Primary Hyperparathyroidism

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Continuing Education Activity

Primary hyperparathyroidism is an endocrine disorder characterized by increased parathyroid hormone secretion, leading to hypercalcemia and renal and skeletal complications. Diagnosis requires excluding secondary causes and awareness about the complexities of abnormal lab values associated with primary hyperparathyroidism. Treatment involves parathyroid surgery for symptomatic cases; medical therapy with calcimimetic agents or bone resorptive medications may suit some patients. Understanding calcium homeostasis is crucial for management. This course explores the complexities surrounding primary hyperparathyroidism and increases understanding of the disorder's evaluation and management.

This activity for healthcare professionals is designed to enhance the learner's competence in differentiating primary hyperparathyroidism from secondary causes, grasping the intricacies of parathyroid hormone regulation, and recognizing clinical manifestations for timely diagnosis and appropriate intervention, ultimately enhancing patient care.

Objectives:

  • Identify the clinical manifestations and laboratory findings associated with primary hyperparathyroidism.

  • Differentiate primary hyperparathyroidism from secondary causes.

  • Assess patients with primary hyperparathyroidism for renal and skeletal complications.

  • Coordinate care within the interprofessional team for the long-term management of primary hyperparathyroidism.

Introduction

Primary hyperparathyroidism is a relatively common endocrine disorder characterized by increased secretion of parathyroid hormone and hypercalcemia that can result in significant renal and skeletal complications. However, most patients diagnosed in recent decades have relatively mild degrees of hypercalcemia. Although once known for the aphorism as a disease of "stones, bones, groans, and moans," as suggested by Fuller Albright, primary hyperparathyroidism is usually asymptomatic when initially diagnosed.[1] Stones refers to nephrolithiasis caused by hypercalciuria. Groaning refers to abdominal pain from constipation often produced by hypercalcemia or bone pain, which can directly or indirectly result from abnormal remodeling, fractures, or osteoporosis. Neuropsychiatric complaints can also be symptoms of primary hyperparathyroidism. Some degree of depression, anxiety, fatigue, cognitive dysfunction, memory loss, and similar psychological symptoms are found in 23% of patients severely affected with hyperparathyroidism.[2] Historically, primary hyperparathyroidism was diagnosed when patients presented with recurrent nephrolithiasis or bone disease. Radiological findings of primary hyperparathyroidism include osteitis fibrosa cystica, brown tumors of bones, evidence of subperiosteal bone resorption, "salt and pepper" erosions of the skull bones, and tapering of the distal portions of the finger bones and clavicles. While radiological evidence of primary hyperparathyroidism is now rare, bone densitometry can detect skeletal abnormalities well before these more obvious skeletal abnormalities become clinically apparent.[3]

Primary hyperparathyroidism involves excess parathyroid hormone (PTH) production by 1 of the 4 very small parathyroid glands normally located peripherally along the margins on the posterior aspect of the thyroid gland. The average parathyroid gland is approximately 6mm by 4 mm, weighing only 20 to 40 mg. Surgery remains the definitive, curative treatment, but observation alone or medical therapy is appropriate for selected patients.[4][5][6][7] PTH secretion is a tightly regulated process involving a complex interplay among serum calcium, serum phosphorus, vitamin D, activated vitamin D, and fibroblast growth factor-23 (FGF23). The primary regulator of PTH release is serum calcium, acting on the calcium-sensing receptors on the parathyroid surface. Calcitriol (ie, activated 1,25-vitamin D) and possibly phosphorus reduce PTH release. A basic understanding of normal calcium homeostasis and the natural history of primary hyperparathyroidism is essential to diagnose and properly manage patients with this disorder.

Etiology

Parathyroid Gland Physiology

Parathyroid glands are made up of 2 cell types:

  • Chief cells: The most common producers of PTH. They have a very prominent Golgi apparatus and endoplasmic reticulum.
  • Oxyphil cells: These cells are larger, but their exact function is unclear. They may have additional endocrine functions or support chief cell activity.[8]

Secretion of PTH is inversely related to the ionized calcium concentration in the extracellular fluid as determined by the parathyroid calcium-sensing receptors (CaSR), G-protein coupled molecular chemoreceptors 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 PTH. Conversely, as serum calcium levels decline, the activity of the CaSR decreases, and PTH secretion increases.[9][10] PTH activates PTH receptors, increasing the resorption of calcium and phosphate from bone, enhancing the distal tubular calcium reabsorption, and decreasing renal phosphorus reabsorption. The net renal effect is to increase urinary phosphate excretion but decrease urinary calcium until overwhelmed by serum hypercalcemia. PTH also plays an essential role in vitamin D metabolism, activating vitamin D 1-alpha hydroxylase, which increases the renal synthesis of 1,25-dihydroxyvitamin D.[11] 

Etiologies of Hyperparathyroidism

Primary hyperparathyroidism

Primary hyperparathyroidism is a disorder characterized by excessive production of PTH. It is the third most common endocrine disorder after diabetes and thyroid disorders. Eighty percent of patients will present with a single adenoma, approximately 15% with hyperplasia of all 4 glands, 2% to 4% with multiple adenomas, and fewer than 1% with parathyroid carcinoma.[12][13] A combination of increased clonal proliferation of parathyroid tissue with reduced CaSR usually causes primary hyperparathyroidism.[10] Most of these adenomas will be located in the parathyroid glands, but in up to 10% of cases, they may be in an ectopic location. Potential ectopic locations include the thymus, thyroid, pericardium, retro-esophageal space, or superior mediastinum. More unusual locations to find ectopic parathyroid glands would be in the pharynx, lateral neck, or esophagus.[14][15]

Parathyroid carcinoma

Parathyroid carcinoma is relatively rare, constituting fewer than 1% of all cases of hyperparathyroidism.[16] Compared to patients with parathyroid adenomas, those with parathyroid carcinomas tend to be younger, more hypercalcemic, and with extremely high levels of PTH. The serum calcium often exceeds 14 mg/dL, with PTH levels 5 to 10 times the upper limit of the reference range. These cancers tend to be relatively aggressive and potentially life-threatening, usually due to severe and intractable hypercalcemia rather than direct invasion by malignant tissue.[16] While rare, the incidence may be increasing in both the US and China.[17]

Parathyromatosis

Parathyromatosis is the presence of multiple small functional nests of parathyroid tissue, usually after surgical removal of the parathyroid glands. This exceedingly rare condition can mimic the appearance of parathyroid carcinoma due to the nests being surrounded by fibrous post-surgical tissue. Parathyromatosis can be distinguished from parathyroid carcinoma by histologic criteria. Parathyromatosis is thought to have 2 etiologies: proliferation of parathyroid tissue residual from embryologic development and, more frequently, seeding during parathyroidectomy or percutaneous ablation, which often occurs in patients with CKD who have persistently elevated PTH.[18] This can be a cause of recurrent, persistent, or intractable hyperparathyroidism.[19][20][21] Although there are reports of successful treatment with calcimimetics and bisphosphonates, optimal therapy involves complete surgical excision as the removal of all hyperfunctioning nodules is curative, but this is often quite challenging.[19][21][22][23] Denosumab, a novel RANK ligand inhibitor, has been used for long-term management. Both medical and surgical treatment are challenging due to the frequent miliary tissue distribution.[18] 

Normocalcemic primary hyperparathyroidism

Normocalcemic primary hyperparathyroidism is the presence of persistently elevated PTH levels over at least 6 months despite normal corrected serum calcium and ionized calcium concentrations after excluding all causes of secondary hyperparathyroidism, including calcium and vitamin D deficiencies. Imaging studies to identify hyperfunctioning parathyroid glands are less likely to be positive than those with classical hypercalcemic primary hyperparathyroidism. Evaluation and treatment are similar to primary hyperparathyroidism.[5][24] Many patients remain asymptomatic and require no treatment except routine and regular monitoring. See the companion StatPearls article, "Normocalcemic Hyperparathyroidism," for further information.[24]

Lithium

Lithium use can cause a degree of CaSR resistance, requiring higher serum calcium levels to suppress PTH secretion. The incidence of this effect is unknown, as PTH levels are not routinely checked in patients on lithium therapy, and cases are often asymptomatic. Lab values will generally show hypercalcemia, non-suppressed PTH, normal serum phosphorus, and hypocalciuria similar to familial hypocalciuric hypercalcemia. Lithium-related hyperparathyroidism is considered secondary hyperparathyroidism but can be associated with parathyroid gland hypertrophy requiring surgery and can present similarly to primary hyperparathyroidism.[25][26][27]

Malignancy-related hypercalcemia

Malignancy-related hypercalcemia can be found in as many as 20% to 30% of all cancer patients. It can be confused with primary hyperparathyroidism, especially if hypercalcemia symptoms are the first clinical sign of the malignancy. The most common cause of malignancy-related hypercalcemia is the production and secretion of PTH-related protein, most often due to squamous cell carcinoma of the lung and renal cancers.[28][29] PTH-related protein binds and activates the same receptor as PTH, causing hypercalcemia, hypercalciuria, and hypophosphatemia. The immunoassay used to quantify PTH-related protein does not detect PTH, and PTH assays do not detect PTH-related protein. Therefore, patients with humoral hypercalcemia of malignancy have high levels of PTH-related protein and low PTH levels, making it easy to differentiate these entities.[28][29][30] In the absence of known malignancy, physicians should be suspicious of occult cancer, especially in patients with paraneoplastic-like symptoms such as unexplained fatigue, weight loss, skin rashes, or muscle weakness.[30] See the companion StatPearls article "Malignancy-Related Hypercalcemia" for further information.[28]

Genetic Conditions Associated with Primary Hyperparathyroidism

Up to 10% of primary hyperparathyroidism cases have a genetic basis. Genetic mutations associated with hyperparathyroidism include multiple endocrine neoplasia types 1, 2A, and 4, hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism, neonatal severe hyperparathyroidism, and familial hypocalciuric hypercalcemia.[10][31][32][33][34] 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.[35] Genetic conditions underlying primary hyperparathyroidism include:

  • Multiple endocrine neoplasias: Multiple endocrine neoplasias (MEN) typically involve multiple glands.[36] The first clinical sign of MEN type 1 is usually primary hyperparathyroidism, which commonly appears at an early age, typically 20 to 25 years, and will be seen in over 90% of affected patients. Primary hyperparathyroidism in MEN type 1 individuals usually affects all the parathyroid glands and is typically asymptomatic. Surgery is the recommended treatment if patients are symptomatic or have significant hypercalcemia.[6] See the companion StatPearls articles Multiple Endocrine Neoplasias Types 1, 2, and 4.[37][38][39] 
  • Tumor-jaw syndrome: Tumor-jaw syndrome is a rare, autosomal dominant disorder caused by a mutation of the CDC73 gene associated with parathyroid adenomas and carcinomas.[6] In addition to hyperparathyroidism, uterine tumors and renal abnormalities, such as Wilms tumor and adenocarcinoma, are associated.[40]
  • Familial hypocalciuric hypercalcemia: Familial hypocalciuric hypercalcemia is an autosomal dominant inherited disorder that can cause elevated PTH. In this disease, a mutation in the calcium-sensing receptor on the parathyroid gland chief cells causes decreased receptiveness. This leads to mild hypercalcemia, hypophosphatemia, hypercalciuria, and mildly elevated PTH. This condition is usually asymptomatic and does not require treatment. In this situation, PTH levels will be inappropriately normal in 80% of cases despite hypercalcemia and hypophosphatemia and elevated in the remaining 20%.[41] Histologically, the parathyroid glands appear normal. There is usually a known family history of the disorder, and this condition is more likely if hypercalcemia is detected before age 40.[42] See the companion reference StatPearls article on "Familial Hypocalciuric Hypercalcemia" for further information.[42][43]
  • Severe neonatal hyperparathyroidism: This condition is sometimes seen in parents with familial hypocalciuric hypercalcemia due to heterozygous CaSR mutations. This is a life-threatening disorder manifesting as severe hypercalcemia, respiratory distress, rib cage abnormalities, and hypotonia. Patients may initially respond to medical treatment but usually require parathyroidectomy, sometimes emergently.[18] 
  • Familial isolated hyperparathyroidism: This etiology is seen in various gene mutations, including incomplete expression of MEN1CDC73, or CASR or a germline-activating mutation in GCM2. Clinical symptoms are variable.[18] 

Epidemiology

Primary hyperparathyroidism is the most common, identifiable cause of hypercalcemia diagnosed in postmenopausal women. The female-to-male ratio is approximately 3 to 4 times that of men, and the peak age group is between 50 and 60.[44] 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.[45][46][47][48][49][50] Thiazides were formerly 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 been discontinued would be suggestive of hyperparathyroidism.[51]

The primary contributor leading to the diagnosis of primary hyperparathyroidism is the widespread availability of standard laboratory testing, as the majority of cases are diagnosed through asymptomatic hypercalcemia. Before 1970, the diagnosis was made when patients presented with specific symptoms, typically nephrolithiasis or bone pain. Since then, most patients have been diagnosed with hyperparathyroidism when serum calcium is incidentally discovered to be elevated on a routine chemistry profile ordered as a screening test or for an unrelated problem.[10] 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 presentation.[44][52][53]

The current incidence of hyperparathyroidism in the United States has been estimated to be at 233 per 100,000 person-years in women and 85 per 100,000 person-years in men. In North America, incidence is higher among Blacks than Whites, with Asians and Hispanics having lower incidence.[10] Parathyroid cancer is quite rare, as it constitutes less than 0.5% of all cases of primary hyperparathyroidism. Higher serum calcium and PTH levels are commonly seen compared to benign primary hyperparathyroidism.[54] There is an association with hyperparathyroidism-jaw tumor syndrome, an autosomal disorder in which up to 15% will develop parathyroid carcinomas.[55] Wilms tumors, hamartomas, and polycystic renal disease are also associated with this syndrome.[56]

Pathophysiology

Parathyroid Hormone

PTH is a crucial hormone required to maintain calcium homeostasis, whose net effect is to increase serum calcium levels. To accomplish this, it regulates 3 principal activities.

