Continuing Education Activity

Primary hyperparathyroidism is a relatively common disorder that can cause significant renal and skeletal complications. Surgery remains the definitive treatment. However, alternative therapies may be appropriate for select patients. Basic knowledge of normal calcium homeostasis is essential in diagnosing and managing patients with hyperparathyroidism. A basic understanding of normal calcium homeostasis as well as the natural history of primary hyperparathyroidism is essential in diagnosing and properly managing patients with this disorder. This activity reviews the evaluation and management of primary hyperparathyroidism and highlights the role of the interprofessional team in the management of patients with this disorder.

Objectives:

• Identify the etiology of primary hyperparathyroidism.
• Describe the presentation of a patient with primary hyperparathyroidism.
• Review the management options available for primary hyperparathyroidism.
• Outline interprofessional team strategies to improve care coordination and communication to advance the diagnosis of primary hyperparathyroidism and improve patient outcomes.

Introduction

Primary hyperparathyroidism is a relatively common endocrine disorder that can cause hypercalcemia with significant renal and skeletal complications over time, although most patients identified in recent decades have relatively mild degrees of serum calcium elevations. Once known for the aphorism as a disease of "stones, bones, groans, and moans," as suggested by Fuller Albright, it is now usually asymptomatic when initially diagnosed.[1] (Stones refers to nephrolithiasis caused by hypercalciuria from the hyperparathyroid-induced hypercalcemia. Groaning refers to abdominal pain from the ileus often produced by hypercalcemia and/or bone pain, which can directly or indirectly result from abnormal remodeling, fractures, or osteoporosis. Depression (psychological moans) can also be a side effect of persistent hypercalcemia. Some degree of depression, anxiety, fatigue, cognitive dysfunction, memory loss, and similar psychological symptomatology is found in 23% of severe hyperparathyroid patients.[2] 

Historically, the diagnosis of primary hyperparathyroidism was made by the radiological findings of osteitis fibrosa cystica (brown tumors on long bones, evidence of subperiosteal bone resorption, "salt and pepper" radiographic erosions of the skull bones, and tapering of the distal portions of the finger bones and clavicles). While radiological evidence of hyperparathyroid bone disease is now rare at <2% of cases, bone densitometry can detect skeletal abnormalities well before they become clinically apparent.[3]

Primary hyperparathyroidism involves the excess production of parathyroid hormone (PTH) by one or more of the four pea-sized parathyroid glands normally located peripherally along the margins on the posterior aspect of the thyroid gland. Surgery remains the definitive, curative treatment but observation alone or medical therapy is appropriate for selected patients.[4][5][6][7] While normally associated with hypercalcemia, another type of primary hyperparathyroidism (normocalcemic) has recently been described and may comprise 15% of all primary hyperparathyroidism patients.[8][9] (This normocalcemic variant is more fully reviewed in our companion article on normocalcemic hyperparathyroidism.)[10] A basic understanding of normal calcium homeostasis and the natural history of primary hyperparathyroidism is essential in diagnosing and properly managing patients with this disorder.

Etiology

Primary hyperparathyroidism is a disorder resulting in excessive, uncontrolled production of parathyroid hormone. It is the third most common endocrine disorder (after diabetes and thyroid disorders). Eighty percent of patients will present with a single adenoma, about fifteen percent will have hyperplasia of all four glands, 2%-4% will have multiple adenomas, and less than 1 percent will have a malignancy.[11][12][13][14] The majority of these adenomas will be located in one of the two inferior parathyroid gland locations, but they may also appear ectopically in up to 10% of cases.[15] Potential ectopic locations include the thymus, thyroid, pericardium, behind the esophagus, or in the superior mediastinum.[15][16] Unusual locations to find ectopic parathyroid glands would be in the pharynx, the lateral neck region, the esophagus, or the retro-esophageal space.[15][16][17][18]

Rarely primary hyperparathyroidism will be associated with a heritable familial germline mutation syndrome such as multiple endocrine neoplasia type 1. In such cases, primary hyperparathyroidism is often the initial clinically identified abnormality and will be found in over 90% of these patients, usually between 20 and 25 years.[19] This amounts to about 3% of all primary hyperparathyroidism cases and will almost always appear before age 50.[20] It is usually asymptomatic, which can frequently delay the diagnosis, which is ultimately made by the finding of unexplained hypercalcemia on routine blood testing.[19] The definitive diagnosis is then made by genetic testing. Involvement of multiple glands is typical in all hereditary hyperparathyroid conditions, including multiple endocrine neoplasia type 1, type 2A, type 4, and familial isolated hyperparathyroidism.[19]

Parathyroid carcinoma is relatively rare, constituting <1% of all cases of hyperparathyroidism.[21] Compared to non-malignant hyperparathyroid patients, those with parathyroid carcinomas tend to be younger, have more extreme parathyroid hormone and calcium levels, and the cancer tends to be relatively aggressive.[21] It is potentially life-threatening, usually due to severe and intractable hypercalcemia rather than direct malignant tissue invasion.[21] While rare, the incidence is increasing in both the US and China.[22]

Summary:

PTH-dependent Causes of Hypercalcemia

• Primary Hyperparathyroidism

  • Single adenoma

  • Multigland disease

    • Familial causes of hyperparathyroidism

      • Multiple endocrine neoplasia Type 1

      • Multiple endocrine neoplasia Type 2a

      • Familial hyperparathyroidism (chief cell parathyroid hyperplasia)

      • Hyperparathyroidism-jaw tumor syndrome

  • Parathyroid carcinoma

  • Parathyromatosis

• Familial hypocalciuric hypercalcemia, autosomal dominant inactivating mutations of the calcium-sensing receptor

• Treatment with lithium (may also increase calcium reabsorption in the loop of Henle as well as disrupt calcium feedback mechanisms within parathyroid cells that would typically suppress PTH production

PTH Independent Causes of Hypercalcemia

• Malignancy

• Granulomatous diseases

• Hyperthyroidism

• Thiazide therapy

• Vitamin D intoxication

• Milk-alkali syndrome

• Adrenal insufficiency

• Vitamin A intoxication

Epidemiology

Primary hyperparathyroidism is the most common identifiable cause of hypercalcemia and is typically found most frequently in postmenopausal women.[23] The male to female ratio is approximately 3-4:1.[23] The peak age group is between 50 and 60 years.

