Leslie S. Wu
Julie Ann Sosa
Presentation
A 75-year-old woman is brought to the emergency department from a nursing home with a 5-day history of worsening lethargy and confusion. From prior hospital records, her past medical history is notable for nephrolithiasis, gastroesophageal reflux disease, and hypertension. Her medications include hydrochlorothiazide, metoprolol, omeprazole, and aspirin. Physical examination reveals a frail-appearing woman, who is arousable to voice, and oriented only to person. She is afebrile and normotensive but mildly tachycardic with a heart rate of 100 beats per minute. Her neurologic exam is nonfocal. The remainder of her examination is significant only for poor skin turgor and dry mucous membranes. Laboratory studies are notable for a mildly elevated white blood cell count 11.2 thou/υL (normal, 4.2 to 9.9 thou/υL), mild hemoconcentration with hematocrit 42% (normal, 38% to 50%), blood urea nitrogen (BUN) 25 mg/dL (normal, 6 to 19 mg/dL), serum creatinine 1.3 mg/dL (normal, 0.5 to 1.3 mg/dL), serum calcium 14.7 mg/dL (normal, 8.6 to 10.4 mg/dL), and albumin 4.3 g/dL (normal, 3.4 to 5.4 g/dL). Urinalysis of cloudy urine is notable for pyuria, positive nitrites, and positive leukocyte esterase.
The patient is admitted to the hospital with a urinary tract infection and hypercalcemia. She is hydrated with intravenous crystalloid fluid and treated with the appropriate antibiotics. There is subsequent improvement of her mental status and a decline in calcium level. Additional laboratory evaluation is obtained, revealing an intact parathyroid hormone (iPTH) level of 250 pg/mL (normal, 10 to 65 pg/mL).
Differential Diagnosis
The most common reason for hypercalcemia in the out-patient setting is primary hyperparathyroidism (HPT), while hypercalcemia in the inpatient population often is secondary to malignancy. Population-based estimates reveal an overall incidence of approximately 25 per 100,000 in the general population, with 50,000 new cases identified annually. The peak incidence is in the fifth and sixth decades of life, with a female to male ratio of 3:1. Some studies have estimated the overall prevalence of primary HPT in the elderly at 2% to 3%, with approximately 200 cases per 100,000 population. Making the correct diagnosis requires careful clinical evaluation coupled with biochemical testing. After a thorough history and physical examination, laboratory measurements of fasting serum calcium, iPTH, creatinine, and vitamin D levels should be performed to determine if the hypercalcemia is non-parathyroid-mediated (in which serum iPTH levels are suppressed appropriately) or parathyroid-mediated (in which serum iPTH levels are elevated inappropriately). Etiologies of non-parathyroid-mediated hypercalcemia include malignancy (a parathyroid hormone-related protein, or PTHrP, level may be elevated), granulomatous diseases, endocrinopathies, medications, and immobilization. Parathyroid-mediated hypercalcemia is due to HPT, benign familial hypocalciuric hypercalcemia (BFHH), or lithium therapy. Primary HPT generally is caused by a benign, solitary parathyroid adenoma in 80% to 85% of patients. Approximately 5% of patients harbor two distinct adenomas (“double adenoma”), 15% to 20% have multigland parathyroid hyperplasia, and fewer than 1% of patients have parathyroid carcinoma (Table 1).
TABLE 1. Differential Diagnosis of Hypercalcemia
Workup
With the advent of routine serum calcium screening, the typical presentation of primary HPT has changed from a severe, debilitating illness to a disease with subtle symptoms and physiologic derangements. Common signs include nephrolithiasis, nephrocalcinosis, osteopenia, and osteoporosis; rarely, pancreatitis and peptic ulcer disease will occur. Hypertension frequently is present in patients with primary HPTH, and it appears to be most closely correlated with the degree of renal impairment seen in patients with hypercalcemia. In addition, there are many subtle abnormalities associated with primary HPT, including decreased cognitive function, anxiety and/or depression, lethargy/fatigue, myalgias and arthralgias, constipation, and urinary symptoms, such as increased thirst and urinary frequency (Table 2).
