cinacalcet does not, however, reduce bone turnover or improve bone mineral density. At present, use of this agent in primary hyperparathyroidism is limited to control of serum calcium in patients with symptomatic hypercalcemia who are unable to undergo corrective surgery.[20]

Cinacalcet can be considered for patients with hypercalcemia secondary to parathyroid carcinoma, secondary hyperparathyroidism, and primary hyperparathyroidism. Currently, cinacalcet is approved for use only in cases of severe PHPT and parathyroid cancer; it is not approved for use in asymptomatic PHPT.[11] For hypercalcemia from primary hyperparathyroidism or parathyroid malignancy, the starting dose is usually 30 mg orally twice daily. For those with secondary hyperparathyroidism, the starting dose is 30 mg once daily. After initiation of cinacalcet, measure the serum calcium level within 1 week to allow dose adjustment.

Loop diuretics

Class Summary

These agents may be helpful following hydration in individuals who are hypercalcemic.

Furosemide (Lasix)

Increases excretion of water and calcium. Interferes with chloride-binding cotransport system by inhibiting the reabsorption of sodium and chloride in the ascending loop of Henle and distal renal tubule.

Hormonal therapy

Class Summary

Hormone therapy is indicated in postmenopausal females with hyperparathyroidism.

Estrogen (Premarin)

Reduces bone resorption resulting from hyperparathyroidism.

Calcimimetic agents

Class Summary

Cinacalcet is useful in the management of hyperparathyroid patients for whom parathyroidectomy is contraindicated or in whom surgical correction of their hyperparathyroidism gas failed.[33] Cinacalcet has been shown to significantly lower PTH and calcium levels in patients on dialysis with secondary hyperparathyroid disease ranging from mild to severe.[6] Calcium regulators are also used in hypercalcemia of malignancy. These agents bind to and modulate the parathyroid calcium-sensing receptor, increase sensitivity to extracellular calcium, and reduce PTH secretion. Cinacalcet is a first-in-class calcimimetic drug that works to directly inhibit PTH in patients with CRF. Calcimimetics allosterically modulate the Ca-sensing receptor, increasing its sensitivity to extracellular calcium and thereby lowering PTH secretion from the parathyroid gland.[8]

Cinacalcet is expensive; the cost per month per patient is estimated to vary from about $300 (30 mg) to $1800 (180 mg).

Cinacalcet (Sensipar)

Directly lowers PTH levels by increasing sensitivity of calcium-sensing receptor on chief cell of parathyroid gland to extracellular calcium. Also results in concomitant serum calcium level decrease. Indicated for hypercalcemia with parathyroid carcinoma and for secondary hyperparathyroidism of chronic renal failure.

Bisphosphonate Derivative

Class Summary

Bisphosphonates are effective in decreasing bone turnover in patients with primary hyperparathyroidism and improving bone mineral density. Bisphosphonates have the potential to provide skeletal protection in patients with primary hyperparathyroidism, but the data available confirming this are limited at present. The effect on serum calcium has been inconsistent and may be affected by baseline 25-hyroxyvitamin D levels. Bisphosphonates also do not significantly lower parathyroid hormone levels.[20]


Available in the United States, but not yet indicated for treatment of hypercalcemia; alendronate probably is useful for long-term prevention of recurrence of hypercalcemia following use of more conventional therapy (ie, hydration and pamidronate). Useful in preventing and treating osteoporosis, which is a complication of prolonged mild hypercalcemia.



Further Outpatient Care

Calcium levels must be periodically monitored for several months postparathyroidectomy.

If calcium levels begin to rise postoperatively, the patient needs to be evaluated for possible accessory parathyroid glands.

Monitor asymptomatic patients for worsening hypercalcemia, deteriorating bone density or renal function, and other complications of hyperparathyroidism.

If the serum calcium concentration falls below 8 mg/dL postparathyroidectomy with a concomitant rise in serum phosphate level, consider the possibility of postsurgical hypoparathyroidism.

Untreated mild hyperparathyroidism is not associated with rapid bone loss at any of the commonly measured skeletal sites: femur, forearm, and lumbar spine. Therefore, while periodic monitoring of bone mineral density in patients with primary hyperparathyroidism is recommended, doing so every 1–2 years is unnecessary since several years of follow-up are required for the decline in the average patient’s bone mineral density to surpass the smallest detectable change.[12]

Further Inpatient Care

Admit patients with significant symptoms due to hyperparathyroid-induced hypercalcemia and substantial elevations of calcium levels.

Patients who are markedly symptomatic or those with significant electrolyte disturbances should be evaluated by endocrinologists and surgeons experienced in parathyroid removal.


Although patients should refrain from the ingestion of more calcium than is recommended for adults (1200-1500 mg/d), the calcium intake should not be excessively restricted (to < 750 mg/d) because calcium-poor diets may promote processes associated with excessive secretion of parathyroid hormone (PTH).

Because many patients with asymptomatic primary hyperparathyroidism have levels of 25-hydroxyvitamin D that are at the lower end of the reference range or frankly low, the addition of a low level of supplementation achievable with a multivitamin (400 IU of vitamin D daily) is advisable.