Risk factors associated with hyperparathyroidism include specific germline and somatic mutations, chronically low dietary calcium, obesity, prolonged use of furosemide, history of neck radiation therapy, lithium therapy, hypertension, and physical inactivity.[24][25][26][27][28][29] Thiazides formerly were included in this list, but recent reviews have suggested that thiazides are more likely to unmask an underlying parathyroid problem than to cause it. Persistent hypercalcemia after thiazide therapy has stopped would be suggestive of hyperparathyroidism.[30]

Once considered a relatively rare disease associated with significant morbidity, primary hyperparathyroidism is now considered a relatively common endocrine disorder, often asymptomatic. Prior to 1970, the diagnosis went unsuspected until patients presented with specific symptoms, typically nephrolithiasis or bone pain. Since then, most patients are diagnosed with hyperparathyroidism when serum calcium is incidentally discovered to be elevated on a chemistry profile ordered as screening tests or for an unrelated problem. The current incidence in the United States has been estimated at a mean of 66 per 100,000 person-years in women and from 13 to 36 per 100,000 person-years in men.[31] It has also been estimated that 0.2% of all patients are over 60 years of age. 

Primary hyperparathyroidism is typically asymptomatic in most Western countries, where biochemical blood screening is commonly performed. In those global regions where vitamin D deficiency is widespread and biochemical screening is not a common or routine part of the healthcare system, symptomatic disease with skeletal abnormalities and nephrolithiasis are the more likely presentations.[23][32] India has a relatively low rate of primary hyperparathyroidism compared to the US, Canada, and Western Europe. China and Latin America have increased their routine serum biochemical testing, which is now associated with a rising incidence in the diagnosis of primary hyperparathyroidism.[33][34][35]

Parathyroid cancer is quite rare as it constitutes less than 0.5% of all cases of primary hyperparathyroidism. Higher serum calcium levels and parathyroid hormone are commonly seen compared to benign primary hyperparathyroidism.[36] There is no clear risk factor that has been identified except for hereditary syndromes such as familial isolated hyperparathyroidism and MEN1.[37][38][39][40] There is an association with hyperparathyroidism-jaw tumor syndrome (a rare, hereditary, autosomal disorder) where up to 15% will develop parathyroid carcinomas.[37][41] There may also be an association with various kidney lesions such as Wilms tumors, hamartomas, and polycystic renal disease.[42] 

Pathophysiology

Parathyroid Hormone

The function of parathyroid hormone is to increase serum calcium levels as part of the calcium homeostasis mechanism. To accomplish this, it performs three principal activities. First, it increases the rate of bone resorption, which releases calcium and phosphate into the serum. Secondly, it decreases urinary calcium excretion by increasing its reabsorption in the distal convoluted renal tubule and thick, ascending loop of Henle. Finally, it activates 1-α-hydroxylase in the renal proximal tubule, which converts relatively inactive 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D. This active vitamin D then increases gastrointestinal absorption of calcium and phosphate.[43] All three of these actions taken together have the net effect of increasing serum calcium levels.[43] (Calcitonin, which is produced by the parafollicular (C-cells) in the thyroid gland, is a hormone that has the opposite effect of parathyroid hormone. It lowers serum calcium by decreasing the bone resorption rate and reducing calcium reabsorption by the kidneys.)

Parathyroid hormone also increases urinary phosphate excretion, which explains why patients with hyperparathyroidism are hypophosphatemic despite increased gastrointestinal phosphate absorption and higher bone resorption rates.[44] However, patients with renal failure lose the ability to excrete phosphate in the urine, developing hyperphosphatemia. In these cases, hyperparathyroidism makes hyperphosphatemia worse primarily by increasing the rate of bone resorption, which releases phosphate as well as calcium which is stimulated by the excess parathyroid hormone without any compensatory increase in renal phosphate excretion.[44][45] The finding of hypercalcemia with hypophosphatemia is highly suggestive of hyperparathyroidism.[44][45] Hyperparathyroidism is associated with hypercalciuria when the hypercalcemia produced exceeds the maximum renal calcium reabsorption threshold. The kidneys then excrete excess calcium despite the usual parathyroid hormone effect of reducing it.

Parathyroid glands are made up of two cell types:[46]

• Chief cells are the most common and produce parathyroid hormone. They have a very prominent Golgi apparatus and a very developed endoplasmic reticulum.
• Oxyphil cells are larger, but their exact function is unclear. It is thought they may have additional endocrine functions or may be supportive of chief cell activity. 

Secretion of parathyroid hormone is inversely related to the ionized calcium concentration in the extracellular fluid. The calcium-sensing receptor (CaSR) is a G-protein coupled receptor whose activity varies with changes in serum calcium. As the calcium concentration in the extracellular fluid increases, this receptor is activated, and parathyroid chief cells decrease their production and secretion of parathyroid hormone. Conversely, the activity of the CaSR decreases, and parathyroid hormone secretion increases as serum calcium levels decline.

Parathyroid hormone activates PTH receptors increasing the resorption of calcium and phosphate from bone, enhancing the distal tubular reabsorption of calcium, and decreasing the renal tubular reabsorption of phosphorus which increases urinary phosphate excretion. Furthermore, parathyroid hormone plays an essential role in vitamin D metabolism, activating the vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihydroxyvitamin D.[43]

Renal failure elevates serum parathyroid hormone levels. This becomes clinically significant as the glomerular filtration rate falls below 30 ml/min.[47] Some parathyroid assays will tend to falsely elevate PTH concentrations in renal failure.[48][49] There is reduced parathyroid clearance in chronic renal failure, so levels tend to rise. The failing kidneys are unable to maintain 1,25-dihydroxyvitamin D levels, which reduce intestinal calcium absorption, lower serum calcium, and ultimately stimulate parathyroid hormone production.[50][51] Low vitamin D levels can also directly increase parathyroid hormone production.[52] Chronic parathyroid overstimulation results in diffuse, multiglandular parathyroid hyperplasia and the development of monoclonal nodules, which are particularly resistant to vitamin D and calcimimetic medications.[51][53][54] 