TABLE 2. Symptoms and Associated Conditions in Patients with Primary Hyperparathyroidism
The diagnosis of primary HPT typically is made by biochemical evidence of an elevated serum calcium concentration, usually in conjunction with an elevated or inappropriately high normal serum iPTH. The clinical entity termed “normocalcemic primary HPT” recently has emerged. It appears to be an early form of primary HPT in which patients have serum calcium levels in the high-normal range associated with an elevated serum PTH level and bone loss. When these patients are symptomatic, surgical intervention is appropriate. Approximately half of patients with primary HPT have hypophosphatemia. However, in the presence of significant renal impairment, serum phosphate levels may be elevated. Because of the effect of PTH on bicarbonate excretion in the kidney, patients with primary HPT often have a hyperchloremic metabolic acidosis. To distinguish patients with BFHH from those with primary HPT, a 24-hour urinary calcium excretion study should be performed; this measurement is low (<40 mg per specimen; normal, 25 to 300 mg per specimen) in the setting of BFHH, and normal or elevated in primary HPT. Approximately 10% to 40% of primary HPT patients have elevated levels of alkaline phosphatase, which indicates some degree of increased bone turnover. Although osteitis fibrosis cystica, the classic form of parathyroid bone disease, is rarely seen today, even patients with mild disease can have biochemical or histologic evidence of bone involvement. Dual-energy x-ray absorption (DEXA) scanning of the lumbar spine, hip, and forearm has become the standard method for assessing bone density to diagnose osteoporosis in the setting of primary HPT.
Imaging modalities for the purposes of localization should be employed only after establishing the biochemical diagnosis of primary HPT. Imaging studies can be sorted into noninvasive and invasive techniques. The noninvasive studies include the following: nuclear medicine scans, such as methoxyisobutylisonitrile (sestamibi) studies, which can be combined with single photon emission computed tomography (SPECT) imaging; ultrasound (Figure 1); computed tomography (CT) scans; and magnetic resonance imaging (MRI). The noninvasive localization study of choice is dependent largely on the availability and quality of imaging modalities at each institution. There is evidence to suggest that the best studies are technetium (99mTc)-sestamibi scan with SPECT, which results in a three-dimensional reconstruction that can delineate the location of an enlarged parathyroid gland in 85% of cases, as well as ultrasound by an experienced ultra-sonographer (or surgeon). There are emerging data to suggest that four-dimensional CT (4D CT) also might afford excellent localization (Figure 2A,B). Invasive techniques usually are reserved for reoperative cases, and include angiography and venous sampling for PTH gradients. Recently, the rapid PTH assay has been used in the ultrasound and angiography suites, as well as the operating room. It yields real-time feedback and has become invaluable in the development of minimally invasive surgical techniques.
FIGURE 1 • Parathyroid adenoma. Sagittal ultrasound shows a parathyroid adenoma (white arrows) behind the lower pole of the right thyroid lobe (black arrows)
FIGURE 2A • Scintigraphic image from 99mTc-sestamibi depict ing a left inferior parathyroid adenoma (arrow) in a patient with primary HPT
FIGURE 2B • Scintigraphic images from sestamibi single-photon emission tomography of the same patient presented in Figure 3A depicting multiple rotational tomographic planes. The posterior location of the parathyroid adenoma (arrow) is consistent with an ectopic superior parathyroid gland in an inferior retroesophageal location.
Diagnosis and Treatment
Parathyroidectomy is the only effective long-term treatment for HPT. There is universal agreement that patients with clear symptoms and signs associated with primary HPT should undergo parathyroid surgery. However, controversy still exists about the management of patients with “asymptomatic” primary HPT. In 1990 and 2002, the National Institutes of Health (NIH) convened consensus conferences to delineate the surgical indications in patients with both symptomatic and asymptomatic primary HPT (Table 3) In 2008, an international workshop on HPT convened to review and update previous recommendations. Guidelines also were created for the management of patients with asymptomatic primary HPT who did not undergo surgery, including biannual serum calcium, annual serum creatinine measurements, and annual bone density measurements. It has been suggested, however, that the NIH criteria for parathyroidectomy in asymptomatic patients are too limited, and that all patients with primary HPT should be referred for surgical therapy.
TABLE 3. Surgical Indications in Patients with Primary Hyperparathyroidism
There is no long-term effective pharmacologic treatment for primary HPT. There are several pharmacologic agents that can transiently lower the serum calcium level (Table 4). These can limit further loss of bone by reducing the activation of new remodeling units in the skeleton. Estrogen replacement, salmon calcitonin, bisphosphonates, and more recently, calcimimetics (cinacalcet) have been used to treat primary HPT in patients with complex comorbid medical conditions who either are unwilling or considered unfit for surgery. In addition, glucocorticoids and calcimimetics can be employed during refractory hypercalcemia of metastatic parathyroid carcinoma. However, these therapies are not definitive, and with adequate preoperative parathyroid localization, high-volume parathyroid surgeons may employ minimally invasive techniques with excellent outcomes.
