Primary hyperparathyroidism

Abstract

Primary hyperparathyroidism is a common endocrine disorder caused by overactivation of parathyroid glands resulting in excessive release of parathyroid hormone. The resultant hypercalcemia leads to a myriad of symptoms. Primary hyperparathyroidism may increase a patient’s morbidity and even mortality if left untreated. During the last few decades, disease presentation has shifted from the classic presentation of severe bone and kidney manifestations to most patients now being diagnosed on routine labs. Although surgery is the only curative therapy, many advances have been made over the past decades in the diagnosis and the surgical management of primary hyperparathyroidism. The aim of this review is to summarize the characteristics of the disease, the work up, and the treatment options.

Keywords: Primary hyperparathyroidism, parathyroid hormone, parathyroidectomy

Introduction

Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by autonomous production of parathyroid hormone (PTH). Classically characterized as hypercalcemia in the presence of elevated serum PTH concentration , it is now recognized as a spectrum ranging from inappropriately high or even normal PTH in the setting of high-normal or even normal calcium (1). It is the third most common clinical endocrine disorder after diabetes and thyroid disease, with a prevalence between 0.1-1.0% (2, 3) and an incidence of approximately 28 cases per 100,000 individuals in general population (4). The incidence is highest between 50 and 60 years of age, affecting 2% of the population aged 55 years or older, and it occurs 2-3 times more commonly in females (3).

The vast majority of cases (90-95%) are sporadic, in which the PHPT is attributable to a solitary parathyroid adenoma in about 80%-85% of the cases. A double adenoma is present in up to 4% of the cases, and four-gland hyperplasia makes up the remaining 10-15% of the cases (3). Parathyroid carcinoma is a very rare cause of PHPT, accounting for less than 1% of the cases (2). Familial parathyroid disorders are responsible of 5% of the PHPT cases (2), and include such entities as multiple endocrine neoplasia type 1 (MEN 1) and type 2A (MEN 2A), hyperparathyroidism-jaw tumor syndrome, and isolated familial hyperparathyroidism (5). The focus of this review is on non-familial, sporadic PHPT.

The underlying cause for PHPT remains largely unknown, but there are a few known risk factors. Long term use of the drug lithium is associated with an increased risk of PHPT (2). Previous neck irradiation either in the form of external beam radiation or radioactive iodine from previous thyroid ablation is also a risk factor (2, 6). Parathyroid tumors can be due to defects in growth factor genes, proto-oncogenes, or tumor suppressor genes. While sporadic tumors are usually associated with abnormalities in the PRAD1/cyclin D1 genes, familial tumors are due to defects in the RET gene. Both sporadic and familial tumors are associated with HPRT and MEN 1 genes abnormalities (5).

History
Parathyroid glands were the last organs to be discovered in mammals. In 1850, Sir Richard Owen identified the parathyroid glands in an Indian rhinoceros (7). Thirty years later, a Swedish medical student called Ivar Sandstorm described and actually named the parathyroid glands in humans (7). Between 1908 and 1917, W.G. MacCallum and Carl Voegtlin published a series of studies trying to describe the connection between the parathyroids, calcium, and tetany (7). They also postulated the renal effect of parathyroid secretion. The connection between parathyroid gland’s overactivity and bone diseases was established by Schlagenhaufer in 1915 (7). Ten years later, Felix Mandl performed the first parathyroidectomy (conventional bilateral exposure) in a patient with osteitis fibrosa cystica in Vienna (7). The term hyperparathyroidism was first used by Dr. Fuller Albright in 1940s to describe the phenomena of overproduction of PTH (7). In 1963, Berson and Yalow developed an immunoassay for the measurement of parathyroid hormone (8). In 1970s, serum calcium screening test became common practice, which led to increasing numbers of patients diagnosed with PHPT in early stages (8).

Symptoms and Presentation
Currently, the majority of PHPT patients do not present with the classic symptoms of kidney stones or severe bone disease. Individuals are more often diagnosed today through routine biochemical laboratory testing done for other purposes. Although patients often lack the classic symptoms, PHPT is associated with many non-specific complaints such as depression, memory loss, fatigue, sleep problems, bone or muscle pains, gastroesophageal reflux disease, and decreased concentration. In fact, neither patients nor their providers may even recognize these symptoms initially as attributable to the diagnosis of PHPT, but postoperatively, there is often significant improvement resulting in improved quality of life (9-12).