Hyperphosphatemia develops due to the inability of the kidneys to excrete phosphate (while hypophosphatemia is seen in classic primary hyperparathyroidism). Band keratopathy, from corneal calcium phosphate crystal deposition, has been reported in dialysis patients but is rarely visible without a slit lamp examination; even then, it is quite uncommon.[55] 

Treatment includes a low phosphorus diet, oral phosphate binders, vitamin D supplements, calcimimetic agents, parathyroid surgery (total parathyroidectomy with or without auto-transplantation, and subtotal parathyroidectomy).[51][56][57][58] Successful parathyroid surgery in chronic renal failure patients significantly improves symptoms such as arthralgias, muscle weakness, psychological disorders, and bone pain.[57][58][59] Surgery can also improve bone mineral density, reduce major cardiovascular events, correct anemia, boost the immune system, and increase overall long-term survival by 10% to 15%.[51][60][61][62][63] 

Normal Calcium Homeostasis

Under physiologic circumstances, calcium concentration in the extracellular fluid is maintained within a very narrow range. Normal calcium homeostasis is dependent upon a complex set of hormonal regulatory mechanisms that include the effects of parathyroid hormone, vitamin D metabolites, and calcitonin on calcium transport in the bones, kidney, and gastrointestinal tract.[43][64]

Only about ten to twenty percent of ingested calcium is ultimately absorbed in the small intestine; the rest is excreted untouched.[65] PTH production is normally minimal at serum calcium levels above 10 mg/dL and maximal when the level drops to 7.5mg/dL or less.

Approximately 50% of total serum calcium is protein-bound, principally to albumin. Forty-five percent is ionized, while a small proportion forms complexes with anions such as phosphate and citrate. Only the ionized calcium is biologically active, yet most laboratories routinely report total serum calcium levels. Measurements of ionized calcium are available when requested. An approximate correction of serum calcium can be made by adjusting for differences in the serum albumin level.

Corrected calcium = Measured calcium + 0.8 x (4.0 - albumin).

Caution is necessary when evaluating normal total serum calcium levels in patients with hypoalbuminemia. Such patients may have elevated ionized calcium levels and are truly hypercalcemic. Conversely, the ionized calcium is often normal when there is a low total calcium concentration in the presence of hypoalbuminemia. 

Histopathology

Parathyroid adenomas tend to be encapsulated and are typically composed mostly of chief cells. Adenomas of oxyphilic cells are rare but have been reported in a few cases of primary hyperparathyroidism.[66]

Newer non-invasive imaging technologies suggest that the effects of hyperparathyroid hormone excess on skeletal bone may be more significant than previously thought. Trabecular bone score (TBS) is an indirect analysis of trabecular microstructure taken from the DEXA scan. TBS demonstrates the deterioration of the trabecular spinal microstructure in patients with primary hyperparathyroidism, although this appears normal on the DXA scan.[67] 

High-resolution peripheral quantitative CT scans of the distal radius and tibia show fewer, thinner, and more widely spaced trabeculae in primary hyperparathyroidism patients.[68][69][70] Trabecular microstructural defects may account for the relatively high number of vertebral fractures in primary hyperparathyroid patients despite apparently preserved bone mineral density in the lumbar spine.[71][72][73] Recent data suggest that these fractures may sometimes be asymptomatic.[74] Interestingly, the risk for hip fractures does not increase in hyperparathyroid patients.[75]

History and Physical

In past decades most patients were diagnosed when they had complaints of nephrolithiasis, bone pain, fractures, muscle weakness, or bone deformities. Of these, the most common clinical symptoms are nephrolithiasis, nephrocalcinosis, and muscle weakness. Most patients with primary hyperparathyroidism are asymptomatic, diagnosed when hypercalcemia is incidentally discovered on a chemistry profile.[76] Patients should be asked about any history of kidney stones, bone pain, myalgias or muscle weakness, symptoms of depression, use of thiazide diuretics, calcium products ingestion, vitamin D supplements, or other symptoms associated with the multiple etiologies of hypercalcemia.[23] 

A familial syndrome should be considered when primary hyperparathyroidism is diagnosed at an early age or there is a family history of hypercalcemia, pituitary adenomas, pancreatic islet cell tumors, pheochromocytomas, or medullary thyroid cancer.[77] Multiple endocrine neoplasia type 1 (MEN 1) is a germline mutation involving menin, a tumor-suppressor protein. The first clinical sign of MEN 1 is usually primary hyperparathyroidism which typically appears at an early age (typically 20 to 25 years) and will be seen in over 90% of affected patients. Primary hyperparathyroidism in MEN 1 individuals usually affects all the parathyroid glands and is typically asymptomatic. Surgery is the recommended treatment.[19]

When the serum calcium level exceeds 12 mg/dL, patients are likely to start noticing symptoms associated with hypercalcemia such as anorexia, cardiac arrhythmias, altered mental states, constipation, dehydration, polyuria, and polydipsia.[4] 

While most primary hyperparathyroidism patients are asymptomatic, up to 55% will actually have previously undiagnosed nephrocalcinosis or non-obstructing renal calculi, and up to 75% of the symptomatic patients will present with acute renal colic and/or nephrolithiasis.[78][79][80] This is why a routine check of serum calcium should be done for all patients with calcium nephrolithiasis. About 40% of patients with primary hyperparathyroidism will also have hypercalciuria.[81]

Patients with hypercalcemia should be tested for hyperparathyroidism. For those hyperparathyroid patients who undergo surgery, their increased risk of nephrolithiasis persists for ten years after their parathyroidectomy.[82] Aside from hyperparathyroidism in some form, virtually all other causes of hypercalcemia are associated with a low or suppressed parathyroid hormone level.

Besides kidney stones, other potential symptoms of hypercalcemia and hyperparathyroidism include: 

• Weak bones that break easily (osteoporosis)
• Bone pain
• Nephrocalcinosis
• Excessive urination
• Stomach (abdominal) pain
• Tiring easily, chronic fatigue
• Muscle weakness
• Depression, memory loss, or forgetfulness
• Trouble concentrating
• Difficulty sleeping
• Joint pain
• Loss of appetite
• Body aches
• Headaches
• Hypertension
• Cardiac arrhythmias
• Left ventricular hypertrophy
• Decreased coronary artery flow reserve
• Aortic valve calcification
• Increased overall cardiovascular disease
• Renal Failure
• Frequent complaints of illness with no apparent cause

The physical examination of a patient with primary hyperparathyroidism is usually normal. However, the physical examination can help find abnormalities that could suggest other etiologies of hypercalcemia.

