eMedicine Specialties > Emergency Medicine > Endocrine & Metabolic

Hyperparathyroidism

Philip N Salen, MD, Clinical Professor, Department of Emergency Medicine, PA Program, Desales University; Adjunct Clinical Associate Professor, Department of Emergency Medicine, Temple University Medical School; Research Director, Emergency Medicine Education, Saint Luke's Hospital

Updated: Nov 16, 2009

Introduction

Background

The parathyroid glands regulate serum calcium and phosphorus levels through the secretion of parathyroid hormone (PTH), which raises serum calcium levels while lowering the serum phosphorus concentration. 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, which accounts for most hyperparathyroidism cases, results from excessive release of PTH and manifests as hypercalcemia.¹ Patients with hypercalcemia who have normal renal function and no malignancy must be suspected of having primary hyperparathyroidism and must be subsequently tested for elevated PTH levels.

Hyperparathyroidism is often incidentally discovered during routine laboratory testing when hypercalcemia is noted. In 80% of patients with hyperparathyroidism, the symptoms of hypercalcemia are mild or are not notable at the time of discovery. Management of these patients is not clear-cut because routine laboratory tests have not been shown to assist in predicting 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.²

Pathophysiology

Primary hyperparathyroidism is one of the most common causes of hypercalcemia and should be considered in any individual with an elevated calcium level.³ Primary hyperparathyroidism is usually the result of a single benign adenoma; a minority of patients have hyperplasia in all 4 parathyroid glands. Parathyroid carcinoma accounts for an insignificant minority (<0.5% of patients with hyperparathyroidism).

Asymptomatic primary hyperparathyroidism 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 primary hyperparathyroidism, 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.

When hyperparathyroidism manifests with hyperplasia in all 4 glands, familial-genetic syndromes should be considered 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. Also, a syndrome of familial isolated hyperparathyroidism has been observed. Radiation therapy to the head and neck predisposes patients to 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. This has been classically attributed to an underlying state of hypocalcemia in those with chronic renal failure (CRF). However, hypocalcemia is not necessary for the development of secondary hyperparathyroidism in this setting. Eventually, nearly all patients on maintenance dialysis will develop secondary hyperparathyroidism.⁴ Calcium balance is an issue of concern due to findings of accelerated vascular calcification 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.

With long-term 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.

Frequency

United States

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

Mortality/Morbidity

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

All patients with symptomatic biochemically confirmed primary hyperparathyroidism should be referred for surgical treatment. In symptomatic patients, there is evidence that has demonstrated 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 surgery in symptomatic patients.⁶ Complication rates and symptom relief are similar in younger and older patients who undergo surgery.³

Of note, many "supposedly asymptomatic" patients do not realize that their hyperparathyroid symptoms may be a manifestation of their disease until after these symptoms diminish or wondrously disappear after parathyroidectomy.⁷

Sex

Most individuals with hyperparathyroidism are older women.³

Age

Although hyperparathyroidism can arise at any age, its occurrence rises markedly after age 40 years. Hyperparathyroidism is rare in children.

Clinical

History

Most patients with primary hyperparathyroidism are asymptomatic or minimally symptomatic. At present in the United States, more than 80% of patients with primary hyperparathyroidism present with a myriad of nonclassical, subclinical signs and symptoms of this disease.⁷ 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.

Nephrolithiasis that results in ureteral colic is secondary to serum calcium elevations. As many as 75% of patients who undergo surgical treatment for primary hyperparathyroidism present with nephrolithiasis. Furthermore, patients with primary hyperparathyroidism not only have a greater risk of renal stone disease, but this risk persists for 10 years after surgery.⁸ Overt bone disease, including subperiosteal bone resorption and osteitis fibrosa cystica, is a serious but rare manifestation of hyperparathyroidism. 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, hyperparathyroidism may abruptly worsen and may cause severe hypercalcemic complications such as profound dehydration, altered mental status, or coma. This is referred to as hypercalcemic parathyroid crisis.

• 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 parathyroid hormone (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.
• The most frequent complication of primary hyperparathyroidism is nephrolithiasis, which occurs in about 20% of patients.⁵ Renal effects of the disease also include decreased glomerular filtration rate. Hypercalciuria (>300 mg daily calcium excretion) is observed in a significant subset of patients (£ 30%).
• Some patients suffer from easy fatigability, a sense of generalized weakness, or mild cognitive impairment.