  • Increases bone resorption, which releases calcium and phosphorus into the serum
  • Decreases urinary calcium excretion by increasing its reabsorption in the distal convoluted renal tubule and thick ascending loop of Henle
  • Activates vitamin D 1-α-hydroxylase in the renal proximal tubule, which converts relatively inactive 25-hydroxyvitamin D (25-VitD) to active 1,25-dihydroxyvitamin D (1,25-VitD), which increases the gastrointestinal absorption of calcium and phosphorus [11] 

All 3 of these actions taken together have the net effect of increasing serum calcium levels. Calcitonin, produced by the parafollicular in the thyroid gland, is a hormone that has the opposite effect of PTH, decreasing bone resorption, although its role in the physiological regulation of bone metabolism in humans seems minimal.[57] PTH inhibits the proximal tubular reabsorption of phosphorus, leading to increased urinary excretion of phosphorus. It also increases bone resorption and, due to its effects on vitamin D metabolism, increases the gastrointestinal absorption of phosphorus. The net effect is that most patients diagnosed with primary hyperparathyroidism have normal levels of serum phosphorus, but the finding of hypercalcemia with hypophosphatemia is highly suggestive of hyperparathyroidism.[58][59]

Urinary calcium excretion in patients with primary hyperparathyroidism depends on the degree of hypercalcemia, glomerular filtration rate (GFR), and the effect of PTH increasing the renal tubular reabsorption of calcium. Therefore, the 24-hour urine calcium excretion is variable, although often increased due to increased glomerular filtration of calcium. PTH normally reduces urinary calcium excretion, but this effect can be overcome by significant hypercalcemia, which is why hypercalciuria can be found in primary hyperparathyroidism. The calcium-sensing receptor (CaSR) found on the parathyroid gland is also found in kidney tubules, especially the thick ascending loop of Henle, where about 25% of filtered calcium is reabsorbed. Defects in CaSR will lead to hypocalciuria by decreasing renal tubular urinary concentrating ability while activating mutations in this receptor will cause hypercalciuria.[10] 

Normal Calcium Homeostasis

Under physiologic circumstances, calcium concentration in the extracellular fluid is maintained within a narrow range. Normal calcium homeostasis depends on a complex set of hormonal regulatory mechanisms that include the effects of PTH, vitamin D metabolites, and calcitonin on calcium transport in the bones, kidney, and gastrointestinal tract.[11][60] Calcium is absorbed in the gastrointestinal tract by active and passive transport mechanisms. The active transport of calcium is increased by 1,25-VitD. Physiologic secretion of PTH is minimal at serum calcium levels above 10 mg/dL and maximal when the level decreases to less than 7.5 mg/dL.[61]

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. The following formula can be used to approximate the correction of serum calcium 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.

Chronic kidney disease causes a secondary increase in serum PTH levels due to hypocalcemia from decreased 1,25-VitD.[62][63][64][65] Some parathyroid assays will also tend to elevate PTH concentrations in renal failure falsely.[66][67] The failing kidneys are unable to maintain 1,25-VitD levels, which reduces intestinal calcium absorption and lowers serum calcium, which stimulates PTH production.[68][69] Reduced PTH clearance in chronic renal failure further increases serum PTH levels. Ultimately, the chronic stimulation of the parathyroid glands results in diffuse, multiglandular parathyroid hyperplasia. Most patients with chronic kidney disease have secondary hyperparathyroidism with low or normal levels of serum calcium. However, some develop tertiary hyperparathyroidism, characterized by autonomous overproduction of PTH and hypercalcemia.[69][70][71] See the companion StatPearls article, "Renal Osteodystrophy," for further information.[72]

Histopathology

Parathyroid adenomas tend to be encapsulated and are typically composed primarily of chief cells. Adenomas of oxyphilic cells are rare but have been reported in a few cases of primary hyperparathyroidism.[73] In patients with primary hyperparathyroidism, the chronic excess of PTH leads to increased proliferation and activity of osteoclasts with thinning and increased porosity of the bone cortex. When prolonged and severe, some patients develop osteitis fibrosa cystica characterized by an increased number and activity of osteoclasts, replacement of bone with granulation and fibrous tissue, and brown hemosiderin deposits (brown tumors).[74]

History and Physical

Clinical Features

In past decades, most patients with primary hyperparathyroidism were diagnosed when presenting with nephrolithiasis, bone pain, bone fractures, muscle weakness, or bone deformities. Since the 1970s, most patients diagnosed with primary hyperparathyroidism in the developed world are asymptomatic, diagnosed when hypercalcemia is incidentally discovered on a chemistry profile.[75] The definitive diagnosis is then made by definitive laboratory testing.

Clinicians should ask patients about any history of kidney stones, bone pain, myalgias or muscle weakness, symptoms of depression, use of thiazide diuretics, calcium-containing products, vitamin D supplements, or other symptoms associated with the multiple etiologies of hypercalcemia.[44] While most patients with primary hyperparathyroidism are asymptomatic, up to 55% will have previously undiagnosed nephrocalcinosis or nonobstructing renal calculi, and up to 75% of the symptomatic patients will present with acute renal colic or nephrolithiasis.[76][77][78] For this reason, serum calcium should be measured in all patients with calcium nephrolithiasis. When the serum calcium level exceeds 12 mg/dL, patients are more likely to notice symptoms associated with hypercalcemia, including anorexia, altered mental states, constipation, dehydration, polyuria, and polydipsia.[79] Approximately 40% of patients with primary hyperparathyroidism will also have hypercalciuria.[80] For patients with primary hyperparathyroidism and nephrolithiasis, the risk of future stones decreases but can persist for as long as 10 to 15 years after successful parathyroidectomy.[81] Twenty-four-hour urine testing is recommended for nephrolithiasis patients even after successful parathyroid surgery to minimize other chemical risk factors.[82] 

The physical examination of a patient with primary hyperparathyroidism is usually normal. However, the examination can help uncover other etiologies of hypercalcemia. For example, parathyroid adenomas are rarely palpable, but the presence of a large, firm mass in the neck of a patient with hypercalcemia should raise suspicion of parathyroid carcinoma.[83] Besides nephrolithiasis, other potential symptoms and problems related to hypercalcemia and hyperparathyroidism include: 

  • Abdominal pain
  • Aortic valve calcification
  • Body aches
  • Bone pain
  • Cardiac arrhythmias
  • Decreased coronary artery flow reserve
  • Depression, memory loss, or forgetfulness
  • Difficulty sleeping
  • Easy fatiguability, chronic fatigue
  • Fractures
  • Frequent complaints of illness with no apparent cause
  • Headaches
  • Hypertension
  • Increased overall cardiovascular disease
  • Joint pain
  • Left ventricular hypertrophy
  • Loss of appetite
  • Muscle weakness
  • Nephrocalcinosis
  • Osteoporosis and increased risk of fractures
  • Polyuria
  • Trouble concentrating

Acute primary hyperparathyroidism

Acute primary hyperparathyroidism (ie, parathyroid crisis, parathyroid storm) is a rare condition in which there is a sudden episode of potentially life-threatening hypercalcemia in a patient with or without a prior history of primary hyperparathyroidism. Laboratory studies indicate very high serum calcium levels, higher than 14 mg/dL, with PTH levels up to 20 times normal.[84][85] It is sometimes associated with parathyroid cancers.[86] Serum calcium levels higher than 15 mg/dL can be immediately life-threatening, leading to coma and death. They should be treated as hypercalcemic medical emergencies with intravenous (IV) normal saline, diuretics (furosemide, not thiazides), calcitonin, bisphosphonates, denosumab (a RANK-ligand inhibitor), and cinacalcet. Additionally, dialysis, particularly for patients with renal failure, and emergency parathyroidectomy may be utilized.[79][87][88][89][90][91] Calcitonin and IV normal saline hydration are most effective within the first 48 hours, while bisphosphonates may require several days. Bisphosphonates may be more effective than denosumab, although the 2023 Endocrine Society Clinical Practice Guidelines recommend denosumab.[92] Denosumab can reasonably be considered in patients who appear refractory to bisphosphonates. Dialysis can be considered even in patients without renal failure where other therapies have failed.[93][94] Adjustments to the dialysis fluid may be needed to avoid complications like hypophosphatemia.[94] Treatment is directed at managing the severe degree of hypercalcemia with aggressive medical therapy, and surgical excision is curative.[84][85][86][95]

Osteitis fibrosa cystica

Osteitis fibrosa cystica is a late bony manifestation of long-term hyperparathyroidism. It is characterized by bony swelling, pain, lowered mineral density, and fractures. While previously very common, it is now quite rare in the developed world. Treatment of the underlying parathyroid condition, particularly surgical therapy, cures the condition.[96] See the companion StatPearls article "Osteitis Fibrosa Cystica."[96] 

Evaluation

All patients with hypercalcemia should be tested for hyperparathyroidism through laboratory studies. The finding of hypercalcemia together with hypophosphatemia is highly suggestive but not diagnostic of hyperparathyroidism. Most patients with primary hyperparathyroidism have normal serum phosphorus, but hypercalcemia with hypophosphatemia is highly suggestive of hyperparathyroidism or humoral hypercalcemia of malignancy. The definitive test for primary hyperparathyroidism is the finding of hypercalcemia (ie, ionized calcium or corrected serum calcium) with a simultaneous elevation of PTH. Most causes of hypercalcemia are associated with appropriately low or suppressed PTH levels.[44] Borderline low vitamin D levels should be treated with supplemental vitamin D to achieve a 25-hydroxyvitamin D value >30 ng/mL to help rule out vitamin D deficiency as a secondary cause of an elevated PTH level.[4] Patients with primary hyperparathyroidism and other causes of PTH-dependent hypercalcemia often have frankly elevated levels of PTH; others will have values that fall within the reference range but are inappropriately normal. PTH levels should be undetectable or very low in patients with PTH-independent hypercalcemia.[44] PTH levels typically increase with age. In populations with a high incidence of vitamin D deficiency, the "normal" PTH levels tend to be higher.[97] Recommended serum intact parathyroid tests include immunochemiluminometric or immunoradiometric assays, which readily discriminate between primary hyperparathyroidism and malignancy-related hypercalcemia. PTH-related protein, which causes humoral hypercalcemia of malignancy, is not detected in the intact PTH assays.

Biotin, also known as vitamin B-7, is a nutritional supplement that can cause a laboratory artifact, interfering with the accurate measurements of several hormones, including PTH.[98] The biotin should be discontinued, and the PTH level should be retested in such cases. Patients on drugs such as lithium and thiazide should have these medications stopped for 3 to 6 months, if possible, and their serum calcium and PTH levels retested. If PTH levels remain elevated, this suggests primary hyperparathyroidism.