Since calcium homeostasis is important to normal cellular function, the manifestations of PHPT may include musculoskeletal, renal, gastrointestinal, cardiovascular, neuromuscular and neuropsychiatric symptoms (2). A common mnemonic medical students learn about hypercalcemia symptoms is “bones, stones, groans, and psychic moans” (2). The renal manifestations include nephrolithiasis, nephrocalcinosis and hypercalciuria. Since the filtered load of calcium exceeds the reabsorption capacity of the renal tubules, hypercalciuria may occur in about 35-40% of cases (3). Nephrolithiasis can be observed in up to 20% of patients with PHPT (13), but it is becoming a much more infrequent finding at presentation today.

Musculoskeletal manifestations occur from hypercalcemia, but also due to the direct effect of PTH on cortical bones. Parathyroid hormone acts on PTH receptors in osteoblasts, which stimulates osteoblasts differentiation to osteoclasts with subsequent cortical bone resorption (14). Therefore, the persistent high PTH level can lead to osteopenia, osteoporosis, or even to cyst formation and fibrosis. The most severe form of bone disease in PHPT is known as osteitis fibrosa cystica (15). Osteoporosis/osteopenia is by far the most common bone disease associated with PHPT, while osteitis fibrosa cystica is rarely seen in modern clinical practice (3).

In 1988, Joborn et al. (16) stated that 23% of PHPT patients present with neuropsychiatric manifestations, and the majority of them (78%) suffer from depression and anxiety. Recently, the third international workshop held in 2008 reported that presentation of PHPT with psychological and neurological manifestations is common, but the true extent of neuropsychiatric symptoms is still not clear, especially in mild PHPT (9). Many PHPT patients report nonspecific symptoms such as fatigue, mood and sleep disorders, memory loss, irritability, difficulty in concentrating, and loss of initiative. Often, these improve after parathyroidectomy (12), neuropsychiatric manifestations have not yet been considered as one of the indications for parathyroidectomy (9).

In addition to these common symptoms and findings, recent studies have demonstrated that PHPT can affect other organ systems. High PTH levels have been found to have a strong association with several cardiovascular conditions, including valvular and myocardial calcification, arterial hypertension, coronary artery disease, left ventricular hypertrophy, conduction disturbances, and lipid abnormalities (13). Hypercalcemia can also effect the gastrointestinal tract and lead to anorexia, nausea, vomiting, constipation, GERD, and rarely acute pancreatitis (12).

Rarely, PHPT patients may present with parathyroid (hypercalcemic) crisis, which may occur due to significant fluid loss or dehydration leading to rapid rise in blood calcium. During the crisis, patients may experience cardiac and renal function impairment, rapid deterioration of the central nervous system, nausea, vomiting, severe abdominal pain, stomach ulcers, and/or constipation (17).

Diagnosis
The differential diagnosis of hypercalcemia includes: malignancy, PHPT, drugs like lithium and thiazides, vitamins D & A excess, increased oral calcium intake, prolonged immobilization, and medical diseases like milk-alkali syndrome, hyperthyroidism, sarcoidosis, and multiple myeloma (18). While cancer was considered to be the most common cause of hypercalcemia in the inpatient setting, PHPT is the most common cause of hypercalcemia in both outpatient and inpatient settings (19). Hypercalcemia due to PHPT associates with high or inappropriately normal PTH level, whereas other causes of hypercalcemia are usually associated with suppressed PTH levels, because the normal negative feedback mechanism of calcium on the parathyroid glands is intact.

The first step in diagnosing PHPT is collecting a thorough history with particular attention to the symptoms described above. Family history should also be taken to check for the possibility of hereditary forms of PHPT, particularly MEN types 1 and 2A (20). If there is a family history of PHPT, especially in patients younger than 50 years of age, genetic testing for MEN should be considered (20). It is also important to take a detailed drug history from the patients asking specifically about thiazide diuretics, which can raise serum calcium independently of PTH, and lithium, since its long term use is associated with PHPT (20).