Physical

No highly specific physical findings are present in hyperparathyroidism.

• CNS
  • Neuropsychiatric illness: 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.⁷
  • Altered mental status
• Cardiovascular system: A growing body of evidence has demonstrated an increased incidence of hypertension, left ventricular hypertrophy, vascular calcification and stiffness, and deleterious myocardial events from primary hyperparathyroidism.⁹
• Musculoskeletal system
  • Considerable evidence suggests that both men and women with primary hyperparathyroidism are more likely to have low bone density, osteopenia/osteoporosis, and increased fracture risk in comparison to controls without hyperparathyroidism.⁹
  • Cystic bone lesions
  • Vertebral collapse
  • Chondrocalcinosis and pseudogout
  • Easily fatigued muscle (particularly proximal muscle groups)
  • Many patients with primary hyperparathyroidism will have low bone mineral density and increased fracture risk in part due to their age and gender and in part due to their hyperparathyroidism. It is clear that surgical correction of primary hyperparathyroidism is followed by reduction in bone turnover and significant improvements in bone mineral density.¹⁰
• GI system
  • Pancreatitis, pancreatic calcification, or both
  • Peptic ulcer disease (may be present at a higher rate)
• Renal system: The renal manifestations of primary hyperparathyroidism include recurrent calcium nephrolithiasis, nephrocalcinosis, and impaired renal function.⁸

Causes

• A single parathyroid adenoma is the underlying pathology in 85% of cases.
• Diffuse hyperplasia of all parathyroid glands occurs in approximately 15% of cases. More than half of these are part of a familial syndrome.
• Parathyroid carcinoma is a very rare cause of primary hyperparathyroidism.
• Secondary hyperparathyroidism occurs when the parathyroid glands are chronically stimulated to release PTH.
  • Chronic renal failure
  • Malabsorption syndromes
  • Rickets
• Long-standing secondary hyperparathyroidism may progress into autonomous hypersecretion of PTH even after correction of chronic hypocalcemia; it is termed tertiary hyperparathyroidism.
• External radiation to the head, neck, and chest regions is associated with an increased likelihood of developing benign parathyroid tumors. Parathyroid adenomas reported after radiation exposure are usually hyperfunctioning and are usually detected upon manifestations of primary hyperparathyroidism.¹¹ Patients with radiation-induced hyperparathyroidism are also more likely to have coexistent nodular goiter and thyroid gland carcinoma than patients with spontaneous hyperparathyroidism.¹²

Differential Diagnoses

Sarcoidosis

Other Problems to Be Considered

Adverse drug reaction to lithium
Adverse reaction to parenteral nutrition
Adverse drug reaction to thiazide diuretics
Cancers producing parathyroid hormone–related protein
Cancers producing ectopic production of 1,25-dihydroxyvitamin D
Familial hypocalciuric hypercalcemia
Berylliosis
Histoplasmosis
Coccidioidomycosis
Immobilization
Leprosy
Lytic bone metastasis
Milk-alkali syndrome
Multiple endocrine neoplasms
Pheochromocytoma
Vasoactive intestinal polypeptide hormone–producing tumor
Ectopic hyperparathyroidism
Exogenous calcium intake
Sarcoidosis

Workup

Laboratory Studies

• Elevated parathyroid hormone (PTH) levels in the setting of hypercalcemia establish the diagnosis of hyperparathyroidism. The most common other 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, thus, this correction is of particular importance.
• The normal range for the PTH-intact assay is generally 10-65 pg/mL.
• A decreased serum phosphate level of less than 2.5 mg/dL (0.81 mmol/L) may be seen.
• Increased bone turnover may be reflected in elevated levels of markers of bone formation (alkaline phosphatase) and bone resorption (urinary pyridinoline), though these tests are not likely of diagnostic value.
• Urinary calcium excretion may be elevated.
• A newly introduced immunoradiometric assay for PTH detects only the fully intact molecule and, as such, may be more accurate than the most commonly used assay that measures truncated, nonfunctional molecules along with the full-length molecule. This may be of benefit in cases of diagnostic uncertainty.
• 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.¹³  The commercially available rapid PTH assay provides an accurate PTH level that can be used intraoperatively to determine quantitatively 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%¹⁴ and has decreased the need for performing frozen sections.¹⁵