Parathyroid adenomas are rarely palpable on physical examination, but the presence of a large, firm mass in the neck of a patient with hypercalcemia should raise suspicion of a possible parathyroid carcinoma.[83]

Evaluation

The finding of hypercalcemia together with hypophosphatemia is highly suggestive of hyperparathyroidism.[84] However, the definitive test for primary hyperparathyroidism is the finding of hypercalcemia (ionized calcium or corrected serum calcium) together with an elevated parathyroid hormone level. (Virtually all other causes of hypercalcemia will demonstrate low parathyroid hormone levels.) In borderline cases with low vitamin D levels, it has been suggested that the 25-hydroxyvitamin D level be raised to at least 30 ng/mL for at least three months to help rule out vitamin D deficiency.

Patients with primary hyperparathyroidism and other causes of PTH-dependent hypercalcemia often have frankly elevated levels of PTH, while some will have values that fall within the reference range for the general population. A normal PTH in the presence of significant hypercalcemia is considered inappropriate and still consistent with PTH-dependent hypercalcemia.[10] If persistent, it might indicate normocalcemic hyperparathyroidism (see below).[10] Parathyroid hormone levels should normally be very low in patients with PTH-independent hypercalcemia.[23][85] Parathyroid hormone levels typically increase with age. In populations with a high incidence of vitamin D deficiency, the "normal" parathyroid hormone levels tend to be higher.[86][87]

Patients on known hypercalcemic drugs, such as lithium and thiazide, should have these medications stopped for 3 to 6 months, if possible, and their serum calcium & parathyroid hormone levels retested. Patients with low vitamin D levels should receive supplements to maintain at least 30 mg/mL. If parathyroid hormone levels are still elevated, this suggests hyperparathyroidism. Familial hypocalciuric hypercalcemia can be excluded by a 24-hour urine calcium determination (<100 mg calcium/24  hours) or by a low calcium/creatinine excretion ratio [(urinary calcium x serum creatinine) / (serum calcium x urinary creatinine)] typically <0.02.[88] It may present as early as age 30 and virtually never after age 50.[88][89] 

Biotin (also known as vitamin B-7) is a nutritional supplement that helps produce energy from food. It is significant here because biotin supplementation can interfere with parathyroid hormone assays.[84] The biotin should be discontinued and the PTH level retested in such cases.

Recommended serum intact parathyroid tests include immunochemiluminometric or immunoradiometric assays, which readily discriminate between primary hyperparathyroidism and malignancy-related hypercalcemia. (Parathyroid hormone-related protein, which causes malignancy-related hypercalcemia, does not react with parathyroid hormone assays.)

A comprehensive clinical evaluation complemented by routine laboratory and radiologic studies should be sufficient to establish a diagnosis of primary hyperparathyroidism in a patient with persistent hypercalcemia and a concomitant elevated serum level of parathyroid hormone. It is uncommon for clinically occult malignancies to cause hypercalcemia. Most patients with malignancy-associated hypercalcemia are known to have cancer, or their cancer is readily detectable on initial evaluation, and PTH levels will be suppressed.[90]

A review of previous medical records can often be of significant value in establishing the cause of hypercalcemia. Most patients with hyperparathyroidism have persistent or intermittent hypercalcemia for many years before a definitive diagnosis is established. Very few diseases, other than hyperparathyroidism, will allow a healthy-appearing individual to be hypercalcemic for more than a few years without any clinical signs or symptoms. 

List of tests for primary hyperparathyroidism: 

• Total serum calcium

• Calculation of the "corrected" serum calcium; approximately 50% of total serum calcium is protein-bound, principally to albumin, and only the free or ionized fraction is biologically active. Corrected calcium = Measured calcium + 0.8 x (4.0 - albumin) (calcium measured in mg/dL; albumin measured in g/dL)

• Ionized calcium in selected cases when there are questions about the accuracy of the corrected calcium

• Parathyroid hormone

• Phosphate (hypercalcemia with hypophosphatemia is highly suggestive of hyperparathyroidism)

• BUN and creatinine

• Alkaline phosphatase and osteocalcin (usually elevated)

• Sclerostin (a bone formation regulator) is usually suppressed in primary hyperparathyroidism

• 25-hydroxyvitamin D

• Serum albumin

• Urine calcium and creatinine

• Imaging to screen for renal calcifications or urolithiasis (KUB, renal ultrasound, or non-contrast CT scan)

• Bone densitometry (DEXA) scans, including measurement at the distal 1/3 radius (which is preferentially affected in hyperparathyroid patients)

• Localization studies for potential surgical patients (see below)

• EKG

• Genetic testing in selected individuals if there is suspicion of a genetic syndrome[91]

• The need for other studies such as PTHrP levels, serum or urine protein electrophoresis, 1,25-dihydroxyvitamin D levels, thyroid tests, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia.

Parathyroid Localization (Imaging) Studies[92]

Neck ultrasonography and parathyroid nuclear medicine (Tc-Sestamibi) scans are standard imaging tests for the localization of hyperfunctioning parathyroid glands. Neck ultrasonography is highly operator-dependent but can be very successful in centers with experience and expertise.[93] Tc-Sestamibi scans are generally considered the most sensitive and specific standard imaging test.[94] These tests are not considered definitively diagnostic because there can be false-negative results, and they are generally less useful in multiglandular parathyroid disease.[95] They should generally not be ordered unless there are plans for surgery. They are most useful when they can assist the surgeon as a "roadmap" in localizing an enlarged, hyperfunctioning parathyroid gland, particularly when an ectopic gland is suspected. The sensitivity of parathyroid imaging scans can be enhanced when combined with single-photon emission computed tomography (SPECT).[96] 

Parathyroid four-dimensional multiphase (4D) CT should be considered when surgery is planned, particularly when the abnormal parathyroid glands cannot be localized with Sestamibi scans or neck ultrasound imaging.[96][97] 4D CT also appears to be superior to Sestamibi SPECT/CT.[98] It is an emerging method of localization of parathyroid adenomas for pre-surgical planning, although implementation, instrumentation, and correct interpretation are still somewhat challenging.[97][99]