The biochemical hallmark of PHPT is hypercalcemia caused by excessive secretion of PTH from one or more parathyroid glands (1). The diagnosis of PHPT is classical when corrected calcium is high in the presence of elevated PTH (20). However, mild PHPT occur when either the PTH or serum calcium level is normal by laboratory definition, but the two values, when considered together, are biochemically abnormal. High PTH in the presence of normal calcium level is called normocalcemic PHPT, and inappropriate secretion of PTH is seen in patients with hypercalcemia and inappropriately normal, or unsuppressed, PTH level (1). Hypercalcemia should cause negative feedback on the parathyroid glands to suppress secretion of PTH, so normal PTH in the setting of high calcium may be an indication of PHPT (Table 1). Different hypothesis have been reported to explain the normocalcemic variety to PHPT. While some surgeons think that this is an early stage of classical PHPT due to an alteration in the regulation of PTH secretion, others believe it is due to the relative resistance to the action of PTH (21).

Table 1. Primary hyperparathyroidism: clinical presentation

Other diagnoses that can present with similar laboratory findings as PHPT include tertiary HPT and familial benign hypocalciuric hypercalcemia (FHH). Tertiary hyperparathyroidism can have the same high calcium and high PTH laboratory findings as PHPT, but it is found in patients with a history of secondary hyperparathyroidism. Secondary hyperparathyroidism converts to tertiary hyperparathyroidism when the physiologic overproduction of PTH in response to low serum calcium converts over to autonomously functioning parathyroid tissue that does not respond to the negative feedback of high calcium. Classically, this is seen in patients with renal failure and secondary hyperparathyroidism who undergo kidney transplant and the parathyroid glands continue to be overactive (2). FHH is an autosomal dominant disease caused by a mutation that inactivates the calcium sensing receptor gene expressed in parathyroid and kidney tissues (23). This perceived lack of calcium by parathyroid cells then causes an increase in PTH secretion that raises serum calcium. It is as if patients with FHH have a higher set point for both calcium and PTH, and these patients are usually asymptomatic young adults with mild hypercalcemia and a positive family history. This may not be a known family history of FHH, per se, but may be something more subtle like having one or more family members who have had failed parathyroid surgery in the past. It is essential to differentiate PHPT from FHH, since surgery is not indicated in FHH, and a 24-hour urine collection for calcium/creatinine clearance ratio should be ordered if there is any suspicion. Low calcium/creatinine clearance ratio (less than 0.01) is highly suggestive of FHH (23).

Imaging
The main aims of preoperative radiological work-up in PHPT are to locate the hyperfunctioning gland or glands and to assess the effect of the disease on end organs. Primary hyperparathyroidism is due to a single, enlarged, adenomatous gland in roughly 80% of patients, and much research in the past 20 years has been dedicated to the question of which patients may be candidates for a targeted approach of that single gland or a more classic identification of all four parathyroid glands and removal of any that are enlarged. Preoperative localization studies should be ordered only if the patient is planned for surgical intervention. Such studies can help the surgeon to decide which surgical approach is best for which patient (20), but it is important to note that negative preoperative parathyroid images do not exclude the diagnosis. Whether or not a patient needs an operation to cure their PHPT is based on laboratory data and history; imaging only serves to guide the type of operation. These preoperative localization studies can be either invasive or non-invasive. Noninvasive methods include neck ultrasound (US), Tc-99m sestamibi imaging, single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), positron emission tomography combined with CT scan (PET/CT), and 4-dimensional CT scan (4-D CT) (Table 2) (24, 25).

Table 2. Localization imaging studies

Invasive methods can be employed for reoperative situations and include selective arteriography (60% sensitivity), selective venous sampling (80% sensitivity), and fine needle aspiration (FNA) (24). Selective arteriography depends on the fact that all enlarged parathyroid glands are highly vascular, thus, a contrast can be injected into the inferior and superior thyroid arteries or thyrocervical trunk and can stain the glands. This technique can identify small and ectopic parathyroid glands, but equivocal findings occur in 10-15% of cases due to intrathyroidal parathyroid adenoma or thyroid nodules (25). Arteriography is often combined with venous sampling for more accurate results. Extensive sampling of the thyroid venous plexus and thymic veins is needed. This technique is helpful to differentiate between adenoma and hyperplasia because adenomas produce unilateral hypersecretion of PTH whereas hyperplasia exhibits elevated PTH throughout the venous plexus bilaterally (25). The invasive methods carry a higher risk of complications, such as embolism, stroke and renal impairment (24).