Imaging Studies

Positive imaging studies are not useful for the confirmation of a diagnosis of primary hyperparathyroidism. Moreover, negative imaging study results do not exclude the diagnosis of primary hyperthyroidism. All imaging parathyroid imaging studies demonstrate both false-positive and false-negative findings that can be misleading. Therefore, all patients being evaluated for preoperative parathyroid imaging studies should have a biochemically confirmed diagnosis of primary hyperparathyroidism.⁶

Preoperative imaging in the setting of primary hyperparathyroidism 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 primary hyperparathyroidism include technetium-99m (^99m Tc) sestamibi imaging, ultrasonography, CT scanning, and MRI.⁶

• Ultrasonography and^99m Tc sestamibi scanning have the advantages of being widely available and relatively inexpensive compared with other noninvasive modalities. 
  • The most sensitive and reliable technique is^99m 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.¹⁶
  • In sestamibi scanning, the dual isotope technique in which an I-123NaI or^99m Tc sestamibi image of the thyroid is subtracted from a^99m Tc sestamibi image is commonly used.¹⁷
  • 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 best ultrasonography results reveal parathyroid tissue in one of the normal cervical locations adjacent to the thyroid gland.¹⁷
  • Ultrasonography may be useful but is also operator-dependent.¹⁶
• 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 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 primary hyperthyroidism, regardless of age.³
• Cystic bone lesions called brown tumors are seen only in patients who are severely affected. 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.

Other Tests

• Several techniques are available for preoperative localization of hypersecreting parathyroid glands.

Procedures

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

Treatment

Prehospital Care

Only in the most severe acute manifestation of hyperparathyroidism, hypercalcemia-induced altered mental status, 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.¹⁸ 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 is 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.¹⁸
• 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.¹⁸ 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.
• Surgery that involves open surgical excision with frozen section diagnosis 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,¹⁹ bone mineral density in the femoral neck rises by 6% after 1 year and rises by 14% after 10 years.¹⁶
• 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 hyperparathyroid disease meet the following criteria:²⁰
  • 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 greater 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.¹⁶ 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/kgxday), and the absence of osteoporosis by bone density T-score.⁹
• 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.¹⁶

Consultations

Surgical consultation is necessary for patients with severe hypercalcemia due to hyperparathyroidism who meet current National Institute of Health guidelines for curative surgical intervention. 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 only approximately 1.5%.¹⁶

• 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.¹⁶
• 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; thus, 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.¹⁶
• 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.

Medication

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

Bisphosphonate and hormone replacement therapy provide skeletal protection in patients with primary hyperparathyroidism. 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 primary hyperparathyroidism is comparable to that which occurs after surgical correction of primary hyperparathyroidism.¹⁰ Of the two agents, bisphosphonates are preferred because of the adverse nonskeletal effects of long-term hormone replacement therapy.

The calcimimetic cinacalcet reduces both serum calcium and parathyroid hormone (PTH) levels and raises serum phosphorus. Cinacalcet does not, however, reduce bone turnover or improve BMD. 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.¹⁰

Cinacalcet, a calcimimetic drug that reduces PTH secretion by altering the function of parathyroid calcium-sensing receptors, can be initiated in patients with hypercalcemia secondary to parathyroid carcinoma, secondary hyperparathyroidism, and primary hyperparathyroidism. 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

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.

Dosing

Adult

40 mg PO bid for patients already taking furosemide; give PO dose as IV bolus

Pediatric

1 mg/kg PO/IV as single dose

Interactions

Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently

Contraindications

Documented hypersensitivity; hepatic coma; anuria; state of severe electrolyte depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Observe for blood dyscrasias and liver or kidney damage; perform frequent serum electrolyte, carbon dioxide, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Hormonal therapy

Hormone therapy is indicated in postmenopausal females with hyperparathyroidism.

Estrogen (Premarin)

Reduces bone resorption resulting from hyperparathyroidism.