F-18-Fluorocholine positron emission tomography/CT (F-18-choline PET/CT) has shown promising results in parathyroid adenoma localization in difficult or equivocal cases, suggesting superiority over Sestamibi scanning, ultrasound, or CT scans alone.[100]

When non-invasive preoperative localization studies (ultrasound, Tc-Sestamibi single-photon emission computed tomography (SPECT), and 4D CT imaging) are negative, selective parathyroid venous sampling can help identify the anatomical location of abnormal hyper-functioning parathyroid glands.[101][102]

The need for other studies such as PTHrP levels, serum or urine protein electrophoresis, 1,25-dihydroxyvitamin D levels, thyroid tests, bone scans, fine needle parathyroid aspiration, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia. DEXA scans will typically show a loss of bone density, particularly in the distal third of the radius, although any pattern may be present.[103][104] This is different from the typical bone density loss associated with a post-menopausal state that preferentially affects the lumbar spine.[103][105][106] It is usually performed in patients who have had unsuccessful parathyroid surgery, and all other localization methods have been unsuccessful.[107]

Specific Hyperparathyroid and Hypercalcemic Disorders

Acute primary hyperparathyroidism (parathyroid crisis, parathyroid storm) is a rare condition in which there is a sudden episode of potentially life-threatening hypercalcemia in a patient with known primary hyperparathyroidism. Laboratory studies indicate very high serum calcium levels, >14 mg/dL,  with parathyroid hormone readings up to twenty times normal.[108][109] It is sometimes associated with parathyroid cancers.[110] Treatment is directed at severe hypercalcemia with aggressive medical therapy, and surgical excision is curative.[108][109][110][111] Serum calcium levels >15 mg/dL can be immediately life-threatening, leading to coma and death. They should be treated as medical emergencies. 

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant inherited disorder that is sometimes easily confused with primary hyperparathyroidism. It is characterized by hypercalcemia, hypocalciuria, and high-normal to mildly increased parathyroid hormone secretion.[88][112] Familial hypocalciuric hypercalcemia is caused by a mutation in the calcium-sensing receptor of the chief cells of the parathyroid gland. Histologically, the parathyroid glands appear normal. There is usually a known family history of the disorder. There are no clinical symptoms, and it requires no treatment. The diagnosis is usually made by history or the calcium/creatinine excretion ratio, although 24-hour urine testing showing severe hypocalciuria of <100 mg/24 hours is highly suggestive. The calcium/creatinine excretion ratio [(urinary calcium x serum creatinine) / (serum calcium x urinary creatinine)] in the urine of patients with familial hypocalciuric hypercalcemia is very low, typically <0.01 in 80% of cases, and FHH is more likely if hypercalcemia is detected before age 40.[88] Other causes of hypocalciuric hypercalcemia should be ruled out (vitamin D deficiency, severely calcium-deficient diet, mild renal failure, use of thiazide or lithium). A calcium infusion test can also help distinguish FHH from primary hyperparathyroidism. A calcium load will increase urinary calcium excretion in primary hyperparathyroidism but not familial hypocalciuric hypercalcemia.[88] A definitive diagnosis can be made in questionable cases by genetic testing.[88] 

Normocalcemic hyperparathyroidism can be primary or secondary and is defined as the presence of persistently elevated parathyroid hormone levels over at least six months despite normal readings of corrected serum calcium or ionized calcium with 25 (OH) levels of 30 ng/ml or more and a GFR of at least 60 mL/min. An increased serum calcium/phosphate ratio is also suggestive of this diagnosis.[10] Evaluation and treatment are similar to primary hyperparathyroidism.[10]

Malignancy-related hypercalcemia can be found in as many as 30% of all cancer patients.[113] (It is usually considered a poor prognostic sign with a median survival of fewer than two months after onset.)[90][114][115] It is particularly common with pulmonary, breast, squamous cell cancers, multiple myeloma, head and neck, ovarian, urothelial, and renal malignancies in the US.[90][116] While previously thought to be due to local invasion and direct bone destruction by malignancy, other factors are now known to be etiology. Bony metastases can locally release cytokines along with osteoclast activating factors, and various tumors can produce 1,25 dihydroxyvitamin D resulting in hypercalcemia. The most common cause of malignancy-related hypercalcemia is the production and secretion of parathyroid hormone-related protein (PTHrP) by the cancer, most often lung and kidney.[117] Parathyroid hormone-related protein results in pathophysiology that is very similar to primary hyperparathyroidism (with hypercalcemia, hypercalciuria, and hypophosphatemia) but with normal or low parathyroid hormone levels, which makes it easy to differentiate the two entities.[90][117] (Ectopic tumoral secretion of parathyroid hormone (PTH) and parathyroid cancer can also cause hypercalcemia, but they are quite rare.) 

In the absence of known cancer, physicians should be suspicious of a hidden malignancy, especially in patients with paraneoplastic-like symptoms such as unexplained fatigue, weight loss, skin rashes, or muscle weakness. Bone scans are useful for osteolytic metastases as they are quite sensitive but relatively non-specific. Bone marrow biopsy examinations can be useful in patients with unexplained anemia or abnormal blood smears. Treatment would be directed to the specific malignancy. When this is not possible, the hypercalcemia can be severe and relatively resistant to standard hypercalcemia therapy (hydration with normal saline or increased salt intake, diuresis with furosemide, bisphosphonates, denosumab (rank ligand inhibitors), oral phosphates, calcitonin, glucocorticoids, cinacalcet, and dialysis).[90] (Mithramycin and gallium nitrate are no longer used as bisphosphonates, and rank ligand inhibitors act similarly and have been proven more effective.)[117]

Parathyromatosis has also been reported as an exceedingly rare cause of primary hyperparathyroidism. In this condition, scattered non-malignant but hyperfunctioning islands of parathyroid tissue are found in the superior mediastinum and/or the neck.[118][119] It is thought to be due to seeding at the time of parathyroid surgery, usually for secondary hyperparathyroidism in dialysis patients. It can be a cause of recurrent, persistent, or intractable hyperparathyroidism.[118][120][121] Although there are reports of successful treatment with calcimimetics and bisphosphonates, treatment involves complete surgical excision as complete removal of all hyperfunctioning nodules is often quite challenging.[118][121][122][123] 