A focus of tissue that is seen on imaging that is suspicious for parathyroid tissue may be sampled by FNA, and then the aspirate can be tested for PTH level. FNA of suspicious parathyroid adenomas for definitive diagnosis is not necessary in most situations, but can be quite useful in reoperative situations or in situations where the area of suspicion is unusual for parathyroid, such as intrathyroidal or lateral to the carotid artery. There is a controversy regarding the cutoff point for a positive test of PTH aspirate from FNA. Frasoldati and colleagues reported that a PTH washout value of more than 101 pg/mL had a 100% specificity and sensitivity for confirmation of parathyroid tissue (28). Furthermore, Maser and colleagues regarded a PTH washout value of >1,000 pg/mL as positive for sampling parathyroid tissue (29). In 2013, Abdelghani and his colleagues stated that due to the hormone dilution in the FNA, a PTH washout value greater than the serum PTH should be considered diagnostic in localizing the parathyroid (30). Although parathyroid sampling can be done using FNA, Conrad et al showed that 1 mm3 biopsy with PTH cutoff of 1000 pg/dl is more accurate and more sensitive than FNA (4).

Regarding end–organ assessment in PHPT, renal US, abdominal plain film, or CT scan could be done to rule out nephrolithiasis or nephrocalcinosis if there is any renal complaint, as these are findings that would argue for surgical intervention (13). Moreover, bone mineral density using dual energy X-ray absorptiometry of the lumbar spine, femur, and distal 1/3 radius should be done in all patients with PHPT to assess the extent of skeletal bone involvement (13). Finally, if patients have specific skeletal complaints, targeted plain film X-rays may reveal subperiosteal resorption of the middle and distal phalanges, a mottled or “ salt and pepper “ skull pattern, thinning of the distal clavicles, or bone cysts and brown tumors in the long bones and pelvis, though these are found in severe cases that are rarely seen today (3).

Treatment

Surgical treatment
Surgery is the only curative therapy for PHPT. Currently, surgery is recommended for all symptomatic PHPT patients. Recent consensus guidelines recommend surgery for asymptomatic PHPT patients under the age of 50, with evidence of osteoporosis or vertebral fracture, with a calcium higher than 1 mg above the upper limits of normal, a creatinine clearance of <60 cc/min, or presence of nephrolithiasis or nephrocalcinosis in radiological images (Table 3) (31). Inability to participate in adequate follow up is also considered one of the criteria (31).

Table 3. A comparison of Guidelines for Parathyroidectomy in Asymptomatic PHPT patients

Outside of the consensus guidelines, several researches demonstrated that medical follow up is time-consuming and expensive (26), while parathyroidectomy is cost-effective compared to observation in treating both symptomatic and asymptomatic PHPT patients with a life expectancy of more than 6.5 years (32). Risk of surgery is low, and continues to improve especially in the hands of experienced, high-volume endocrine surgeons (33). Because of these considerations, and also because we now recognize a host of symptoms that improve with parathyroidectomy, many authors advocate operating on patients with milder disease before consensus guideline criteria are met (26, 32-34).

The two main operative approaches are bilateral neck exploration and minimally invasive parathyroidectomy (MIP). The classic bilateral neck exploration was the standard surgical treatment for PHPT up until about the last 15 years. In this approach, the surgeon identifies and inspects all 4 glands with subsequent removal of enlarged and presumed to be hyperfunctioning gland(s). The success rate for this approach is over 95% (2).

Over 80% of PHPT is due to a single adenoma, and imaging techniques are ever improving at being able to identify a single enlarged gland. Additionally, the introductions of intraoperative PTH (ioPTH) monitoring in 1988 and radioguided operative techniques in 1997 (35, 36) have contributed to the trend that focused, or MIP, has replaced the conventional bilateral exploration in many cases.

Minimally invasive parathyroidectomy approach focuses on a targeted, unilateral neck exploration with removal of the hyperfunctioning adenoma (26). This approach relies on preoperative and intraoperative localization techniques (11). Currently, there are several perioperative adjuncts that can facilitate the MIP approach and increase its success rate (Table 4) (26, 29, 30, 37-39). The most important adjunct is the ioPTH monitoring, which is an important tool used in MIP to predict operative success. Different criteria have been proposed for determination of operative cure using ioPTH, and each has different sensitivity for predicting cure and detecting multiglandular disease. The most common criteria for ioPTH assay are: Halle, Miami, Rome, Vienna, and Wisconsin criteria (Table 5) (37). In 2009, Barczynski et al. (37) evaluated these different criteria except Wisconsin criterion in predicting cure and multiglandular disease and concluded that Miami criterion followed by Vienna criterion were the best in predicting cure, while Rome criterion followed by Halle criterion are the most useful ones in detecting multiglandular disease.