TABLE 4. Pharmacologic Treatment for Primary Hyperparathyroidism
aOff-label use in primary HPTH except parathyroid carcinoma
Parathyroidectomy has a high rate of success (>95%) with few complications when performed by experienced parathyroid surgeons. Complications associated with parathyroidectomy include recurrent laryngeal nerve injury, transient or persistent hypocalcemia, postoperative hemorrhage, and pneumothorax. Despite this, the specific operative approach has continued to evolve through the influence of a number of synergistic factors, including improvements in preoperative localization studies, rapid intraoperative PTH measurements, and adjunctive surgical technologies such as handheld gamma detection probes and improved videoscopic equipment. The net result has influenced patient selection, such that the majority of parathyroid explorations are very well tolerated. However, a small fraction of these explorations remain challenging, especially those with atypical gland location or previously operated fields. Therefore, any surgeon performing parathyroidectomy must be facile with standard four-gland parathyroid exploration. In fact, experienced parathyroid surgeons today achieve cure rates of up to 98% with both minimally invasive and conventional techniques.
Surgical Approach
The conventional technique for parathyroid exploration requires bilateral cervical access and four gland exploration. This operation is usually performed under general anesthesia, although it can be performed under bilateral regional superficial cervical block. The goal is to identify all normal and abnormal parathyroid glands, thus distinguishing single-gland from multigland disease. Patients who have a single parathyroid adenoma undergo curative resection once the gland is removed. In the instance of multigland hyperplasia, a subtotal parathyroidectomy (leaving a normal-sized remnant of one well-vascularized parathyroid gland in situ), or total cervical parathyroidectomy with immediate heterotopic autotransplantation of parathyroid tissue, typically into the brachioradialis muscle in the forearm, is required (Table 5).
TABLE 5. Key Technical Steps and Potential Pitfalls to Parathyroidectomy
The conventional approach has been challenged with increasing frequency in recent years, and minimally invasive parathyroid exploration now is performed routinely in a growing number of institutions. Three techniques have emerged: image-guided local exploration, most often in conjunction with the intraoperative rapid PTH assay; intraoperative gamma probe-guided exploration after sestamibi injection; and image-guided video parathyroidectomy.
Image-guided local exploration has emerged as the most commonly employed minimally invasive technique. It is dependent on high-quality preoperative imaging, usually in the form of sestamibi scans, ultrasound studies, or, less commonly, 4D CT. This technique is appropriate even for patients who have had multiple previous explorations, as long as the preoperative imaging is adequate. When performed by an experienced parathyroid surgeon well-versed in minimally invasive techniques, this surgical procedure can be performed on an outpatient basis and can avoid the increased risks associated with bilateral neck exploration and general anesthesia.
Gamma probe exploration involves preoperative administration of 99mTc sestamibi to localize the abnormal parathyroid gland. The probe is then used in the operating room to find the area of increased radioactivity. In addition, the gamma probe can be used to measure radioactivity after tumor extraction to confirm the adequacy of resection. Although this technique has not gained widespread acceptance, the curative rates are comparable to the previously described technique.
Image-guided video parathyroidectomy has been employed by several investigators. Like other minimally invasive techniques, preoperative imaging is required to locate the adenoma. The procedure usually requires general anesthesia with or without carbon-dioxide insufflation to aid the dissection. There may be very select patients in whom this technique is indicated; however, this modality has not assumed a dominant role in parathyroid surgery in the United States.
Regardless of the chosen technique of parathyroidectomy, the key steps remain constant. Parathyroidectomy can be performed under general anesthesia or under anterior superficial cervical block with mild sedation. Proper positioning of the patient on the operating table is of paramount importance. The patient should be placed in a semi-Fowler position with the patient’s neck extended dorsally to provide optimal access to the anterior neck. The arms of the patient should lie alongside the body to allow the surgeon and assistant to stand on both sides of the neck. All appropriate pressure points should be padded for protection. A symmetric Kocher incision is made, preferentially in a natural skin crease, approximately 3 to 4 cm cranially to the suprasternal notch. Flaps are developed in the subplatysmal plane, and dissected upward to the level of the thyroid cartilage and inferiorly to the suprasternal notch. Early identification of the recurrent laryngeal nerve expedites the exploration and is invaluable in protecting the nerve. Throughout the procedure, the operative field should be kept as bloodless as possible to prevent discoloring the parathyroid glands, which may impede their identification.