Evaluation Summary

• Hyperparathyroidism should be suspected when there are unexplained elevated serum calcium levels.
• Hypercalcemia with hypophosphatemia is also suggestive of primary hyperparathyroidism.
• Patients at risk are more likely to be female and older.
• All potential causes of secondary hyperparathyroidism must be ruled out.
• Familial hypocalcemic hypercalcemia can be differentiated from primary hyperparathyroidism by calcium/creatinine excretion ratio and 24-hour urine testing for calcium excretion.
• Patients with low vitamin D levels may need supplementation and a retest of calcium and PTH levels after three months.
• Primary hyperparathyroidism can be confirmed with an ionized calcium (or a corrected serum calcium) determination together with a parathyroid hormone test. 
• Imaging for possible nephrocalcinosis and nephrolithiasis is recommended.
• A baseline DEXA bone scan is recommended in all patients with confirmed primary hyperparathyroidism, including the lumbar spine, hip, and distal third of the radius.
• Localization studies are not diagnostic; they are unnecessary except for patients considering possible parathyroid surgery.
• A diagnosis of normocalcemic primary hyperparathyroidism requires persistent parathyroid levels with normal serum calcium determinations at least six months apart.
• The treatment of normocalcemic primary hyperparathyroidism is similar to classic primary hyperparathyroidism.

Treatment / Management

Medical Treatment

Surgery remains the definitive treatment for primary hyperparathyroidism, but non-operative surveillance may be the appropriate option for some, particularly for patients who are elderly with mild hypercalcemia and no significant complications. Medical treatment with bisphosphonates and/or cinacalcet can be extremely useful in selected patients. The decision of whether to recommend surgery is based on age, the degree of hypercalcemia, and the presence or absence of complications due to hyperparathyroidism, as well as patient comorbidities and surgical/anesthesia risk.

Patients who are not surgical candidates may benefit from medical management of primary hyperparathyroidism. Calcium intake should not be restricted as this could further stimulate PTH production.[6] There is substantial evidence that chronic vitamin D deficiency is a risk factor for hyperparathyroidism.[124][125] It is recommended that hyperparathyroid patients with deficient vitamin D levels receive supplements starting at 1,000 IU daily.[5][126] 

Long-term outcomes in hyperparathyroid patients who do not undergo surgery are available out to 15 years.[127] They generally show relatively stable chemistries until close to year 15, with a decrease in identifiable bone mineral density starting at about year 8 and becoming more significant after year 10.[23][127] A small number of patients lost more than 10% of the measured bone mineral density after 15 years.[127] Renal function tends to remain stable, but hypercalciuria remains, so there is an increased risk of nephrolithiasis.[127] 

Current guidelines for monitoring hyperparathyroid patients being treated medically now recommend annual serum calcium and creatinine levels.[5] DEXA scans are recommended either annually or bi-annually.[5] Parathyroid hormone levels, creatinine clearance, and 24-hour urine calcium levels are no longer recommended routinely but may be done electively.[5] Limiting dietary calcium intake can increase parathyroid hormone levels, while supplemental calcium can reduce it.[128][129] The consensus opinion among experts is that dietary calcium intake should follow normal nutritional guidelines. Vitamin D should be supplemented if 25-hydroxyvitamin D is less than 30 ng/mL based on studies showing that vitamin D can lower blood parathyroid hormone and improve bone mineral density without significantly increasing serum or urinary calcium levels.[6][126] 

Medical therapy in non-surgical hyperparathyroid patients is designed to treat osteoporosis or hypercalcemia (defined as >1 mg/dL above the normal range) but usually not both. If both entities require treatment, combination therapy is recommended.[130][131]

• Oral phosphates can reduce serum calcium levels up to 1 mg/dL. They reduce intestinal calcium absorption by direct phosphate binding, lower vitamin D levels, and reduce bone resorption.[132][133] Since phosphates can increase PTH levels, they are no longer routinely used in the long-term medical management of primary hyperparathyroidism. 

• Estrogen therapy for postmenopausal women with primary hyperparathyroidism has shown a benefit in increasing bone mineral density, particularly in the lumbar spine, but with no change in serum PTH or calcium.[134][135][136] In view of concerns over long-term, chronic estrogen use, it is not routinely recommended for medical management of primary hyperparathyroidism.[134]

• Oral bisphosphonates and denosumab (a rank ligand inhibitor) are anti-resorptive agents and can increase bone mineral density in hyperparathyroid patients with osteoporosis or osteopenia and help control hypercalcemia.[23][137][138] While they have been effective in restoring bone mineralization, they have relatively little effect on serum calcium and do not significantly affect parathyroid hormone levels.[138][139] However, there are reports of denosumab controlling refractory hypercalcemia in patients with parathyroid malignancy, and intravenous bisphosphonates have successfully treated severe hypercalcemia but are not a feasible long-term therapy.[140][141][142][143][142]

• Agonists to the calcium-sensing receptor, such as cinacalcet, will significantly lower serum PTH and calcium in hyperparathyroid patients but not increase their bone density.[144][145] However, over 70% will normalize their blood calcium levels on these medications.[5][144][145][146][145] Parathyroid hormone levels typically drop by 35% to 50% but may not reach normal levels even after serum calcium is within normal limits.[147][148] Cinacalcet has also been successfully used as bridging therapy in surgical patients whose procedures were postponed due to Covid or other reasons.[149] Cinacalcet is quite effective in patients with otherwise intractable hyperparathyroidism and can normalize serum calcium even in cases of inoperable parathyroid carcinoma.[147][150] Vitamin D and urinary calcium levels do not change significantly. Cinacalcet is also used for treating secondary hyperparathyroidism in patients with end-stage renal failure on dialysis.[151]

• The use of combination therapy with a calcium-sensing receptor medication along with either a bisphosphonate or rank ligand inhibitor is reasonable to control serum calcium and increase bone mineral density, but there are only limited studies on this approach.[130][131][137][123][152]