Table 4. Perioperative adjuncts

Table 5. Intra-operative parathyroid hormone criteria

Complications
After parathyroidectomy, there are some complications that can occur regardless of the type of surgery. These complications include hematoma formation leading to airway obstruction, hypoparathyroidism/hypocalcemia, recurrent laryngeal nerve injury, and failure to cure hyperparathyroidism (11). Recurrent laryngeal nerve injury, which can be transient (<6 months) or permanent (>6 months), unilateral or bilateral, is rare (less than 1%) especially in expert hands (26), but can lead to voice changes, aspiration, or even airway obstruction in cases of bilateral injury. Hypocalcemia is seen more frequently, especially transient hypocalcemia, which can occur in up to 30% of patients after surgery (42). Normally, this can be managed with oral calcium supplementation with or without activated vitamin D. Patients with severe hypercalcemia and very high preoperative PTH levels are at higher risk for transient hypoparathyroidism, as post-parathyridectomy transient hypocalcemia can be due to suppression of the remaining parathyroid glands, devascularization, hungry bone syndrome (which is an immediate uptake of calcium by the bone after successful parathyroidectomy that results in severe hypocalcemia), or to a lesser extent due to hypomagnesemia (42). Permanent hypocalcemia is due to removal or devascularization of all functioning parathyroid tissue and is thankfully rare (1-2%).

Benefits of Parathyroidectomy
Parathyroidectomy is the only definitive therapy for PHPT. It may correct the biochemical abnormality, improve the quality of life, improve BMD, and decrease the risk of fractures (26).
Improvement in BMD postparathyroidectomy in both symptomatic and asymptomatic patients has been reported by both observational studies and clinical trials (13). Previous studies suggested that parathyroidectomy reduces the risk of fracture in PHPT patients (26). In addition, parathyroidectomy can reduce the risk of nephrolithiasis. Silverberg et al. (43) reported that the recurrence rate of renal stones is 75% in patients treated conservatively, while it is 0% in patients treated surgically. Furthermore, neuropsychiatric manifestations such as cognition, mood, and anxiety may improve after parathyroidectomy (26). Some studies demonstrated that parathyroidectomy has cardiovascular benefits such as improvement of the left ventricular diastolic function, the blood pressure, and left ventricular mass index, while other studies failed to confirm these findings (26). The majority of the current data is from observational studies that have several limitations, such as selection bias (10, 26). Well designed long-term randomized studies are needed to define the actual benefits of parathyroidectomy for each manifestation (44).

Follow up
Cure is defined as normocalcemia 6 months after resection (26). Thus, patients should be evaluated in the clinic for serum calcium 1-2 weeks postoperatively and then 6 months after resection. If normal, the patient should be followed by checking the calcium level annually (26). Since we are now operating on milder forms of PHPT, including those patients with normocalcemic hyperparathyroidism, one may question whether normal serum calcium levels after surgery is an adequate measure of cure. Normocalcemia with high PTH level can be detected in up to 40% of patients post-parathyroidectomy and may not indicate operative failure (45). The significance of elevated PTH postoperatively is not yet fully understood. High postoperative PTH level can be due to vitamin D deficiency, hungry bone syndrome, inadequate calcium intake, vitamin D end-organ resistance, renal insufficiency with impaired vitamin D production, or the use of loop diuretics such as furosemide that increase calcium excretion (45). Interestingly, Ning et al. (46) demonstrated that recurrent disease is significantly more common in patients with postoperative high PTH and it was always associated with a serum calcium level ≥9.7 mg/dL. Moreover, Ning et al. (46) and Oltmann et al. (45) recommended early postoperative PTH level measurement to detect such patients in the early stages. If PTH is high on the first check, the surgeon should replete vitamin D and check PTH level again in a month to six weeks.

Persistent and Recurrent PHPT
Approximately 2-5% of PHPT patients who undergo parathyroidectomy will need further surgical intervention for either persistent or recurrent disease (26, 47). Persistent PHPT is defined as hypercalcemia within 6 months of parathyroidectomy and it occurs in about 3.9% (48). It is likely due to failure to identify and remove all hyperfunctioning glands. Recurrent PHPT can occur in 2-3% of cases (40) and it is defined as hypercalcemia that occurs six months after parathyroidectomy, provided that the patient has been eucalcemic during the first six months after resection. It is thought to be due to regrowth of abnormal parathyroid tissue (26).