Primary hyperparathyroidism can be differentiated from familial hypocalciuric hypercalcemia by measuring the 24-hour urine calcium and creatinine. In familial hypocalciuric hypercalcemia, the 24-hour urine calcium excretion is often lower than 100 mg calcium. The calcium clearance ratio should be calculated using the formula (urinary calcium x serum creatinine)/(serum calcium x urinary creatinine). This ratio is typically l<0.01 in familial hypocalciuric hypercalcemia and >0.02 in those with primary hyperparathyroidism. Many patients have values between 0.01 and 0.02, which can be confounded by vitamin D deficiency or chronic kidney disease. Repeat testing after vitamin D repletion may be necessary.[99] Although rarely done, a calcium infusion test can also help distinguish familial hypocalciuric hypercalcemia from primary hyperparathyroidism. A calcium load will increase urinary calcium excretion in primary hyperparathyroidism but not familial hypocalciuric hypercalcemia. See the companion reference StatPearls review article "Familial Hypocalciuric Hypercalcemia."[42]

Reviewing previous medical records can often be of significant value. 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. The need for different studies such as PTH-related protein levels, serum or urine protein electrophoresis, 1,25-dihydroxy vitamin D levels, thyroid tests, or mammography can be individualized and are usually only needed in those with PTH-independent hypercalcemia. The following diagnostic studies are used to evaluate patients for primary hyperparathyroidism: 

  • Intact PTH
  • Phosphorus 
  • Total and ionized calcium
  • Twenty-four-hour urine calcium and creatinine, with creatinine clearance
  • Vitamin D level (ie, 25-hydroxyvitamin D)
  • Albumin and corrected calcium level
  • Alkaline phosphatase
  • Bone densitometry (DEXA), including measurement at the distal one-third radius, which is preferentially affected in patients with hyperparathyroidism
  • BUN and creatinine
  • Genetic testing for suspicion of a genetic syndrome [100]
  • Imaging studies (eg, nuclear medicine and ultrasonography) for surgical candidates 
  • Imaging to screen for renal calcifications or urolithiasis
    • Kidney, ureters, bladder (KUB) x-ray or renal ultrasound
    • Noncontrast computed tomography (CT) scan
  • Markers of bone formation and resorption (not routinely recommended)

Parathyroid Localization Imaging Studies

Neck ultrasonography and parathyroid nuclear medicine (Tc-sestamibi) scans are standard imaging tests for the localization of hyperfunctioning parathyroid glands. However, these tests are not considered definitive because there can be false-negative results, and they are generally less useful in multiglandular parathyroid disease.[101] They should not be ordered unless there are plans for surgery, as they are most useful to assist the surgeon as a "roadmap" in localizing enlarged, hyperfunctioning parathyroid glands, particularly when an ectopic gland is suspected. Neck ultrasonography is highly operator-dependent but accurate in centers with experience and expertise.[102] These are considered more sensitive than sestamibi scans, which often cannot detect nodules smaller than 500mg.[103][104] The sensitivity of parathyroid imaging scans can be enhanced when combined with single-photon emission computed tomography (SPECT).[105] 

Parathyroid 4-dimensional multiphase (4D) CT should be considered when surgery is planned, and the abnormal parathyroid glands cannot be localized with sestamibi scans or neck ultrasound, or these two imaging modalities have discordant results.[105][106] There is evidence that 4D CT is superior to sestamibi SPECT/CT.[107] This 4D modality is an emerging method of localization of parathyroid adenomas for presurgical planning, although implementation, instrumentation, and correct interpretation are still somewhat challenging.[106][108] F-18-Fluorocholine positron emission tomography/CT has shown promising results in parathyroid adenoma localization in difficult or equivocal cases, suggesting superiority over sestamibi scanning, ultrasound, or CT scans alone.[109]

Infrared thermal scanning is another promising imaging technique for localizing parathyroid hyperactivity. This is potentially most useful where other imaging modalities are conflicting or inadequate. It is based on hyperfunctioning parathyroid lesions being hypervascular and averaging about 2 degrees warmer than normal tissue, allowing them to be picked up by thermal imaging. Such thermal scanning has successfully identified parathyroid adenomas not easily visualized by other techniques.[110] When noninvasive preoperative localization studies are negative, selective parathyroid venous sampling, although technically challenging, can help identify the anatomical location of abnormal hyperfunctioning parathyroid glands.[111][112] 

Bone Imaging

Bone biopsies are rarely indicated in evaluating patients with primary hyperparathyroidism, so DEXA and other techniques assess the quantity and quality of bone. Newer noninvasive imaging technologies suggest that the effects of PTH excess on skeletal tissue may be more significant than previously thought. The trabecular bone score is an indirect analysis of trabecular microstructure extracted from data obtained from the DEXA. Trabecular bone score demonstrates decreased connectivity of the trabecular spinal microstructure in patients with primary hyperparathyroidism, although the T-score on the DEXA may not be significantly reduced.[113] High-resolution peripheral quantitative CT scans of the distal radius and tibia show fewer, thinner, and more widely spaced trabeculae in primary hyperparathyroidism.[114][115][116] Trabecular microstructural defects may account for the relatively high number of vertebral fractures in primary hyperparathyroidism despite apparently preserved bone mineral density in the lumbar spine.[117][118][119] These fractures may sometimes be asymptomatic.[120]

Treatment / Management

In 2022, a panel of experts in parathyroid disorders published updated guidelines for managing primary hyperparathyroidism. The task force included endocrinologists, nephrologists, pathologists, epidemiologists, radiologists, pharmacologists, and endocrine surgeons.[4][5][6][10][74][121]

Management Approach

Surgery remains the definitive treatment for primary hyperparathyroidism. Nonoperative surveillance may be an appropriate option for some, particularly for patients who are elderly with mild hypercalcemia and no significant complications. Medical treatment with bisphosphonates 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 of 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; calcium is often supplemented in the setting of bone disease.[5] There is substantial evidence that chronic vitamin D deficiency is a risk factor for hyperparathyroidism.[122][123] Experts recommend that patients with hyperparathyroidism who are deficient in vitamin D levels receive supplements to achieve a 25-hydroxyvitamin D level higher than 30 ng/mL.[4][5][124] Long-term outcomes in patients with hyperparathyroidism who do not undergo surgery are reported for patients followed for as long as 15 years.[125] They generally show relatively stable chemistries. There is a decrease in bone mineral density starting at 8 to 9 years during nonoperative surveillance that becomes more significant after year 10.[44][125] A few patients lost >10% of their measured bone mineral density after 15 years. Renal function remains stable, but hypercalciuria persists, so there is an increased risk of nephrolithiasis.[125] Current guidelines for monitoring patients with primary hyperparathyroidism being treated medically recommend the following:

  • Annual measurement of serum calcium, 25-hydroxyvitamin D, and creatinine clearance
  • PTH levels can be repeated as clinically indicated
  • Repeat 24-hour urine calcium excretion, abdominal imaging for calcifications, and vertebral X-rays can be repeated if clinically indicated
  • Three-site DEXA scans are recommended either annually or biannually[4][5]

Medical Management

Medical therapy in patients with primary hyperparathyroidism is designed to treat osteoporosis or hypercalcemia. Cinacalcet can reduce serum calcium but will generally not increase bone mineral density, while antiresorptive agents can improve bone density but are not as effective in lowering serum calcium. If both problems require treatment, combination therapy is recommended.[5][121][126][127] The following agents may be used in medical management of primary hyperparathyroidism:

  • Oral bisphosphonates and denosumab are antiresorptive agents and can increase bone mineral density in hyperparathyroid patients with osteoporosis or osteopenia.[44][121][128][129] There are reports of denosumab controlling refractory hypercalcemia, and intravenous bisphosphonates have successfully treated severe hypercalcemia but are not a feasible long-term therapy.[130][131][132][133]
  • Medications that activate the calcium-sensing receptor, such as cinacalcet, will significantly lower serum PTH and calcium in hyperparathyroid patients but generally not increase their bone density.[134][135] Over 70% will normalize their blood calcium levels on these medications.[134][135][136][137] PTH levels typically drop by 35% to 50% but may not reach normal levels even after the serum calcium is within normal limits.[138][139] Cinacalcet is quite effective in patients with otherwise intractable hyperparathyroidism and can normalize serum calcium even in cases of inoperable parathyroid carcinoma.[138][140] Vitamin D and urinary calcium levels do not change significantly. Cinacalcet is also used for treating secondary hyperparathyroidism in patients with chronic kidney disease.[141]

  • Estrogen therapy for postmenopausal women with primary hyperparathyroidism has shown a benefit in increasing bone mineral density, particularly in the lumbar spine, but does not change serum PTH or calcium.[142][143][144] Given concerns over long-term, chronic use, estrogen is not routinely recommended for medical management of primary hyperparathyroidism.[142]
  • Oral phosphates can reduce serum calcium levels up to 1 mg/dL. They reduce intestinal calcium absorption by calcium binding, lower vitamin D levels, and reduce bone resorption.[145][146] Since phosphates can increase PTH levels and the risk of soft tissue calcification, they are no longer routinely used in the long-term medical management of primary hyperparathyroidism. 

Surgical Therapy

Surgery is the treatment of choice for those with symptomatic disease, including those with recurrent kidney stones or overt bone disease.[4][147][148] Successful parathyroidectomy results in permanent normalization of serum calcium decreased PTH levels, and a dramatic improvement in bone mineral density at all sites. Following successful parathyroid surgery, bone mineral density, microstructure, and strength improve while patients also experience a reduced risk of fractures and kidney stones.[114][149][150][151][152][153] Rubin et al reported an improvement in bone mineral density of approximately 10% at all sites after successful parathyroidectomy, a benefit extended for at least 15 years.[125][154] These benefits were seen in all parathyroidectomy patients regardless of whether they met the surgery criteria. However, there is conflicting data on whether neurocognitive function or cardiovascular events improve after successful parathyroid surgery.[114][155][156][157] While there are reports that hyperparathyroid patients with cognitive impairment could see improvement in their mental functioning as early as 2 weeks following parathyroid surgery, the 5th International Workshop task force concluded that there was insufficient evidence to recommend parathyroidectomy to improve quality of life, neurocognitive function, or cardiovascular indices.[4][158]

Surgery is an option for all patients with primary hyperparathyroidism if the patient and physician agree and there are no 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.[6][159][160] Current guidelines recommend surgery as the gold standard treatment for all patients with symptomatic primary hyperparathyroidism.[4] Indications for surgery for patients with asymptomatic primary hyperparathyroidism include:[4]

  • Age younger than 50 years
  • GFR or creatinine clearance is <60 mL/min
  • Evidence of renal calcifications, nephrocalcinosis, or urinary stones
  • Hypercalciuria (>300 mg/24 hours in men or 250 mg 24 hours in women)
  • Osteoporosis on DEXA scan (T-score <-2.5 at any site)
  • Serum calcium >1 mg/dL above the upper limit of normal
  • Vertebral compression fracture on imaging

Preoperative localization studies are recommended in patients undergoing surgery, especially if a minimally invasive technique is utilized. Imaging studies are not recommended for diagnosis alone due to poor sensitivity and specificity, with a false-positive rate as high as 25%.[104] Minimally invasive parathyroidectomy is now the preferred surgery for hyperparathyroidism in most centers. This surgery is directed specifically to the location of the previously identified abnormal parathyroid gland.[161] Additionally, the use of intraoperative PTH measurements is recommended to verify the efficacy of the surgery. The half-life of PTH is only 3 to 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.[162][163][164][165] About 2% of abnormal parathyroid tissue sources (an adenoma in 88% of cases or hyperplastic tissue in 12%) are found in the thyroid gland. Ultrasonography and sestamibi scanning are usually successful in finding and localizing the abnormally functioning tissue. Surgical cures are generally possible with either local excision or thyroid lobectomy.[166] Radiofrequency ablation of isolated parathyroid adenomas has been successfully reported with minimal complications in small series.[167][168] This may be an acceptable alternative for patients who would not otherwise be surgical candidates.

Left untreated, many patients with primary hyperparathyroidism have progressive loss of cortical bone. However, successful surgery leads to a substantial increase in bone mineral density, an effect that can persist for up to 15 years.[125][155] Patients with nephrolithiasis who undergo surgery tend to have fewer stones. However, other chemical promoters of kidney stones are still possible, so a 24-hour urine kidney stone risk profile analysis is recommended.[148] During the period of nonoperative surveillance, surgery is recommended if patients develop symptoms, complications, worsening hypercalcemia, or any of the following occur:[4]

  • Low trauma fracture
  • Nephrolithiasis or nephrocalcinosis
  • Serum calcium consistently >1 mg/dL above the upper limit of normal
  • Significant reduction in BMD to a T-score <2.5 at any site
  • Significant decrease in creatinine clearance

Hungry Bone Syndrome 

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. While there is no definitive consensus, most sources will define hungry bone syndrome as persistent low serum calcium of lower than 8.4 mg/dL for longer than 4 days after definitive parathyroid surgery.[169][170] The sudden drop in PTH levels immediately after surgery results in unopposed accelerated osteoblastic activity as serum calcium quickly becomes incorporated into new bone, causing significant hypocalcemia.[169][170] This is often accompanied by hypophosphatemia, hypomagnesemia, and elevated alkaline phosphatase.[170] 

Hypocalcemia and hypophosphatemia can persist for months or even years.[170] Other causes of hypocalcemia after parathyroid surgery include hypoparathyroidism and hypomagnesemia. As opposed to the hungry bone syndrome, the serum phosphorus should be high in those with hypoparathyroidism. The likelihood of hungry bone syndrome increases with the duration and severity of hyperparathyroidism.[169] This 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.[171] 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.[170] 

Treatment generally includes high oral doses of supplemental calcium, with calcium citrate being preferred, and vitamin D. However, if the serum calcium is <7.6 mg/dL, there are symptoms from hypocalcemia, or there are related EKG changes (eg, prolonged QT), intravenous calcium supplementation is indicated. Calcium gluconate is usually preferred over calcium chloride for IV calcium supplementation due to easier administration, as a central line is unnecessary, and there is less chance of tissue necrosis if the IV infiltrates.[169][170][172] See the companion StatPearls article "Hungry Bone Syndrome" for further information.[169]

Differential Diagnosis

The differential diagnosis of primary hyperthyroidism is broad but can often be differentiated based on laboratory studies. Some conditions presenting with hypercalcemia or other similar presentations include the following: secondary hyperparathyroidism, normocalcemic primary hyperparathyroidism, familial hypocalciuric hypercalcemia, malignancy-related hypercalcemia, granulomatous diseases, hyperthyroidism, lithium therapy, thiazide therapy, milk-alkali syndrome, vitamin A intoxication, and vitamin D intoxication.