Surgical Therapy

Surgery is the treatment of choice for those with recurrent kidney stones or decreased bone mineral density.[153][154] Successful parathyroidectomy results in permanent normalization of serum calcium and parathyroid hormone levels as well as a dramatic improvement in bone mineral density at all sites. Following successful parathyroid surgery, bone mineral density, microstructure, and strength improve while patients also enjoy a reduced risk of fractures and kidney stones.[68][155][156][157][158][159] Improvement in bone mineral density in all locations after successful parathyroidectomy is reported as >10%, and this benefit extends out at least 15 years.[127][160] (These benefits were seen in all parathyroidectomy patients regardless of whether or not they met the criteria for surgery.) However, there is no good evidence of any benefit in neurocognitive function or cardiovascular events from surgery.[4][68][161]

Since 1990, several workshops have developed guidelines to assist physicians in managing asymptomatic hyperparathyroidism. Surgical and medical experts, internationally recognized for their experience in managing patients with hyperparathyroidism, reviewed the evidence-based medical literature, and a consensus of their opinions was disseminated to the medical community. The most recent guidelines were published in 2014.[4][5][6][85][162]

The current guidelines recommend surgery for all symptomatic primary hyperparathyroidism patients.[23] It is also recommended for asymptomatic primary hyperparathyroidism when:[5][23]

• Age younger than 50 years

• Serum calcium is more than 1 mg/dL above the upper limit of normal

• Osteoporosis on DEXA scan (T-score <-2.5 at any site)

• History of fractures

• Vertebral compression fracture on imaging

• GFR less than 60 mL/min

• Hypercalciuria with urine calcium greater than 400 mg/24 hours

• Evidence of renal calcifications, nephrocalcinosis, or urinary stones

• Electively for all hyperparathyroid patients, even if they do not meet any of the above criteria and have no medical contraindications.

Surgery should optimally be done by experienced parathyroid surgeons who perform these surgeries frequently and are knowledgeable about preoperative localization. Success rates exceed 95% in such hands.[163][164] [163] 

Preoperative localization studies are recommended in patients undergoing surgery, especially if a minimally invasive technique is being used. Imaging studies are not recommended for diagnosis due to poor sensitivity and specificity, with a false-positive rate as high as 25%.[94] Minimally invasive parathyroidectomy is now the preferred surgery for hyperparathyroidism in most centers.[165] The surgery is directed specifically to the location of the previously identified abnormal parathyroid gland.[165] Rapid PTH assays are highly recommended for this procedure to successfully control parathyroid hormone levels.[166]

The use of intraoperative parathyroid hormone measurements is recommended to verify the efficacy of the surgery. The half-life of parathyroid hormone is only about 4 minutes, so the PTH level should drop by at least 50% from the preoperative level in 10 to 20 minutes after successful excision and should normalize within 30 minutes.[167][168][169] 

Left untreated, many patients with primary hyperparathyroidism have progressive loss of cortical bone while successful surgery leads to a substantial increase in bone mineral density, an effect that can persist for up to 15 years.[4][127]

Radiofrequency ablation of isolated parathyroid adenomas has been successfully reported with minimal complications in small series.[170][171] This may be an acceptable alternative for patients who would not otherwise be surgical candidates.

Nephrolithiasis patients who undergo surgery tend to have fewer stones, but other chemical promoters of kidney stones are possible, so 24-hour urine testing is recommended in such patients after recovery from parathyroid surgery.[154]

For patients where observation is the selected course of action, periodic monitoring of serum and urine calcium levels, renal function, and bone densitometry is required. Blood testing of calcium and parathyroid hormone every six months, as well as annual 24-hour urine measurements and DEXA scans, are suggested.[5][172] If there is worsening hypercalcemia, the development of complications, or PTH-related symptoms, then surgery should be recommended.[5][23]

Hungry Bone Syndrome (Bone Hunger)

Immediately following the surgical correction of primary or secondary hyperparathyroidism, a period of profound, severe, and prolonged hypocalcemia may ensue, which is called hungry bone syndrome or bone hunger. While there is no definitive consensus, most sources will define hungry bone syndrome as persistent low serum calcium of <8.4 mg/dL present for more than four days after definitive parathyroid surgery.[173][174] Hypocalcemia occurs when the rate of skeletal calcium incorporation exceeds osteoclastic bone resorption. The sudden drop in parathyroid hormone levels immediately after surgery results in unopposed osteoblastic activity as serum calcium quickly becomes incorporated into new bone. This is often accompanied by hypophosphatemia, hypomagnesemia, and elevated alkaline phosphatase.[174] While a drop in serum calcium is expected after parathyroid surgery, this usually does not cause prolonged or severe hypocalcemia and typically resolves in no more than four days. When severe hypocalcemia persists for more than four days, this constitutes hungry bone syndrome.[174] Hypocalcemia and hypophosphatemia can persist for months or even years.[174] 

The likelihood of hungry bone syndrome increases as the duration and severity of hyperparathyroidism rise. It is also more commonly seen in older patients with radiographic bony changes, osteitis fibrosa cystica, obesity, a larger volume of parathyroid tissue removed at surgery, preoperative vitamin D deficiency, presurgical elevated alkaline phosphatase levels, and high numbers of osteoclasts on bone biopsy.[174][175] The incidence is highly variable, and there may be a significantly higher prevalence in Asia than in the West.[176] 

Hungry bone syndrome may also occur after correction of secondary hyperparathyroidism, thyrotoxicosis, vitamin D supplementation in calcitriol deficient patients, or treatment of malignant tumors, including prostate cancer, that affect calcium metabolism.[177] It is now more common to see hungry bone syndrome in patients with secondary hyperparathyroidism from renal failure and chronic dialysis than from primary parathyroid disease. In these cases, the severity of the hungry bone syndrome is generally less than after primary hyperparathyroidism surgery.[174] Again, the cause is the rapid incorporation of serum calcium into bone, resulting in hypocalcemia.[178] There is conflicting evidence regarding the benefit of preoperative vitamin D supplementation, but correction of low 25-hydroxyvitamin D levels seems reasonable.[179][180]

Symptoms of severe hypocalcemia would include seizures, paresthesias, numbness, arrhythmias, cardiomyopathy, and laryngospasms. Physical signs would include evidence of recent parathyroid or thyroid surgery or hyperexcitability of nerves as in a prominent Chvostek or Trousseau sign.[173][174][175]

Treatment generally includes high oral doses of supplemental calcium and vitamin D. However, if the serum calcium is below 7.6 mg/dL, if there are symptoms from hypocalcemia, or if there are related EKG changes such as QTc prolongation, intravenous calcium supplementation is indicated (Calcium gluconate is usually preferred over calcium chloride due to easier administration as no central line is needed).[173][174][181] 100 cc of 10% calcium gluconate in a 1,000 cc bag of D5W will deliver about 1 mg/dL of calcium after full infusion.[173] Switching to oral calcium supplements is reasonable when the patient can tolerate them. Calcium citrate is often preferred over calcium carbonate due to better absorption, especially for patients on chronic proton-pump inhibitors. Treatment may need to be continued for up to one year after parathyroidectomy.[173][182] Correction of any magnesium deficiency is also suggested. The use of preoperative bisphosphonates has been suggested to minimize post-operative hypocalcemia, which has been found in a few small series, but no definitive prospective studies have confirmed the benefit of this approach.[174][175][176][183][184]

Treatment Summary

Criteria for surgery include any parathyroid or hypercalcemic-related symptoms.