Once the diagnosis is established, all the preoperative images, final pathology report, and operative report should be reviewed carefully (26). The first line of investigation is to use noninvasive preoperative localization studies, like neck US, sestamibi scan, MRI or 4-D CT scan. If noninvasive studies failed to localize the diseased gland(s), invasive techniques such as venous sampling for PTH levels may be used (48). Intraoperative adjuncts like US, ioPTH monitoring, and radioguided parathyroidectomy are recommended in reoperative parathyroidectomy. The cure rate for reoperative parathyroidectomy for PHPT ranges from 76% to 94% (48). However, the complication rate of reoperative parathyroidectomy is higher, in which up to 13% of patients may develop permanent hypoparathyroidism, and up to 4% may suffer from recurrent laryngeal nerve injury (49).

Medical Treatment
The medical treatment is an alternative therapy for those patients who cannot undergo surgical intervention. The aims of medical management are either to balance calcium homeostasis by using calcimimetic drugs such as cinacalcet, or to improve the bone mineral density by using antiresorptive drugs (11), which include estrogen, selective estrogen receptor modulators, and bisphosphonate (13, 26). Medical management of PHPT is indicated in the following conditions: patients who are unfit for or refuse surgery, pregnant women in the first or the third trimester, patients who are waiting for surgery, and patients with failed surgical treatment (50).

Medical treatment has been shown to stabilize the disease over a period of ten years, however, over a period of 15 years, laboratory values and/or cortical bone loss may worsen in up to 37% of cases (26). Because there is no way to predict which patient will progress, medically managed patients should be monitored with calcium level and renal function annually, and DEXA scan every 1-2 years (31). They are advised to avoid factors aggravating hypercalcemia such as drugs (thiazide diuretics and lithium), immobilization, dehydration, and high dietary calcium (51).

Conclusion

Primary hyperparathyroidism is the most common cause of hypercalcemia in the outpatient population. Currently, it is often diagnosed in the Western world at an asymptomatic stage. Classical symptoms are due to the affect of hypercalcemia or high PTH level on body systems specifically bone, kidney, and central nervous system. Other nonspecific symptoms include weakness, malaise, fatigue, and mood disturbances. The diagnosis of PHPT is confirmed in the presence of hypercalcemia and an inappropriately normal or elevated PTH level in the absence of conditions that mimic PHPT. Indications for surgery have recently been revised based on international consensus, and surgery is advised in the presence of significant hypercalcemia, impaired renal function, and osteoporosis and in individuals younger than 50 years. The classical complications of PHPT are skeletal fragility, nephrolithiasis, and nephrocalcinosis. Surgery is always appropriate in an individual with confirmed PHPT after excluding conditions that can mimic PHPT and in the absence of contraindications. Individuals with asymptomatic PHPT with contraindications for surgery may be followed and considered for medical management.

This manuscript was prepared by the invitation of the Editorial Board and its scientific evaluation was carried out by the Editorial Board.

Concept - T.M., A.A., H.C., D.E.; Design - T.M., A.A., D.E.; Supervision - A.A., H.C., D.E.; Data Collection and/or Processing - T.M.; Analysis and/or Interpretation - T.M; Literature Search - T.M., A.A.; Writing Manuscript - T.M., A.A.; Critical Review - H.C., D.E.

No conflict of interest was declared by the authors.

The authors declared that this study has received no financial support.