Prognosis

Most patients with primary hyperparathyroidism in the United States are diagnosed when an elevated serum calcium level is found unexpectedly on routine biochemical testing. Long-term studies have determined that laboratory values remain relatively stable for approximately 80% of patients with mild, asymptomatic hyperparathyroidism, but bone mineral density declines over time. Patients with more significant elevations of serum calcium are at higher risk of complications and should be referred for parathyroid surgery. Surgical parathyroidectomy can resolve and permanently cure the disorder with subsequent improvements in bone mineral density and a lower risk of nephrolithiasis.[125]

Complications

Complications of primary hyperparathyroidism include loss of bone mineral density, fractures, bone pain, hungry bone syndrome, gastrointestinal disturbances, neuropsychiatric complaints, nephrocalcinosis, and a higher risk of nephrolithiasis.

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. When performed by an experienced parathyroid surgeon, parathyroidectomy cures over 90% to 95% of patients with primary hyperparathyroidism. Therefore, surgery is an option for all patients with primary hyperparathyroidism if the patient and physician concur and there are no contraindications. Medication follow-up and diagnostic testing should be emphasized if medical management alone is elected.

Pearls and Other Issues

Key factors to bear in mind when managing primary hyperparathyroidism include:

  • Most patients currently diagnosed with primary hyperparathyroidism have normal serum phosphorus levels. However, the diagnosis of primary hyperparathyroidism is likely in patients with hypercalcemia and hypophosphatemia.
  • Hypovitaminosis D and calcium deficiency may also mask or hide hyperparathyroidism.[173] Consideration should be given to a vitamin D and oral calcium supplementation trial in patients with high or borderline elevated PTH levels. This will lower the serum PTH in secondary hyperparathyroidism but not in primary.[62]
  • All patients with calcium nephrolithiasis and nephrocalcinosis should be screened for hypercalcemia. If hypercalcemia is identified, a PTH level should be measured.
  • Primary hyperparathyroidism preferentially reduces cortical bone density with relative sparing of trabecular bone; this increases fracture risk at sites where cortical bone predominates, such as the distal forearm. For this reason, those with hyperparathyroidism should have a 3-site DEXA 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.[155] Patients with primary hyperparathyroidism also have an increased risk of vertebral fractures that might not be predicted by the spinal T-score alone.
  • Primary hyperparathyroidism is associated with neuropsychiatric complaints, including depression, anxiety, fatigue, irritability, lassitude, and sleep disturbances. Surgical correction of hyperparathyroidism may improve these symptoms, but controlled trials have not consistently reported improvement in psychological symptoms and quality of life.[155][174][175][176]
  • When there is a family history of hyperparathyroidism, consider the possibility of multiple endocrine neoplasia types 1, 2a, 4, or familial hypocalciuric hypercalcemia. Urinary calcium excretion, including a calculation of the calcium clearance, is the best initial test to differentiate familial hypocalciuric hypercalcemia from primary hyperparathyroidism.[42] 
  • Patients can be tested for specific genetic mutations of the calcium-sensing receptor when the diagnosis is still uncertain.[177] Patients with familial hypocalciuric hypercalcemia are typically asymptomatic without renal stones, fractures, bone pain, or osteoporosis, and surgery is not recommended. 

Enhancing Healthcare Team Outcomes

Providing patient-centered care for individuals with primary hyperthyroidism requires a collaborative effort among healthcare professionals, including physicians, advanced practice practitioners, nurses, pharmacists, and others. Clinical skills in diagnosis, evaluation, and treatment, along with strategic planning based on evidence-based guidelines and individualized care plans, are essential. Effective interprofessional communication ensures a collaborative environment where information is shared and responsibilities are defined. Ethical considerations guide treatment decisions, respecting patient autonomy. Care coordination among healthcare professionals streamlines patient care from diagnosis through treatment and follow-up, optimizing outcomes and prioritizing patient well-being.


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References


[1]

ALBRIGHT F. A page out of the history of hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 1948 Aug:8(8):637-57     [PubMed PMID: 18877062]


[2]

Joborn C, Hetta J, Johansson H, Rastad J, Agren H, Akerström G, Ljunghall S. Psychiatric morbidity in primary hyperparathyroidism. World journal of surgery. 1988 Aug:12(4):476-81     [PubMed PMID: 2458656]


[3]

Misiorowski W, Czajka-Oraniec I, Kochman M, Zgliczyński W, Bilezikian JP. Osteitis fibrosa cystica-a forgotten radiological feature of primary hyperparathyroidism. Endocrine. 2017 Nov:58(2):380-385. doi: 10.1007/s12020-017-1414-2. Epub 2017 Sep 12     [PubMed PMID: 28900835]


[4]

Bilezikian JP, Khan AA, Silverberg SJ, Fuleihan GE, Marcocci C, Minisola S, Perrier N, Sitges-Serra A, Thakker RV, Guyatt G, Mannstadt M, Potts JT, Clarke BL, Brandi ML, International Workshop on Primary Hyperparathyroidism. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Nov:37(11):2293-2314. doi: 10.1002/jbmr.4677. Epub 2022 Oct 17     [PubMed PMID: 36245251]


[5]

Bilezikian JP, Silverberg SJ, Bandeira F, Cetani F, Chandran M, Cusano NE, Ebeling PR, Formenti AM, Frost M, Gosnell J, Lewiecki EM, Singer FR, Gittoes N, Khan AA, Marcocci C, Rejnmark L, Ye Z, Guyatt G, Potts JT. Management of Primary Hyperparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Nov:37(11):2391-2403. doi: 10.1002/jbmr.4682. Epub 2022 Oct 17     [PubMed PMID: 36054638]


[6]

Perrier N, Lang BH, Farias LCB, Poch LL, Sywak M, Almquist M, Vriens MR, Yeh MW, Shariq O, Duh QY, Yeh R, Vu T, LiVolsi V, Sitges-Serra A. Surgical Aspects of Primary Hyperparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Nov:37(11):2373-2390. doi: 10.1002/jbmr.4689. Epub 2022 Oct 17     [PubMed PMID: 36054175]


[7]

Pretorius M, Lundstam K, Heck A, Fagerland MW, Godang K, Mollerup C, Fougner SL, Pernow Y, Aas T, Hessman O, Rosén T, Nordenström J, Jansson S, Hellström M, Bollerslev J. Mortality and Morbidity in Mild Primary Hyperparathyroidism: Results From a 10-Year Prospective Randomized Controlled Trial of Parathyroidectomy Versus Observation. Annals of internal medicine. 2022 Jun:175(6):812-819. doi: 10.7326/M21-4416. Epub 2022 Apr 19     [PubMed PMID: 35436153]

Level 1 (high-level) evidence

[8]

Ilahi A, Muco E, Ilahi TB. Anatomy, Head and Neck, Parathyroid. StatPearls. 2024 Jan:():     [PubMed PMID: 30725888]


[9]

Chen RA, Goodman WG. Role of the calcium-sensing receptor in parathyroid gland physiology. American journal of physiology. Renal physiology. 2004 Jun:286(6):F1005-11     [PubMed PMID: 15130894]


[10]

Minisola S, Arnold A, Belaya Z, Brandi ML, Clarke BL, Hannan FM, Hofbauer LC, Insogna KL, Lacroix A, Liberman U, Palermo A, Pepe J, Rizzoli R, Wermers R, Thakker RV. Epidemiology, Pathophysiology, and Genetics of Primary Hyperparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Nov:37(11):2315-2329. doi: 10.1002/jbmr.4665. Epub 2022 Oct 17     [PubMed PMID: 36245271]


[11]

Sell J, Ramirez S, Partin M. Parathyroid Disorders. American family physician. 2022 Mar 1:105(3):289-298     [PubMed PMID: 35289573]


[12]

Bilezikian JP, Bandeira L, Khan A, Cusano NE. Hyperparathyroidism. Lancet (London, England). 2018 Jan 13:391(10116):168-178. doi: 10.1016/S0140-6736(17)31430-7. Epub 2017 Sep 17     [PubMed PMID: 28923463]


[13]

Barczyński M, Bränström R, Dionigi G, Mihai R. Sporadic multiple parathyroid gland disease--a consensus report of the European Society of Endocrine Surgeons (ESES). Langenbeck's archives of surgery. 2015 Dec:400(8):887-905. doi: 10.1007/s00423-015-1348-1. Epub 2015 Nov 5     [PubMed PMID: 26542689]

Level 3 (low-level) evidence

[14]

Agirre L, de la Quintana A, Martínez G, Arana A, Servide MJ, Larrea J. Surgical results and the location of pathological glands in the treatment of primary sporadic hyperparathyroidism with negative preoperative (99m)Tc-sestamibi scintigraphy. Cirugia espanola. 2020 Dec 18:():. pii: S0009-739X(20)30385-7. doi: 10.1016/j.ciresp.2020.11.011. Epub 2020 Dec 18     [PubMed PMID: 33349461]


[15]

Nudelman IL, Deutsch AA, Reiss R. Primary hyperparathyroidism due to mediastinal parathyroid adenoma. International surgery. 1987 Apr-Jun:72(2):104-8     [PubMed PMID: 3610535]


[16]

Fingeret AL. Contemporary Evaluation and Management of Parathyroid Carcinoma. JCO oncology practice. 2021 Jan:17(1):17-21. doi: 10.1200/JOP.19.00540. Epub 2020 Feb 10     [PubMed PMID: 32040373]


[17]

Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM. Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer. 2007 May 1:109(9):1736-41     [PubMed PMID: 17372919]


[18]

Jha S, Simonds WF. Molecular and Clinical Spectrum of Primary Hyperparathyroidism. Endocrine reviews. 2023 Sep 15:44(5):779-818. doi: 10.1210/endrev/bnad009. Epub     [PubMed PMID: 36961765]


[19]

Jain M, Krasne DL, Singer FR, Giuliano AE. Recurrent primary hyperparathyroidism due to Type 1 parathyromatosis. Endocrine. 2017 Feb:55(2):643-650. doi: 10.1007/s12020-016-1139-7. Epub 2016 Oct 14     [PubMed PMID: 27743301]


[20]

Haciyanli M, Karaisli S, Gucek Haciyanli S, Atasever A, Arikan Etit D, Gur EO, Acar T. Parathyromatosis: a very rare cause of recurrent primary hyperparathyroidism - case report and review of the literature. Annals of the Royal College of Surgeons of England. 2019 Nov:101(8):e178-e183. doi: 10.1308/rcsann.2019.0105. Epub 2019 Sep 11     [PubMed PMID: 31509000]

Level 3 (low-level) evidence

[21]

Hage MP, Salti I, El-Hajj Fuleihan G. Parathyromatosis: a rare yet problematic etiology of recurrent and persistent hyperparathyroidism. Metabolism: clinical and experimental. 2012 Jun:61(6):762-75. doi: 10.1016/j.metabol.2011.11.001. Epub 2012 Jan 4     [PubMed PMID: 22221828]


[22]

Kollmorgen CF, Aust MR, Ferreiro JA, McCarthy JT, van Heerden JA. Parathyromatosis: a rare yet important cause of persistent or recurrent hyperparathyroidism. Surgery. 1994 Jul:116(1):111-5     [PubMed PMID: 8023257]


[23]

Tzotzas T, Goropoulos A, Karras S, Terzaki A, Siolos A, Doumas A, Zaramboukas T, Tigas S. Effective long-term management of parathyromatosis-related refractory hypercalcemia with a combination of denosumab and cinacalcet treatment. Hormones (Athens, Greece). 2022 Mar:21(1):171-176. doi: 10.1007/s42000-021-00343-w. Epub 2022 Jan 7     [PubMed PMID: 34993886]