Dosing

Adult

1.25 mg PO qd

Pediatric

Administer as in adults

Interactions

May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; pharmacologic and toxicologic effects of corticosteroids may occur as a result of estrogen-induced inactivation of hepatic cytochrome P-450 enzyme; loss of seizure control has been noted when administered concurrently with hydantoins

Contraindications

Documented hypersensitivity; known or suspected pregnancy; breast cancer, undiagnosed abnormal genital bleeding, active thrombophlebitis, or thromboembolic disorders; history of thrombophlebitis, thrombosis, or thromboembolic disorders associated with previous estrogen use (except when used in treatment of breast or prostatic malignancy)

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

Certain patients may have undesirable manifestations of excessive estrogenic stimulation (eg, abnormal or excessive uterine bleeding, mastodynia); may cause some degree of fluid retention (exercise caution); prolonged unopposed therapy may increase risk of endometrial hyperplasia

Calcimimetic agents

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. Cinacalcet has been shown to significantly lower PTH and calcium levels in patients on dialysis with secondary hyperparathyroid disease ranging from mild to severe.⁴

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.

Dosing

Adult

Cinacalcet is available in 30 mg, 60 mg, and 90 mg tablets, and the maximum dose is 180 mg. Initial dosing of cinacalcet is 30 mg PO qd initially; titrate q2-4wk as needed to normalize calcium levels by sequential doses of 30 mg bid, 60 mg bid, 90 mg bid, and 90 mg tid/qid
Take with meals or immediately following; do not crush, chew, or cut tablets

Pediatric

Not established

Interactions

Strong CYP450 2D6 inhibitor; may increase serum levels of CYP 2D6 substrates (eg, flecainide, vinblastine, thioridazine, tricyclic antidepressants); coadministration with CYP450 3A4 inhibitors (eg, ketoconazole, erythromycin, itraconazole) may decrease cinacalcet clearance

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Serum calcium reduction may cause lowered seizure threshold, paresthesia, myalgia, cramping, and tetany; monitor calcium and phosphorus levels closely within 1 wk following initial dose or dose changes, and then monthly (secondary hyperparathyroidism) and q2mo (parathyroid carcinoma); do not initiate treatment if serum calcium level is below 8.4 mg/dL; adynamic bone disease may occur if iPTH levels suppressed below 100 pg/mL; caution with hepatic impairment; common adverse effects include nausea and vomiting. Taking cinacalcet with meals enhances bioavailability by 50% to 80% and improves GI tolerance. The best time for patients on hemodialysis to take the drug is with the first meal following their dialysis treatment.

Bisphosphonate Derivative

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.¹⁰

Alendronate

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.

Dosing

Adult

Not established; usual starting dose is 10 mg PO qam

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; hypocalcemia, abnormalities of the esophagus, inability to stand upright for 30 min

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Must be taken at least 30 min before first food, beverage or medication of the day and should be taken with large amounts of water; caution in renal impairment

Follow-up

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.

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.

Deterrence/Prevention

• 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.

Complications

• 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 (eg, pathologic fracture) may occur.
• Heart failure may occur.
• Surgical complications include the following:
  • Hypoparathyroidism
  • Recurrent laryngeal nerve damage
  • Hemorrhage
  • Infection
  • Unsuccessful surgery
    • Persistent or recurrent disease occurs in 5-10% of individuals who undergo surgery for primary hyperparathyroidism.¹⁷  
    • 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.¹⁷

Prognosis

• 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.
• Secondary hyperparathyroidism is associated with a poor prognosis likely due to underlying advanced chronic renal failure and resultant chronic hypocalcemia.

Patient Education

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

Miscellaneous

Medicolegal Pitfalls

• Failure to address or arrange follow-up for asymptomatic patients who have mild-to-moderate elevations of calcium levels
• Failure to treat significantly elevated calcium levels, especially in symptomatic patients

References

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Keywords

hyperparathyroidism, hypercalcemia, calcium levels, hyperparathyroidism symptoms, hyperparathyroidism treatment, parathyroid hormone, parathyroid glands, phosphorus levels

Contributor Information and Disclosures

Author

Philip N Salen, MD, Clinical Professor, Department of Emergency Medicine, PA Program, Desales University; Adjunct Clinical Associate Professor, Department of Emergency Medicine, Temple University Medical School; Research Director, Emergency Medicine Education, Saint Luke's Hospital
Philip N Salen, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Medical Editor

Erik D Schraga, MD, Consulting Staff, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates; Consulting Staff, Permanente Medical Group, Kaiser Permanente, Santa Clara Medical Center
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Jeffrey L Arnold, MD, FACEP, Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center
Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Erik D Schraga, MD, Consulting Staff, Department of Emergency Medicine, Mills-Peninsula Emergency Medical Associates; Consulting Staff, Permanente Medical Group, Kaiser Permanente, Santa Clara Medical Center
Disclosure: Nothing to disclose.

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