References

1. Carneiro-Pla DM, Irvin GL, 3rd, Chen H. Consequences of parathyroidectomy in patients with “mild” sporadic primary hyperparathyroidism. Surgery 2007; 142: 795-799.
2. Gopinath P, Mihai R. Hyperparathyroidism. Surgery 2011; 29: 451-458.
3. Cordellat IM. Hyperparathyroidism: primary or secondary disease? Rheumatol Clin 2012; 8: 287-291.
4. Conrad DN, Olson JE, Hartwig HM, Mack E, Chen H. A prospective evaluation of novel methods to intraoperatively distinguish parathyroid tissue utilizing a parathyroid hormone assay. J Surg Res 2006; 133: 38-41.
5. Westin G, Bjorklund P, Akerstrom G. Molecular genetics of parathyroid disease. World J Surg 2009; 33: 2224-2233.
6. Colaco SM, Si M, Reiff E, Clark OH. Hyperparathyroidism after radioactive iodine therapy. Am J Surg 2007; 194: 323-327.
7. Eknoyan G. A history of the parathyroid glands. Am J Kidney Dis 1995; 26: 801-807.
8. Organ CH, Jr. The history of parathyroid surgery, 1850-1996: the Excelsior Surgical Society 1998 Edward D Churchill Lecture. J Am Coll Surg 2000; 191: 284-299.
9. Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin MR. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab 2009; 94: 351-365.
10. Bandeira F, Griz L, Caldas G, Bandeira C, Freese E. From mild to severe primary hyperparathyroidism: The Brazilian experience. Arq Bras Endocrinol Metabol 2006; 50: 657-663.
11. Gopinath P, Sadler GP, Mihai R. Persistent symptomatic improvement in the majority of patients undergoing parathyroidectomy for primary hyperparathyroidism. Langenbecks Arch Surg 2010; 395: 941-946.
12. Reiher AE, Mazeh H, Schaefer S, Gould J, Chen H, Sippel RS. Symptoms of gastroesophageal reflux disease improve after parathyroidectomy. Surgery 2012; 152: 1232-1237.
13. Bandeira F, Griz L, Chaves N, Carvalho NC, Borges LM, Lazaretti-Castro M, et al. Diagnosis and management of primary hyperparathyroidism--a scientific statement from the Department of Bone Metabolism, the Brazilian Society for Endocrinology and Metabolism. Arq Bras Endocrinol Metabol 2013; 57: 406-424.
14. Calvi LM, Sims NA, Hunzelman JL, Knight MC, Giovannetti A, Saxton JM, et al. Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest 2001; 107: 277-286.
15. Rubin E, Reisner HM. Essentials of RUBIN’S Pathology. 5th ed. Lippincott Williams & Wilkins, a Wolter Kluwer business 2009, Baltimore, MD, Philadelphia, PA 2009.p.552.
16. Joborn C, Hetta J, Johansson H, Rastad J, Agren H, Akerstrom G, et al. Psychiatric morbidity in primary hyperparathyroidism. World J Surg 1988; 12: 476-481.
17. Gurrado A, Piccinni G, Lissidini G, Di Fronzo P, Vittore F, Testini M. Hypercalcaemic crisis due to primary hyperparathyroidism - a systematic literature review and case report. Endokrynol Pol 2012; 63: 494-502.
18. Jacobs TP, Bilezikian JP. Clinical review: Rare causes of hypercalcemia. J Clin Endocrinol Metab 2005; 90: 6316-6322.
19. Matikainen N. Hypercalcemia. Duodecim 2014; 130: 1404-1412.
20. Hinnie J. The management of primary hyperparathyroidism. Scott Med J 2013; 58: 251-253.
21. Tordjman KM, Greenman Y, Osher E, Shenkerman G, Stern N. Characterization of normocalcemic primary hyperparathyroidism. Am J Med 2004; 117: 861-863.
22. Bollerslev J, Rolighed L, Mosekilde L. Mild primary hyperparathyroidism and metabolism of vitamin D. IBMS BoneKEy 2011; 8: 342-351.
23. Christensen SE, Nissen PH, Vestergaard P, Mosekilde L. Familial hypocalciuric hypercalcaemia: a review. Curr Opin Endocrinol Diabetes Obes 2011; 18: 359-370.
24. Gawrychowski J, Bula G. Imaging diagnostics for primary hyperparathyroidism. Endokrynol Pol 2013; 64: 404-408.
25. Dijkstra B, Healy C, Kelly LM, McDermott EW, Hill AD, O’Higgins N. Parathyroid localisation--current practice. J R Coll Surg Edinb 2002; 47: 599-607.
26. Kelly KJ, Chen H, Sippel RS. Primary hyperparathyroidism. Cancer Treat Res 2010; 153: 87-103.
27. Johnson NA, Tublin ME, Ogilvie JB. Parathyroid imaging: technique and role in the preoperative evaluation of primary hyperparathyroidism. AJR Am J Roentgenol 2007; 188: 1706-1715.