[24]

Rajkumar V, Levine SN. Normocalcemic Hyperparathyroidism. StatPearls. 2024 Jan:():     [PubMed PMID: 32310427]


[25]

Mifsud S, Cilia K, Mifsud EL, Gruppetta M. Lithium-associated hyperparathyroidism. British journal of hospital medicine (London, England : 2005). 2020 Nov 2:81(11):1-9. doi: 10.12968/hmed.2020.0457. Epub 2020 Nov 17     [PubMed PMID: 33263481]


[26]

McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. Lancet (London, England). 2012 Feb 25:379(9817):721-8. doi: 10.1016/S0140-6736(11)61516-X. Epub 2012 Jan 20     [PubMed PMID: 22265699]

Level 1 (high-level) evidence

[27]

Lerena VS, León NS, Sosa S, Deligiannis NG, Danilowicz K, Rizzo LFL. Lithium and endocrine dysfunction. Medicina. 2022:82(1):130-137     [PubMed PMID: 35037871]


[28]

Vakiti A, Anastasopoulou C, Mewawalla P. Malignancy-Related Hypercalcemia. StatPearls. 2024 Jan:():     [PubMed PMID: 29494030]


[29]

Mirrakhimov AE. Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. North American journal of medical sciences. 2015 Nov:7(11):483-93. doi: 10.4103/1947-2714.170600. Epub     [PubMed PMID: 26713296]


[30]

Guise TA, Wysolmerski JJ. Cancer-Associated Hypercalcemia. The New England journal of medicine. 2022 Apr 14:386(15):1443-1451. doi: 10.1056/NEJMcp2113128. Epub     [PubMed PMID: 35417639]


[31]

Wassif WS, Moniz CF, Friedman E, Wong S, Weber G, Nordenskjöld M, Peters TJ, Larsson C. Familial isolated hyperparathyroidism: a distinct genetic entity with an increased risk of parathyroid cancer. The Journal of clinical endocrinology and metabolism. 1993 Dec:77(6):1485-9     [PubMed PMID: 7903311]


[32]

Simonds WF, James-Newton LA, Agarwal SK, Yang B, Skarulis MC, Hendy GN, Marx SJ. Familial isolated hyperparathyroidism: clinical and genetic characteristics of 36 kindreds. Medicine. 2002 Jan:81(1):1-26     [PubMed PMID: 11807402]


[33]

Dionisi S, Minisola S, Pepe J, De Geronimo S, Paglia F, Memeo L, Fitzpatrick LA. Concurrent parathyroid adenomas and carcinoma in the setting of multiple endocrine neoplasia type 1: presentation as hypercalcemic crisis. Mayo Clinic proceedings. 2002 Aug:77(8):866-9     [PubMed PMID: 12173721]


[34]

Agha A, Carpenter R, Bhattacharya S, Edmonson SJ, Carlsen E, Monson JP. Parathyroid carcinoma in multiple endocrine neoplasia type 1 (MEN1) syndrome: two case reports of an unrecognised entity. Journal of endocrinological investigation. 2007 Feb:30(2):145-9     [PubMed PMID: 17392605]

Level 3 (low-level) evidence

[35]

Blau JE, Simonds WF. Familial Hyperparathyroidism. Frontiers in endocrinology. 2021:12():623667. doi: 10.3389/fendo.2021.623667. Epub 2021 Feb 25     [PubMed PMID: 33716975]


[36]

Giusti F, Tonelli F, Brandi ML. Primary hyperparathyroidism in multiple endocrine neoplasia type 1: when to perform surgery? Clinics (Sao Paulo, Brazil). 2012:67 Suppl 1(Suppl 1):141-4     [PubMed PMID: 22584719]


[37]

Singh G, Mulji NJ, Jialal I. Multiple Endocrine Neoplasia Type 1. StatPearls. 2024 Jan:():     [PubMed PMID: 30725665]


[38]

Yasir M, Mulji NJ, Kasi A. Multiple Endocrine Neoplasias Type 2. StatPearls. 2024 Jan:():     [PubMed PMID: 30085596]


[39]

Ahmed FW, Majeed MS, Kirresh O. Multiple Endocrine Neoplasias Type 4. StatPearls. 2024 Jan:():     [PubMed PMID: 33760487]


[40]

Redwin Dhas MP, Karthiga KS, Tatu JE, Eugenia SJ. Hyper Parathyroidisim Jaw Tumor Syndrome: A Rare Condition of Incongruous Features. Ethiopian journal of health sciences. 2017 May:27(3):309-313     [PubMed PMID: 29217931]


[41]

Lee JY, Shoback DM. Familial hypocalciuric hypercalcemia and related disorders. Best practice & research. Clinical endocrinology & metabolism. 2018 Oct:32(5):609-619. doi: 10.1016/j.beem.2018.05.004. Epub 2018 May 26     [PubMed PMID: 30449544]


[42]

Afzal M, Kathuria P. Familial Hypocalciuric Hypercalcemia. StatPearls. 2024 Jan:():     [PubMed PMID: 29083672]


[43]

Alfadda TI, Saleh AM, Houillier P, Geibel JP. Calcium-sensing receptor 20 years later. American journal of physiology. Cell physiology. 2014 Aug 1:307(3):C221-31. doi: 10.1152/ajpcell.00139.2014. Epub 2014 May 28     [PubMed PMID: 24871857]


[44]

Bilezikian JP. Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2018 Nov 1:103(11):3993-4004. doi: 10.1210/jc.2018-01225. Epub     [PubMed PMID: 30060226]


[45]

Vaidya A, Curhan GC, Paik JM, Kronenberg H, Taylor EN. Hypertension, Antihypertensive Medications, and Risk of Incident Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2015 Jun:100(6):2396-404. doi: 10.1210/jc.2015-1619. Epub 2015 Apr 17     [PubMed PMID: 25885946]


[46]

Boehm BO, Rosinger S, Belyi D, Dietrich JW. The parathyroid as a target for radiation damage. The New England journal of medicine. 2011 Aug 18:365(7):676-8. doi: 10.1056/NEJMc1104982. Epub     [PubMed PMID: 21848480]


[47]

Szalat A, Mazeh H, Freund HR. Lithium-associated hyperparathyroidism: report of four cases and review of the literature. European journal of endocrinology. 2009 Feb:160(2):317-23. doi: 10.1530/EJE-08-0620. Epub 2008 Nov 10     [PubMed PMID: 19001061]

Level 3 (low-level) evidence

[48]

Vaidya A, Curhan GC, Paik JM, Wang M, Taylor EN. Physical Activity and the Risk of Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2016 Apr:101(4):1590-7. doi: 10.1210/jc.2015-3836. Epub 2016 Jan 26     [PubMed PMID: 26812691]


[49]

Vaidya A, Curhan GC, Paik JM, Wang M, Taylor EN. Body Size and the Risk of Primary Hyperparathyroidism in Women: A Cohort Study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2017 Sep:32(9):1900-1906. doi: 10.1002/jbmr.3168. Epub 2017 Jun 12     [PubMed PMID: 28488734]


[50]

Paik JM, Curhan GC, Taylor EN. Calcium intake and risk of primary hyperparathyroidism in women: prospective cohort study. BMJ (Clinical research ed.). 2012 Oct 17:345():e6390. doi: 10.1136/bmj.e6390. Epub 2012 Oct 17     [PubMed PMID: 23080543]


[51]

Griebeler ML, Kearns AE, Ryu E, Thapa P, Hathcock MA, Melton LJ 3rd, Wermers RA. Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades. The Journal of clinical endocrinology and metabolism. 2016 Mar:101(3):1166-73. doi: 10.1210/jc.2015-3964. Epub 2016 Jan 11     [PubMed PMID: 26751196]


[52]

Silva BC, Cusano NE, Bilezikian JP. Primary hyperparathyroidism. Best practice & research. Clinical endocrinology & metabolism. 2024 Jan:38(1):101247. doi: 10.1016/j.beem.2018.09.013. Epub 2018 Sep 28     [PubMed PMID: 30477754]


[53]

Silverberg SJ, Bilezikian JP. The diagnosis and management of asymptomatic primary hyperparathyroidism. Nature clinical practice. Endocrinology & metabolism. 2006 Sep:2(9):494-503     [PubMed PMID: 16957763]


[54]

Marcocci C, Cetani F, Rubin MR, Silverberg SJ, Pinchera A, Bilezikian JP. Parathyroid carcinoma. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2008 Dec:23(12):1869-80. doi: 10.1359/jbmr.081018. Epub     [PubMed PMID: 19016595]


[55]

Chen JD, Morrison C, Zhang C, Kahnoski K, Carpten JD, Teh BT. Hyperparathyroidism-jaw tumour syndrome. Journal of internal medicine. 2003 Jun:253(6):634-42     [PubMed PMID: 12755959]


[56]

Carpten JD, Robbins CM, Villablanca A, Forsberg L, Presciuttini S, Bailey-Wilson J, Simonds WF, Gillanders EM, Kennedy AM, Chen JD, Agarwal SK, Sood R, Jones MP, Moses TY, Haven C, Petillo D, Leotlela PD, Harding B, Cameron D, Pannett AA, Höög A, Heath H 3rd, James-Newton LA, Robinson B, Zarbo RJ, Cavaco BM, Wassif W, Perrier ND, Rosen IB, Kristoffersson U, Turnpenny PD, Farnebo LO, Besser GM, Jackson CE, Morreau H, Trent JM, Thakker RV, Marx SJ, Teh BT, Larsson C, Hobbs MR. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nature genetics. 2002 Dec:32(4):676-80     [PubMed PMID: 12434154]


[57]

McLaughlin MB, Awosika AO, Jialal I. Calcitonin. StatPearls. 2024 Jan:():     [PubMed PMID: 30725954]


[58]

Bergwitz C, Jüppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annual review of medicine. 2010:61():91-104. doi: 10.1146/annurev.med.051308.111339. Epub     [PubMed PMID: 20059333]


[59]

Weber TJ, Quarles LD. Molecular Control of Phosphorus Homeostasis and Precision Treatment of Hypophosphatemic Disorders. Current molecular biology reports. 2019 Jun:5(2):75-85. doi: 10.1007/s40610-019-0118-1. Epub 2019 Feb 9     [PubMed PMID: 31871877]


[60]

Matikainen N, Pekkarinen T, Ryhänen EM, Schalin-Jäntti C. Physiology of Calcium Homeostasis: An Overview. Endocrinology and metabolism clinics of North America. 2021 Dec:50(4):575-590. doi: 10.1016/j.ecl.2021.07.005. Epub     [PubMed PMID: 34774235]

Level 3 (low-level) evidence

[61]

Uenishi K, Tokiwa M, Kato S, Shiraki M. Stimulation of intestinal calcium absorption by orally administrated vitamin D3 compounds: a prospective open-label randomized trial in osteoporosis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2018 Mar:29(3):723-732. doi: 10.1007/s00198-017-4351-2. Epub 2017 Dec 23     [PubMed PMID: 29273827]

Level 1 (high-level) evidence

[62]

Muppidi V, Meegada SR, Rehman A. Secondary Hyperparathyroidism. StatPearls. 2024 Jan:():     [PubMed PMID: 32491754]


[63]

Sizar O, Khare S, Goyal A, Givler A. Vitamin D Deficiency. StatPearls. 2024 Jan:():     [PubMed PMID: 30335299]


[64]

Lung BE, Mowery ML, Komatsu DEE. Calcitriol. StatPearls. 2024 Jan:():     [PubMed PMID: 30252281]


[65]

Bindroo S, Quintanilla Rodriguez BS, Challa HJ. Renal Failure. StatPearls. 2024 Jan:():     [PubMed PMID: 30085554]


[66]

Lepage R, Roy L, Brossard JH, Rousseau L, Dorais C, Lazure C, D'Amour P. A non-(1-84) circulating parathyroid hormone (PTH) fragment interferes significantly with intact PTH commercial assay measurements in uremic samples. Clinical chemistry. 1998 Apr:44(4):805-9     [PubMed PMID: 9554492]


[67]

Quarles LD, Lobaugh B, Murphy G. Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia. The Journal of clinical endocrinology and metabolism. 1992 Jul:75(1):145-50     [PubMed PMID: 1619003]


[68]

Martin KJ, González EA. Metabolic bone disease in chronic kidney disease. Journal of the American Society of Nephrology : JASN. 2007 Mar:18(3):875-85     [PubMed PMID: 17251386]


[69]