• Medical therapy for hypercalcemia is primarily with a calcium-sensing receptor (calcimimetic) drug such as cinacalcet, which typically has little effect on bone density.
• Medical treatment for low bone density is mainly bisphosphonates and rank ligand inhibitors with minimal effect on hypercalcemia.
• Combined therapy is necessary to manage both hypercalcemia and low bone density.
• Medical therapy is intended only for patients unable or unwilling to undergo surgery.
• Surgical treatment is always preferred over medical therapy whenever possible.
• Many patients will do quite well for years without symptoms, but they will require routine monitoring and may develop symptoms over time.
• Surgery cures the underlying condition and allows for better reductions in nephrolithiasis and improved bone densities.
• Localization studies are intended only for possible surgical patients. Such studies include neck ultrasound and Sestamibi scans. If these are negative or equivocal, 4D CT scanning or selective parathyroid venous sampling can be done.
• Referral to an experienced parathyroid surgeon is recommended when surgery is selected.
• Be aware of the possibility of hungry bone syndrome (severe, prolonged hypocalcemia) immediately after parathyroidectomy surgery. 

Differential Diagnosis

• Normocalcemic primary hyperparathyroidism

• Secondary hyperparathyroidism

• Familial hypocalciuric hypercalcemia

• Treatment with lithium

• Malignancy related hypercalcemia 

• Granulomatous diseases

• Hyperthyroidism

• Thiazide therapy

• Vitamin D intoxication

• Milk-alkali syndrome

• Adrenal insufficiency

• Vitamin A intoxication

Prognosis

Most patients with primary hyperparathyroidism in the United States are diagnosed while asymptomatic from an incidental elevated serum calcium level. Available studies have followed such patients for 15 years and determined that laboratory values remain relatively stable over time, but bone mineral density starts to decline eventually. An increased risk of renal calculi remains.[127] Surgical parathyroidectomy can resolve and permanently cure the disorder with subsequent improvements in bone mineral density over time. There is an increased risk of cardiovascular events, and it remains unclear if this improves even after treatment or surgery.[151]

Complications

Complications of primary hyperparathyroidism include loss of bone mineral density, fractures, bone pain, gastrointestinal disturbances, psychological issues, a higher risk of urinary stones, and an increased risk of cardiovascular disease.[151]

Deterrence and Patient Education

Patients should be made fully aware of all possible treatments for hyperparathyroidism. Even for patients at higher risk and reluctant to undergo surgery, the long-term benefits of parathyroidectomy should be carefully explained and reviewed, as surgery remains the only definitive cure for this condition. Patients undergoing surgery should also be aware of possible hungry bone syndrome and postoperative hypocalcemia. 

Pearls and Other Issues

Hyperparathyroidism should be suspected if hypercalcemia is found with hypophosphatemia.

All calcium nephrolithiasis and nephrocalcinosis patients should be checked for elevated serum calcium. If hypercalcemia is found, a parathyroid hormone level should be performed.

Primary hyperparathyroidism preferentially reduces cortical bone density and increases fracture risk at sites where cortical bone predominates, such as the distal forearm, with relative sparing of trabecular bone. For this reason, those with hyperparathyroidism should have a dual-energy x-ray absorptiometry that includes the distal third of the radius, a site composed almost exclusively of cortical bone, in addition to the more common measurements at the spine and hip.[4]

Primary hyperparathyroidism is associated with some psychological complaints, including depression, anxiety, fatigue, irritability, lassitude, and sleep disturbances. Surgical correction of hyperparathyroidism seems to help, but the relief of psychological symptoms and improvement in quality of life scores is somewhat inconsistent.[4][185][186][187]

When there is a family history of hyperparathyroidism, consider the possibility of multiple endocrine neoplasia types 1, 2a, 4, or familial hypocalciuric hypercalcemia (FHH). 24-hour urinary calcium excretion with calculating the calcium/creatinine excretion ratio is the best initial test to differentiate familial hypocalciuric hypercalcemia from primary hyperparathyroidism.[88] When the diagnosis is still uncertain, patients can be tested for specific genetic mutations of the calcium-sensing receptor.[85] Patients with familial hypocalciuric hypercalcemia are typically asymptomatic without renal stones, fractures, bone pain, osteopenia, or osteoporosis, and surgery is not recommended. (Subtotal parathyroidectomy does not cure this problem, and total parathyroidectomy results in hypoparathyroidism.)[188]

Enhancing Healthcare Team Outcomes

Primary hyperparathyroidism is a relatively common endocrine disorder. Because hypercalcemia can affect many organs, the condition is best managed by an interprofessional team that includes a radiologist, endocrinologist, urologist, surgeon, and internist. To ensure a successful surgery and minimize complications, parathyroid surgery should only be performed by surgeons who are highly skilled and experienced in parathyroid procedures.

Asymptomatic patients with mild hypercalcemia and no complications related to high parathyroid hormone levels can be observed. However, they need period re-evaluation, usually with annual blood tests and bi-annual DEXA scans, to see if they develop criteria that warrant surgery.

All symptomatic patients and those with complications related to high parathyroid hormone levels need surgery. If hypercalcemia is left untreated, it can severely affect many organs. After surgery, most patients have a favorable long-term outcome.

Following a surgical cure of primary hyperparathyroidism, follow-up can be done by the primary care provider, including nurse practitioners and physician assistants, and monitoring renal function, bone density, calcium levels, and mood changes.