28. Frasoldati A, Pesenti M, Toschi E, Azzarito C, Zini M, Valcavi R. Detection and diagnosis of parathyroid incidentalomas during thyroid sonography. J Clin Ultrasound 1999; 27: 492-8.
29. Maser C, Donovan P, Santos F, Donabedian R, Rinder C, Scoutt L, et al. Sonographically guided fine needle aspiration with rapid parathyroid hormone assay. Ann Surg Oncol 2006; 13: 1690-1695.
30. Abdelghani R, Noureldine S, Abbas A, Moroz K, Kandil E. The diagnostic value of parathyroid hormone washout after fine-needle aspiration of suspicious cervical lesions in patients with hyperparathyroidism. Laryngoscope 2013; 123: 1310-1313.
31. Bilezikian JP, Khan AA, Potts JT, Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab 2009; 94: 335-339.
32. Zanocco K, Angelos P, Sturgeon C. Cost-effectiveness analysis of parathyroidectomy for asymptomatic primary hyperparathyroidism. Surgery 2006; 140: 874-882.
33. Stavrakis AI, Ituarte PH, Ko CY, Yeh MW. Surgeon volume as a predictor of outcomes in inpatient and outpatient endocrine surgery. Surgery 2007; 142: 887-899.
34. Murray SE, Pathak PR, Pontes DS, Schneider DF, Schaefer SC, Chen H, et al. Timing of symptom improvement after parathyroidectomy for primary hyperparathyroidism. Surgery 2013; 154: 1463-1469.
35. Nussbaum SR, Thompson AR, Hutcheson KA, Gaz RD, Wang CA. Intraoperative measurement of parathyroid hormone in the surgical management of hyperparathyroidism. Surgery 1988; 104: 1121-1127.
36. Norman J, Chheda H. Minimally invasive parathyroidectomy facilitated by intraoperative nuclear mapping. Surgery 1997; 122: 998-1004.
37. Barczynski M, Konturek A, Hubalewska-Dydejczyk A, Cichon S, Nowak W. Evaluation of Halle, Miami, Rome, and Vienna intraoperative iPTH assay criteria in guiding minimally invasive parathyroidectomy. Langenbecks Arch Surg 2009; 394: 843-849.
38. Chen H, Mack E, Starling JR. Radioguided parathyroidectomy is equally effective for both adenomatous and hyperplastic glands. Ann Surg 2003; 238: 332-338.
39. Ito F, Sippel R, Lederman J, Chen H. The utility of intraoperative bilateral internal jugular venous sampling with rapid parathyroid hormone testing. Ann Surg 2007; 245: 959-963.
40. Schneider DF, Mazeh H, Sippel RS, Chen H. Is minimally invasive parathyroidectomy associated with greater recurrence compared to bilateral exploration? Analysis of more than 1,000 cases. Surgery 2012; 152: 1008-1015.
41. Hughes DT, Miller BS, Park PB, Cohen MS, Doherty GM, Gauger PG. Factors in conversion from minimally invasive parathyroidectomy to bilateral parathyroid exploration for primary hyperparathyroidism. Surgery 2013; 154: 1428-1435.
42. Brasier AR, Nussbaum SR. Hungry bone syndrome: clinical and biochemical predictors of its occurrence after parathyroid surgery. Am J Med 1988; 84: 654-660.
43. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med 1999; 341: 1249-1255.
44. Selby P. Asymptomatic primary hyperparathyroidism - we have half the answers. Clin Endocrinol (Oxf) 2011; 75: 156-157.
45. Oltmann SC, Maalouf NM, Holt S. Significance of elevated parathyroid hormone after parathyroidectomy for primary hyperparathyroidism. Endocr Pract 2011; 17(Suppl 1): 57-62.
46. Ning L, Sippel R, Schaefer S, Chen H. What is the clinical significance of an elevated parathyroid hormone level after curative surgery for primary hyperparathyroidism? Ann Surg 2009; 249: 469-472.
47. Schneider DF, Mazeh H, Chen H, Sippel RS. Predictors of recurrence in primary hyperparathyroidism: an analysis of 1386 cases. Ann Surg 2014; 259: 563-568.
48. O’Connell RL, Afors K, Thomas MH. Re-explorative parathyroid surgery for persistent and recurrent primary hyperparathyroidism. WJOES 2011; 3: 107-111.
49. Thompson GB, Grant CS, Perrier ND, Harman R, Hodgson SF, Ilstrup D, et al. Reoperative parathyroid surgery in the era of sestamibi scanning and intraoperative parathyroid hormone monitoring. Arch Surg 1999; 134: 699-705.
50. Crowley RK, Gittoes NJ. When would I use medical therapies for the treatment of primary hyperparathyroidism? Clin Endocrinol (Oxf) 2013; 79: 770-773.
51. Pallan S, Khan A. Primary hyperparathyroidism: Update on presentation, diagnosis, and management in primary care. Can Fam Physician 2011; 57: 184-189.