Yuen NK, Ananthakrishnan S, Campbell MJ. Hyperparathyroidism of Renal Disease. The Permanente journal. 2016 Summer:20(3):15-127. doi: 10.7812/TPP/15-127. Epub 2016 Jul 22     [PubMed PMID: 27479950]


[70]

Tominaga Y, Tanaka Y, Sato K, Nagasaka T, Takagi H. Histopathology, pathophysiology, and indications for surgical treatment of renal hyperparathyroidism. Seminars in surgical oncology. 1997 Mar-Apr:13(2):78-86     [PubMed PMID: 9088063]


[71]

Madorin C, Owen RP, Fraser WD, Pellitteri PK, Radbill B, Rinaldo A, Seethala RR, Shaha AR, Silver CE, Suh MY, Weinstein B, Ferlito A. The surgical management of renal hyperparathyroidism. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2012 Jun:269(6):1565-76. doi: 10.1007/s00405-011-1833-2. Epub 2011 Nov 20     [PubMed PMID: 22101574]


[72]

Shah A, Hashmi MF, Aeddula NR. Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD). StatPearls. 2024 Jan:():     [PubMed PMID: 32809577]


[73]

Fleischer J, Becker C, Hamele-Bena D, Breen TL, Silverberg SJ. Oxyphil parathyroid adenoma: a malignant presentation of a benign disease. The Journal of clinical endocrinology and metabolism. 2004 Dec:89(12):5948-51     [PubMed PMID: 15579742]


[74]

El-Hajj Fuleihan G, Chakhtoura M, Cipriani C, Eastell R, Karonova T, Liu JM, Minisola S, Mithal A, Moreira CA, Peacock M, Schini M, Silva B, Walker M, El Zein O, Marcocci C. Classical and Nonclassical Manifestations of Primary Hyperparathyroidism. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Nov:37(11):2330-2350. doi: 10.1002/jbmr.4679. Epub 2022 Oct 17     [PubMed PMID: 36245249]


[75]

Zhu CY, Sturgeon C, Yeh MW. Diagnosis and Management of Primary Hyperparathyroidism. JAMA. 2020 Mar 24:323(12):1186-1187. doi: 10.1001/jama.2020.0538. Epub     [PubMed PMID: 32031566]


[76]

Cipriani C, Biamonte F, Costa AG, Zhang C, Biondi P, Diacinti D, Pepe J, Piemonte S, Scillitani A, Minisola S, Bilezikian JP. Prevalence of kidney stones and vertebral fractures in primary hyperparathyroidism using imaging technology. The Journal of clinical endocrinology and metabolism. 2015 Apr:100(4):1309-15. doi: 10.1210/jc.2014-3708. Epub 2015 Feb 3     [PubMed PMID: 25646791]


[77]

Tay YD, Liu M, Bandeira L, Bucovsky M, Lee JA, Silverberg SJ, Walker MD. Occult urolithiasis in asymptomatic primary hyperparathyroidism. Endocrine research. 2018 May:43(2):106-115. doi: 10.1080/07435800.2018.1431275. Epub 2018 Feb 5     [PubMed PMID: 29400579]


[78]

Lesser T, Bartel M. [Primary hyperparathyroidism. Pathogenesis--diagnosis--therapy]. Zentralblatt fur Chirurgie. 1992:117(1):41-9     [PubMed PMID: 1546499]


[79]

Sadiq NM, Naganathan S, Badireddy M. Hypercalcemia. StatPearls. 2024 Jan:():     [PubMed PMID: 28613465]


[80]

Li SR, McCoy KL, Levitt HE, Kelley ML, Carty SE, Yip L. Is routine 24-hour urine calcium measurement useful during the evaluation of primary hyperparathyroidism? Surgery. 2022 Jan:171(1):17-22. doi: 10.1016/j.surg.2021.04.055. Epub 2021 Jul 27     [PubMed PMID: 34325903]


[81]

Mollerup CL, Vestergaard P, Frøkjaer VG, Mosekilde L, Christiansen P, Blichert-Toft M. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. BMJ (Clinical research ed.). 2002 Oct 12:325(7368):807     [PubMed PMID: 12376441]

Level 2 (mid-level) evidence

[82]

Leslie SW, Sajjad H, Bashir K. 24-Hour Urine Testing for Nephrolithiasis: Interpretation and Treatment Guidelines. StatPearls. 2024 Jan:():     [PubMed PMID: 29494055]


[83]

Sawhney S, Vaish R, Jain S, Mittal N, Ankathi SK, Thiagarajan S, Chaukar D. Parathyroid Carcinoma: a Review. Indian journal of surgical oncology. 2022 Mar:13(1):133-142. doi: 10.1007/s13193-021-01343-3. Epub 2021 Jun 3     [PubMed PMID: 35462650]


[84]

Fitzpatrick LA, Bilezikian JP. Acute primary hyperparathyroidism. The American journal of medicine. 1987 Feb:82(2):275-82     [PubMed PMID: 3812520]


[85]

Bayat-Mokhtari F, Palmieri GM, Moinuddin M, Pourmand R. Parathyroid storm. Archives of internal medicine. 1980 Aug:140(8):1092-5     [PubMed PMID: 7396615]


[86]

Rock K, Fattah N, O'Malley D, McDermott E. The management of acute parathyroid crisis secondary to parathyroid carcinoma: a case report. Journal of medical case reports. 2010 Jan 29:4():28. doi: 10.1186/1752-1947-4-28. Epub 2010 Jan 29     [PubMed PMID: 20181049]

Level 3 (low-level) evidence

[87]

Ameerudden S, He X. Management and surgical treatment of parathyroid crisis secondary to parathyroid tumors: report of four cases. International medical case reports journal. 2011:4():59-66. doi: 10.2147/IMCRJ.S23764. Epub 2011 Aug 15     [PubMed PMID: 23754908]

Level 3 (low-level) evidence

[88]

Bedini I, Sylvestre Begnis G, Poenitz F, Polillo DC, Vargas MC, Bolzán D, Ramírez Stieben LA. Hypercalcemic crisis as a presentation of primary hyperparathyroidism. Medicina. 2023:83(5):804-807     [PubMed PMID: 37870339]


[89]

das Neves MC, Rosano M, Ohe MN, de Mello GM, Ribeiro DK, Santos RO. Planned parathyroidectomy: the new standard in hypercalcemic crisis. Archives of endocrinology and metabolism. 2023 May 12:67(4):e000613. doi: 10.20945/2359-3997000000613. Epub     [PubMed PMID: 37252701]


[90]

Jadhao P, Mangaraj S. Utility of denosumab therapy in management of severe hypercalcaemia caused by primary hyperparathyroidism - Case report with review of literature. The journal of the Royal College of Physicians of Edinburgh. 2023 Jun:53(2):104-108. doi: 10.1177/14782715231159741. Epub 2023 Feb 24     [PubMed PMID: 36825782]

Level 3 (low-level) evidence

[91]

Hayashi S, Oba T, Ichikawa K, Nakamura C, Hara Y, Kanai T, Sato Y, Uehara T, Ito KI. Hypercalcemic crisis caused by primary hyperparathyroidism in a 11-year-old boy: a rare case report and review of the literature. Gland surgery. 2022 Jul:11(7):1279-1286. doi: 10.21037/gs-22-92. Epub     [PubMed PMID: 35935565]

Level 3 (low-level) evidence

[92]

El-Hajj Fuleihan G, Clines GA, Hu MI, Marcocci C, Murad MH, Piggott T, Van Poznak C, Wu JY, Drake MT. Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2023 Feb 15:108(3):507-528. doi: 10.1210/clinem/dgac621. Epub     [PubMed PMID: 36545746]

Level 1 (high-level) evidence

[93]

Koo WS, Jeon DS, Ahn SJ, Kim YS, Yoon YS, Bang BK. Calcium-free hemodialysis for the management of hypercalcemia. Nephron. 1996:72(3):424-8     [PubMed PMID: 8852491]


[94]

Leehey DJ, Ing TS. Correction of hypercalcemia and hypophosphatemia by hemodialysis using a conventional, calcium-containing dialysis solution enriched with phosphorus. American journal of kidney diseases : the official journal of the National Kidney Foundation. 1997 Feb:29(2):288-90     [PubMed PMID: 9016904]


[95]

Sala TD, Mureşan S, Roman R, Lazăr A, Ion R, Paşcanu I. Hypercalcaemic Crisis Due to Primary Hyperparathyroidism: Report of Two Cases. Journal of critical care medicine (Universitatea de Medicina si Farmacie din Targu-Mures). 2019 Jan:5(1):34-39. doi: 10.2478/jccm-2019-0004. Epub 2019 Feb 4     [PubMed PMID: 30766921]

Level 3 (low-level) evidence

[96]

Naji Rad S, Anastasopoulou C, Barnett MJ, Deluxe L. Osteitis Fibrosa Cystica. StatPearls. 2024 Jan:():     [PubMed PMID: 32644523]


[97]

Souberbielle JC, Cormier C, Kindermans C, Gao P, Cantor T, Forette F, Baulieu EE. Vitamin D status and redefining serum parathyroid hormone reference range in the elderly. The Journal of clinical endocrinology and metabolism. 2001 Jul:86(7):3086-90     [PubMed PMID: 11443171]


[98]

Piketty ML, Prie D, Sedel F, Bernard D, Hercend C, Chanson P, Souberbielle JC. High-dose biotin therapy leading to false biochemical endocrine profiles: validation of a simple method to overcome biotin interference. Clinical chemistry and laboratory medicine. 2017 May 1:55(6):817-825. doi: 10.1515/cclm-2016-1183. Epub     [PubMed PMID: 28222020]

Level 1 (high-level) evidence

[99]

Lasbleiz A, Paladino NC, Romanet P, Castinetti F, Cuny T, Sebag F, Taïeb D. Familial hypocalciuric hypercalcemia: the challenge of diagnosis. Endocrine. 2022 Feb:75(2):646-649. doi: 10.1007/s12020-021-02909-5. Epub 2021 Oct 29     [PubMed PMID: 34714514]


[100]

De Sousa SMC, Carroll RW, Henderson A, Burgess J, Clifton-Bligh RJ. A contemporary clinical approach to genetic testing for heritable hyperparathyroidism syndromes. Endocrine. 2022 Jan:75(1):23-32. doi: 10.1007/s12020-021-02927-3. Epub 2021 Nov 13     [PubMed PMID: 34773560]


[101]

Civelek AC, Ozalp E, Donovan P, Udelsman R. Prospective evaluation of delayed technetium-99m sestamibi SPECT scintigraphy for preoperative localization of primary hyperparathyroidism. Surgery. 2002 Feb:131(2):149-57     [PubMed PMID: 11854692]


[102]

Van Husen R, Kim LT. Accuracy of surgeon-performed ultrasound in parathyroid localization. World journal of surgery. 2004 Nov:28(11):1122-6     [PubMed PMID: 15490067]


[103]

Aksoy-Altinboga A, Akder Sari A, Rezanko T, Haciyanli M, Orgen Calli A. Parathyromatosis: critical diagnosis regarding surgery and pathologic evaluation. Korean journal of pathology. 2012 Apr:46(2):197-200. doi: 10.4132/KoreanJPathol.2012.46.2.197. Epub 2012 Apr 25     [PubMed PMID: 23110001]


[104]

Cheung K, Wang TS, Farrokhyar F, Roman SA, Sosa JA. A meta-analysis of preoperative localization techniques for patients with primary hyperparathyroidism. Annals of surgical oncology. 2012 Feb:19(2):577-83. doi: 10.1245/s10434-011-1870-5. Epub 2011 Jun 28     [PubMed PMID: 21710322]

Level 1 (high-level) evidence

[105]

Petranović Ovčariček P, Giovanella L, Carrió Gasset I, Hindié E, Huellner MW, Luster M, Piccardo A, Weber T, Talbot JN, Verburg FA. The EANM practice guidelines for parathyroid imaging. European journal of nuclear medicine and molecular imaging. 2021 Aug:48(9):2801-2822. doi: 10.1007/s00259-021-05334-y. Epub 2021 Apr 10     [PubMed PMID: 33839893]

Level 1 (high-level) evidence

[106]

Broome DT, Naples R, Bailey R, Tekin Z, Hamidi M, Bena JF, Morrison SL, Berber E, Siperstein AE, Scharpf J, Skugor M. Use of Preoperative Imaging in Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2021 Jan 1:106(1):e328-e337. doi: 10.1210/clinem/dgaa779. Epub     [PubMed PMID: 33119066]


[107]

Yeh R, Tay YD, Tabacco G, Dercle L, Kuo JH, Bandeira L, McManus C, Leung DK, Lee JA, Bilezikian JP. Diagnostic Performance of 4D CT and Sestamibi SPECT/CT in Localizing Parathyroid Adenomas in Primary Hyperparathyroidism. Radiology. 2019 May:291(2):469-476. doi: 10.1148/radiol.2019182122. Epub 2019 Mar 5     [PubMed PMID: 30835187]


[108]

Kelly HR, Bunch PM. Parathyroid Computed Tomography: Pearls, Pitfalls, and Our Approach. Neuroimaging clinics of North America. 2022 May:32(2):413-431. doi: 10.1016/j.nic.2022.01.006. Epub     [PubMed PMID: 35526965]


[109]

Dekorsy FJ, Beyer L, Spitzweg C, Schmidmaier R, Todica A, Trupka A, Cyran CC, Berger F, Ladurner R, Zimmermann P, Knösel T, Bartenstein P, Lottspeich C, Wenter V. Preoperative Imaging with [(18)F]-Fluorocholine PET/CT in Primary Hyperparathyroidism. Journal of clinical medicine. 2022 May 23:11(10):. doi: 10.3390/jcm11102944. Epub 2022 May 23     [PubMed PMID: 35629070]


[110]

Şentürk A, Aysan E. A New Technique for Localization of Parathyroid Adenoma: Infrared Thermal Scanning of the Neck. Cureus. 2023 Oct:15(10):e47977. doi: 10.7759/cureus.47977. Epub 2023 Oct 30     [PubMed PMID: 38034183]


[111]

Ho J, Kim D, Lee JE, Hong N, Kim BM, Kim DJ, Kim J, Lee CR, Kang SW, Jeong JJ, Nam KH, Chung WY, Rhee Y. Parathyroid venous sampling for the preoperative localisation of parathyroid adenoma in patients with primary hyperparathyroidism. Scientific reports. 2022 Apr 29:12(1):7058. doi: 10.1038/s41598-022-11238-0. Epub 2022 Apr 29     [PubMed PMID: 35487946]


[112]

Gücek Hacıyanlı S, Acar N, Ballı Ö, Erdoğan N, Hacıyanlı M. Selective venous sampling in primary hyperparathyroidism: Is it worth doing? Turkish journal of medical sciences. 2022 Feb:52(1):144-149. doi: 10.3906/sag-2108-151. Epub 2022 Feb 22     [PubMed PMID: 34688240]


[113]

Silva BC, Boutroy S, Zhang C, McMahon DJ, Zhou B, Wang J, Udesky J, Cremers S, Sarquis M, Guo XD, Hans D, Bilezikian JP. Trabecular bone score (TBS)--a novel method to evaluate bone microarchitectural texture in patients with primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2013 May:98(5):1963-70. doi: 10.1210/jc.2012-4255. Epub 2013 Mar 22     [PubMed PMID: 23526463]


[114]

Hansen S, Hauge EM, Rasmussen L, Jensen JE, Brixen K. Parathyroidectomy improves bone geometry and microarchitecture in female patients with primary hyperparathyroidism: a one-year prospective controlled study using high-resolution peripheral quantitative computed tomography. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2012 May:27(5):1150-8. doi: 10.1002/jbmr.1540. Epub     [PubMed PMID: 22228118]


[115]

Stein EM, Silva BC, Boutroy S, Zhou B, Wang J, Udesky J, Zhang C, McMahon DJ, Romano M, Dworakowski E, Costa AG, Cusano N, Irani D, Cremers S, Shane E, Guo XE, Bilezikian JP. Primary hyperparathyroidism is associated with abnormal cortical and trabecular microstructure and reduced bone stiffness in postmenopausal women. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013 May:28(5):1029-40. doi: 10.1002/jbmr.1841. Epub     [PubMed PMID: 23225022]


[116]

Vu TD, Wang XF, Wang Q, Cusano NE, Irani D, Silva BC, Ghasem-Zadeh A, Udesky J, Romano ME, Zebaze R, Jerums G, Boutroy S, Bilezikian JP, Seeman E. New insights into the effects of primary hyperparathyroidism on the cortical and trabecular compartments of bone. Bone. 2013 Jul:55(1):57-63. doi: 10.1016/j.bone.2013.03.009. Epub 2013 Mar 26     [PubMed PMID: 23541782]


[117]

Khosla S, Melton LJ 3rd, Wermers RA, Crowson CS, O'Fallon Wm, Riggs Bl. Primary hyperparathyroidism and the risk of fracture: a population-based study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 1999 Oct:14(10):1700-7     [PubMed PMID: 10491217]


[118]

Vignali E, Viccica G, Diacinti D, Cetani F, Cianferotti L, Ambrogini E, Banti C, Del Fiacco R, Bilezikian JP, Pinchera A, Marcocci C. Morphometric vertebral fractures in postmenopausal women with primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2009 Jul:94(7):2306-12. doi: 10.1210/jc.2008-2006. Epub 2009 Apr 28     [PubMed PMID: 19401378]


[119]

Mosekilde L. Primary hyperparathyroidism and the skeleton. Clinical endocrinology. 2008 Jul:69(1):1-19. doi: 10.1111/j.1365-2265.2007.03162.x. Epub 2008 Jul 1     [PubMed PMID: 18167138]


[120]

Liu M, Williams J, Kuo J, Lee JA, Silverberg SJ, Walker MD. Risk factors for vertebral fracture in primary hyperparathyroidism. Endocrine. 2019 Dec:66(3):682-690. doi: 10.1007/s12020-019-02099-1. Epub 2019 Oct 3     [PubMed PMID: 31583576]


[121]

Ye Z, Silverberg SJ, Sreekanta A, Tong K, Wang Y, Chang Y, Zhang M, Guyatt G, Tangamornsuksun W, Zhang Y, Manja V, Bakaa L, Couban RJ, Brandi ML, Clarke B, Khan AA, Mannstadt M, Bilezikian JP. The Efficacy and Safety of Medical and Surgical Therapy in Patients With Primary Hyperparathyroidism: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2022 Nov:37(11):2351-2372. doi: 10.1002/jbmr.4685. Epub 2022 Oct 17     [PubMed PMID: 36053960]

Level 1 (high-level) evidence

[122]

Walker MD, Bilezikian JP. Vitamin D and primary hyperparathyroidism: more insights into a complex relationship. Endocrine. 2017 Jan:55(1):3-5. doi: 10.1007/s12020-016-1169-1. Epub 2016 Nov 17     [PubMed PMID: 27858283]


[123]

Battista C, Guarnieri V, Carnevale V, Baorda F, Pileri M, Garrubba M, Salcuni AS, Chiodini I, Minisola S, Romagnoli E, Eller-Vainicher C, Santini SA, Parisi S, Frusciante V, Fontana A, Copetti M, Hendy GN, Scillitani A, Cole DE. Vitamin D status in primary hyperparathyroidism: effect of genetic background. Endocrine. 2017 Jan:55(1):266-272. doi: 10.1007/s12020-016-0974-x. Epub 2016 May 6     [PubMed PMID: 27154872]


[124]

Rolighed L, Rejnmark L, Sikjaer T, Heickendorff L, Vestergaard P, Mosekilde L, Christiansen P. Vitamin D treatment in primary hyperparathyroidism: a randomized placebo controlled trial. The Journal of clinical endocrinology and metabolism. 2014 Mar:99(3):1072-80. doi: 10.1210/jc.2013-3978. Epub 2014 Jan 13     [PubMed PMID: 24423366]

Level 1 (high-level) evidence

[125]

Rubin MR, Bilezikian JP, McMahon DJ, Jacobs T, Shane E, Siris E, Udesky J, Silverberg SJ. The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years. The Journal of clinical endocrinology and metabolism. 2008 Sep:93(9):3462-70. doi: 10.1210/jc.2007-1215. Epub 2008 Jun 10     [PubMed PMID: 18544625]


[126]

Faggiano A, Di Somma C, Ramundo V, Severino R, Vuolo L, Coppola A, Panico F, Savastano S, Lombardi G, Colao A, Gasperi M. Cinacalcet hydrochloride in combination with alendronate normalizes hypercalcemia and improves bone mineral density in patients with primary hyperparathyroidism. Endocrine. 2011 Jun:39(3):283-7. doi: 10.1007/s12020-011-9459-0. Epub 2011 Mar 29     [PubMed PMID: 21445714]


[127]

Keutgen XM, Buitrago D, Filicori F, Kundel A, Elemento O, Fahey TJ 3rd, Zarnegar R. Calcimimetics versus parathyroidectomy for treatment of primary hyperparathyroidism: retrospective chart analysis of a prospective database. Annals of surgery. 2012 May:255(5):981-5. doi: 10.1097/SLA.0b013e31824c5252. Epub     [PubMed PMID: 22470074]

Level 2 (mid-level) evidence

[128]

Kuchay MS, Mathew A, Kaur P, Mishra SK. Denosumab can be used successfully as a bridge to surgery in patients with severe hypercalcemia due to primary hyperparathyroidism. Archives of endocrinology and metabolism. 2021 Oct 29:65(5):669-673. doi: 10.20945/2359-3997000000408. Epub 2021 Sep 29     [PubMed PMID: 34591412]


[129]

Eller-Vainicher C, Palmieri S, Cairoli E, Goggi G, Scillitani A, Arosio M, Falchetti A, Chiodini I. Protective Effect of Denosumab on Bone in Older Women with Primary Hyperparathyroidism. Journal of the American Geriatrics Society. 2018 Mar:66(3):518-524. doi: 10.1111/jgs.15250. Epub 2018 Jan 24     [PubMed PMID: 29364518]


[130]

Roukain A, Alwan H, Bongiovanni M, Sykiotis GP, Kopp PA. Denosumab for the Treatment of Hypercalcemia in a Patient With Parathyroid Carcinoma: A Case Report. Frontiers in endocrinology. 2021:12():794988. doi: 10.3389/fendo.2021.794988. Epub 2022 Jan 31     [PubMed PMID: 35173680]

Level 3 (low-level) evidence

[131]

Vellanki P, Lange K, Elaraj D, Kopp PA, El Muayed M. Denosumab for management of parathyroid carcinoma-mediated hypercalcemia. The Journal of clinical endocrinology and metabolism. 2014 Feb:99(2):387-90. doi: 10.1210/jc.2013-3031. Epub 2013 Oct 31     [PubMed PMID: 24178790]


[132]

Nadarasa K, Theodoraki A, Kurzawinski TR, Carpenter R, Bull J, Chung TT, Drake WM. Denosumab for management of refractory hypercalcaemia in recurrent parathyroid carcinoma. European journal of endocrinology. 2014 Sep:171(3):L7-8. doi: 10.1530/EJE-14-0482. Epub 2014 Jun 17     [PubMed PMID: 24939719]


[133]

Collins MT, Skarulis MC, Bilezikian JP, Silverberg SJ, Spiegel AM, Marx SJ. Treatment of hypercalcemia secondary to parathyroid carcinoma with a novel calcimimetic agent. The Journal of clinical endocrinology and metabolism. 1998 Apr:83(4):1083-8     [PubMed PMID: 9543122]


[134]

Chandran M, Bilezikian JP, Lau J, Rajeev R, Yang SP, Samuel M, Parameswaran R. The efficacy and safety of cinacalcet in primary hyperparathyroidism: a systematic review and meta-analysis of randomized controlled trials and cohort studies. Reviews in endocrine & metabolic disorders. 2022 Jun:23(3):485-501. doi: 10.1007/s11154-021-09694-6. Epub 2022 Jan 18     [PubMed PMID: 35041148]

Level 1 (high-level) evidence

[135]

Peacock M, Bolognese MA, Borofsky M, Scumpia S, Sterling LR, Cheng S, Shoback D. Cinacalcet treatment of primary hyperparathyroidism: biochemical and bone densitometric outcomes in a five-year study. The Journal of clinical endocrinology and metabolism. 2009 Dec:94(12):4860-7. doi: 10.1210/jc.2009-1472. Epub 2009 Oct 16     [PubMed PMID: 19837909]


[136]

Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. The Journal of clinical endocrinology and metabolism. 2014 Oct:99(10):3561-9. doi: 10.1210/jc.2014-1413. Epub 2014 Aug 27     [PubMed PMID: 25162665]


[137]

Yamamoto K, Nakano Y, Tokumasu K, Honda H, Hasegawa K, Sato A, Ogawa H, Obika M, Hanayama Y, Otsuka F. Relationship between patients' characteristics and efficacy of calcimimetics for primary hyperparathyroidism in the elderly. Clinical case reports. 2022 Apr:10(4):e05713. doi: 10.1002/ccr3.5713. Epub 2022 Apr 8     [PubMed PMID: 35425612]

Level 3 (low-level) evidence

[138]

Marcocci C, Chanson P, Shoback D, Bilezikian J, Fernandez-Cruz L, Orgiazzi J, Henzen C, Cheng S, Sterling LR, Lu J, Peacock M. Cinacalcet reduces serum calcium concentrations in patients with intractable primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2009 Aug:94(8):2766-72. doi: 10.1210/jc.2008-2640. Epub 2009 May 26     [PubMed PMID: 19470620]


[139]

Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2005 Jan:90(1):135-41     [PubMed PMID: 15522938]


[140]

Silverberg SJ, Rubin MR, Faiman C, Peacock M, Shoback DM, Smallridge RC, Schwanauer LE, Olson KA, Klassen P, Bilezikian JP. Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma. The Journal of clinical endocrinology and metabolism. 2007 Oct:92(10):3803-8     [PubMed PMID: 17666472]


[141]

Dandurand K, Ali DS, Khan AA. Primary Hyperparathyroidism: A Narrative Review of Diagnosis and Medical Management. Journal of clinical medicine. 2021 Apr 9:10(8):. doi: 10.3390/jcm10081604. Epub 2021 Apr 9     [PubMed PMID: 33918966]

Level 3 (low-level) evidence

[142]

Grey AB, Stapleton JP, Evans MC, Tatnell MA, Reid IR. Effect of hormone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism. A randomized, controlled trial. Annals of internal medicine. 1996 Sep 1:125(5):360-8     [PubMed PMID: 8702086]

Level 1 (high-level) evidence

[143]

Marcus R, Madvig P, Crim M, Pont A, Kosek J. Conjugated estrogens in the treatment of postmenopausal women with hyperparathyroidism. Annals of internal medicine. 1984 May:100(5):633-40     [PubMed PMID: 6324624]


[144]

Gallagher JC, Nordin BE. Treatment with with oestrogens of primary hyperparathyroidism in post-menopausal women. Lancet (London, England). 1972 Mar 4:1(7749):503-7     [PubMed PMID: 4110019]


[145]

Purnell DC, Scholz DA, Smith LH, Sizemore GW, Black MB, Goldsmith RS, Arnaud CD. Treatment of primary hyperparathyroidism. The American journal of medicine. 1974 Jun:56(6):800-9     [PubMed PMID: 4831317]


[146]

Broadus AE, Magee JS, Mallette LE, Horst RL, Lang R, Jensen PS, Gertner JM, Baron R. A detailed evaluation of oral phosphate therapy in selected patients with primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 1983 May:56(5):953-61     [PubMed PMID: 6300178]


[147]

Huang SY, Burchette R, Chung J, Haigh PI. Parathyroidectomy for nephrolithiasis in primary hyperparathyroidism: Beneficial but not a panacea. Surgery. 2022 Jan:171(1):29-34. doi: 10.1016/j.surg.2021.03.077. Epub 2021 Aug 4     [PubMed PMID: 34364687]


[148]

Charles PY, Letavernier E, Périé S, Gauthé M, Daudon M, Haymann JP. Effect of parathyroidectomy on renal stone recurrence. Urolithiasis. 2021 Aug:49(4):327-334. doi: 10.1007/s00240-020-01239-x. Epub 2021 Jan 9     [PubMed PMID: 33420577]


[149]

Rao DS, Phillips ER, Divine GW, Talpos GB. Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2004 Nov:89(11):5415-22     [PubMed PMID: 15531491]

Level 1 (high-level) evidence

[150]

Cusano NE, Rubin MR, Silva BC, Tay YD, Williams JM, Agarwal S, Omeragic B, Guo XE, Bilezikian JP. Skeletal Microstructure and Estimated Bone Strength Improve Following Parathyroidectomy in Primary Hyperparathyroidism. The Journal of clinical endocrinology and metabolism. 2018 Jan 1:103(1):196-205. doi: 10.1210/jc.2017-01932. Epub     [PubMed PMID: 29069380]


[151]

Lundstam K, Heck A, Godang K, Mollerup C, Baranowski M, Pernow Y, Aas T, Hessman O, Rosén T, Nordenström J, Jansson S, Hellström M, Bollerslev J, SIPH Study Group. Effect of Surgery Versus Observation: Skeletal 5-Year Outcomes in a Randomized Trial of Patients With Primary HPT (the SIPH Study). Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2017 Sep:32(9):1907-1914. doi: 10.1002/jbmr.3177. Epub 2017 Jul 7     [PubMed PMID: 28543873]

Level 1 (high-level) evidence

[152]

Yeh MW, Zhou H, Adams AL, Ituarte PH, Li N, Liu IL, Haigh PI. The Relationship of Parathyroidectomy and Bisphosphonates With Fracture Risk in Primary Hyperparathyroidism: An Observational Study. Annals of internal medicine. 2016 Jun 7:164(11):715-23. doi: 10.7326/M15-1232. Epub 2016 Apr 5     [PubMed PMID: 27043778]

Level 2 (mid-level) evidence

[153]

Verdelli C, Corbetta S. MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects. European journal of endocrinology. 2017 Jan:176(1):R39-R52     [PubMed PMID: 27601015]


[154]

Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. The New England journal of medicine. 1999 Oct 21:341(17):1249-55     [PubMed PMID: 10528034]


[155]

Silverberg SJ, Clarke BL, Peacock M, Bandeira F, Boutroy S, Cusano NE, Dempster D, Lewiecki EM, Liu JM, Minisola S, Rejnmark L, Silva BC, Walker MD, Bilezikian JP. Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. The Journal of clinical endocrinology and metabolism. 2014 Oct:99(10):3580-94. doi: 10.1210/jc.2014-1415. Epub 2014 Aug 27     [PubMed PMID: 25162667]


[156]

Singh Ospina N, Maraka S, Rodriguez-Gutierrez R, Espinosa de Ycaza AE, Jasim S, Gionfriddo M, Castaneda-Guarderas A, Brito JP, Al Nofal A, Erwin P, Wermers R, Montori V. Comparative efficacy of parathyroidectomy and active surveillance in patients with mild primary hyperparathyroidism: a systematic review and meta-analysis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2016 Dec:27(12):3395-3407     [PubMed PMID: 27562567]

Level 2 (mid-level) evidence

[157]

Iglesias P, Arias J, López G, Romero I, Díez JJ. Primary Hyperparathyroidism and Cardiovascular Disease: An Association Study Using Clinical Natural Language Processing Systems and Big Data Analytics. Journal of clinical medicine. 2023 Oct 24:12(21):. doi: 10.3390/jcm12216718. Epub 2023 Oct 24     [PubMed PMID: 37959184]


[158]

Lightle WR, Zheng F, Makris KI, Grogan R, Suliburk J. Objectively measured cognitive dysfunction in patients with primary hyperparathyroidism improves after parathyroidectomy. Surgery. 2024 Jan:175(1):161-165. doi: 10.1016/j.surg.2023.07.045. Epub 2023 Nov 18     [PubMed PMID: 37980202]


[159]

Udelsman R, Lin Z, Donovan P. The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Annals of surgery. 2011 Mar:253(3):585-91. doi: 10.1097/SLA.0b013e318208fed9. Epub     [PubMed PMID: 21183844]


[160]

Clark OH. How should patients with primary hyperparathyroidism be treated? The Journal of clinical endocrinology and metabolism. 2003 Jul:88(7):3011-4     [PubMed PMID: 12843135]


[161]

Udelsman R, Donovan PI, Sokoll LJ. One hundred consecutive minimally invasive parathyroid explorations. Annals of surgery. 2000 Sep:232(3):331-9     [PubMed PMID: 10973383]


[162]

Irvin GL 3rd, Solorzano CC, Carneiro DM. Quick intraoperative parathyroid hormone assay: surgical adjunct to allow limited parathyroidectomy, improve success rate, and predict outcome. World journal of surgery. 2004 Dec:28(12):1287-92     [PubMed PMID: 15517474]


[163]

Lala M. Management of Primary Hyperparathyroidism. Indian journal of surgical oncology. 2022 Mar:13(1):143-151. doi: 10.1007/s13193-021-01319-3. Epub 2021 Apr 27     [PubMed PMID: 35462664]


[164]

Graceffa G, Cipolla C, Calagna S, Contino S, Melfa G, Orlando G, Antonini R, Corigliano A, Proclamà MP, Mazzola S, Cocorullo G, Scerrino G. Interpretation of intraoperative parathyroid hormone monitoring according to the Rome criterion in primary hyperparathyroidism. Scientific reports. 2022 Feb 28:12(1):3333. doi: 10.1038/s41598-022-07380-4. Epub 2022 Feb 28     [PubMed PMID: 35228624]


[165]

Rajan S, Ravindhran B, George B, Bantwal G, Ayyar V, Manjuanth S. Simplified intraoperative parathormone assay for primary hyperparathyroidism in a resource-limited setting. Biomarkers in medicine. 2021 Apr:15(5):331-336. doi: 10.2217/bmm-2020-0225. Epub 2021 Feb 17     [PubMed PMID: 33595341]


[166]

Knepprath JK, McHenry CR. How often are intrathyroidal parathyroid glands a cause of primary hyperparathyroidism, and how should they be managed? Surgery. 2024 Mar:175(3):794-798. doi: 10.1016/j.surg.2023.06.061. Epub 2023 Nov 18     [PubMed PMID: 37985315]


[167]

Cansu GB. An effective and safe alternative treatment method in parathyroid adenomas: Radiofrequency ablation. Journal of clinical ultrasound : JCU. 2022 May:50(4):547-548. doi: 10.1002/jcu.23180. Epub     [PubMed PMID: 35521923]


[168]

Ebrahiminik H, Chegeni H, Mosadegh Khah A, Salouti R, Ghomashchi G, Deldar Pasikhani M, Heydari I, Shamsi K, Beiranvand B, Azimi Aval MR, Mohammadi A, Mirza-Aghazadeh-Attari M, Fadaee N. Radiofrequency ablation of parathyroid adenomas causing primary hyperparathyroidism: A report of 27 patients. Journal of clinical ultrasound : JCU. 2022 May:50(4):540-546. doi: 10.1002/jcu.23181. Epub 2022 Mar 12     [PubMed PMID: 35278235]


[169]

Cartwright C, Anastasopoulou C. Hungry Bone Syndrome. StatPearls. 2024 Jan:():     [PubMed PMID: 31751070]


[170]

Jain N, Reilly RF. Hungry bone syndrome. Current opinion in nephrology and hypertension. 2017 Jul:26(4):250-255. doi: 10.1097/MNH.0000000000000327. Epub     [PubMed PMID: 28375869]

Level 3 (low-level) evidence

[171]

Garla VV, Salim S, Kovvuru KR, Subauste A. Hungry bone syndrome secondary to prostate cancer successfully treated with radium therapy. BMJ case reports. 2018 Jul 6:2018():. pii: bcr-2018-225039. doi: 10.1136/bcr-2018-225039. Epub 2018 Jul 6     [PubMed PMID: 29982185]

Level 3 (low-level) evidence

[172]

Turner J, Gittoes N, Selby P, Society for Endocrinology Clinical Committee. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of acute hypocalcaemia in adult patients. Endocrine connections. 2016 Sep:5(5):G7-G8     [PubMed PMID: 27935815]


[173]

Elsherbiny TM. Hypovitaminosis D masking hypercalcemia in primary hyperparathyroidism: case report. Therapeutic advances in endocrinology and metabolism. 2023:14():20420188231213208. doi: 10.1177/20420188231213208. Epub 2023 Nov 17     [PubMed PMID: 38028332]

Level 3 (low-level) evidence

[174]

Pasieka JL, Parsons L, Jones J. The long-term benefit of parathyroidectomy in primary hyperparathyroidism: a 10-year prospective surgical outcome study. Surgery. 2009 Dec:146(6):1006-13. doi: 10.1016/j.surg.2009.10.021. Epub     [PubMed PMID: 19958927]


[175]

Storvall S, Ryhänen EM, Heiskanen I, Sintonen H, Roine RP, Schalin-Jäntti C. Surgery Significantly Improves Neurocognition, Sleep, and Blood Pressure in Primary Hyperparathyroidism: A 3-Year Prospective Follow-Up Study. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2017 Oct:49(10):772-777. doi: 10.1055/s-0043-118347. Epub 2017 Sep 18     [PubMed PMID: 28922677]


[176]

Bollerslev J, Jansson S, Mollerup CL, Nordenström J, Lundgren E, Tørring O, Varhaug JE, Baranowski M, Aanderud S, Franco C, Freyschuss B, Isaksen GA, Ueland T, Rosen T. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. The Journal of clinical endocrinology and metabolism. 2007 May:92(5):1687-92     [PubMed PMID: 17284629]

Level 1 (high-level) evidence

[177]

Eastell R, Brandi ML, Costa AG, D'Amour P, Shoback DM, Thakker RV. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. The Journal of clinical endocrinology and metabolism. 2014 Oct:99(10):3570-9. doi: 10.1210/jc.2014-1414. Epub 2014 Aug 27     [PubMed PMID: 25162666]