In patients with a solitary enlarged parathyroid gland, the vascular stalk of the tumor should be ligated and the tumor removed. During dissection of the parathyroid tumor, the capsule of the gland should not be opened to prevent seeding of parathyroid tissue, which can cause recurrent HPT due to parathyromatosis. In the case of multigland disease, a subtotal parathyroidectomy should be performed, leaving a well-vascularized remnant of approximately 30 mg in situ, which corresponds to the dimensions of a normal gland. An alternative to subtotal parathyroidectomy is total parathyroidectomy with immediate heterotopic autotransplantation of parathyroid tissue into the sternocleidomastoid muscle or the brachioradialis muscle of the nondominant forearm. This alternative procedure often is combined with cryopreservation of some parathyroid tissue. In multigland syndromic disease, the thymus should be removed bilaterally by a transcervical approach, as supernumerary parathyroids are located in the thymus in 3% to 5% of all patients.
In 1994, Irvin et al. reported the use of intraoperative PTH monitoring to determine when all hypersecreting parathyroid tissue has been removed. A decrease in intraoperative PTH from a baseline established prior to incision by over 50% following excision indicates sufficient removal of hyperfunctioning parathyroid tissue. When the PTH value fails to drop by 50%, this suggests that either the hyperfunctioning gland has not been removed or the patient has multigland disease. This modality may be employed as a surgical adjunct to confirm removal of all hypersecreting parathyroid tissue.
After completion of the parathyroidectomy, the operative field is checked thoroughly to achieve meticulous hemostasis. The raphe between the strap muscles and the platysma are reapproximated with absorbable suture. The skin is closed with optimal cosmesis.
Special Intraoperative Considerations
Parathyroid carcinoma is a rare cause of primary HPT, accounting for <1% of cases. Parathyroid carcinoma should be suspected in patients who demonstrate a rapid and sustained rise in both their serum calcium and iPTH levels, which can reach very high levels. A palpable neck mass sometimes may be appreciated, whereas a parathyroid adenoma is rarely, if ever, palpable on physical examination. In addition, sestamibi scan demonstrates a hyperintense focus that correlates with the lesion. If parathyroid carcinoma is suspected preoperatively or is found incidentally at the time of operation, en blocresection with the ipsilateral thyroid lobe and central compartment lymph nodes is appropriate. Although these tumors are slow-growing, they have a high propensity to recur locally, and recurrent disease is difficult to eradicate. Patients with recurrent and metastatic disease often suffer from severe, debilitating hypercalcemia, control of which may involve palliative surgical resection and the use of drugs, including bisphosphonates and calcimimetics, to lower the serum calcium level. Chemotherapy and radiation therapy rarely are effective.
An enlarged parathyroid gland can remain undiscovered after routine exploration of the neck. It is of great importance to identify the normal parathyroid glands during the exploration, because a parathyroid missed at its normal localization can help the surgeon predict the site of the migrated enlarged parathyroid. One must identify correctly whether a superior or inferior gland is missing. In the circumstance in which three normal parathyroid glands have been identified but a superior gland is missing, the retroesophageal space should be explored, and the carotid sheath opened from the level of the carotid bifurcation to the base of the neck. In the situation in which three normal parathyroids have been identified but an inferior gland cannot be identified, the thymus on the side of the missing gland should be exposed. The retrosternal thymus can be mobilized by gentle traction on the thyrothymic ligament, and a transcervical thymectomy can be performed. If the missing inferior gland is not contained within the mediastinal portion of the thymus, an intrathyroidal parathyroid tumor should be considered. In the circumstance in which four normal parathyroid glands have been visualized but increased levels of intact PTH exclude another cause of hypercalcemia, one must consider a hypersecreting supernumerary parathyroid gland, most commonly located within the thymus. Bilateral thymectomy is indicated.
If the abnormal parathyroid tumor cannot be identified at the time of neck exploration and the patient has persistent HPT, additional imaging techniques may need to be employed to localize the ectopic gland. These modalities include thorough neck ultrasonography with potential fine needle aspiration identification of parathyroid tissue, neck and chest 4D CT or MRI studies, sestamibi scans, or selective jugular venous sampling for iPTH differential gradient. The operative note and pathology report from the patient’s initial exploration should be reviewed, and the patient should undergo indirect laryngoscopy prior to remedial exploration to assure the integrity of the recurrent laryngeal nerves. Most missed glands (~40%) are located in eutopic positions. The thymus (~10%) and the anterior mediastinum (~13%) also are common locations for missed adenomas. Remedial parathyroidectomy is associated with increased risks of hypoparathyroidism and recurrent laryngeal nerve injury, and should be performed by experienced parathyroid surgeons.
Postoperative Management
For patients with severe bone disease, often evidenced by markedly elevated preoperative blood alkaline phosphatase levels, subsequent “bone hunger” often necessitates postoperative treatment with calcium supplementation and calcitriol. Normocalcemia generally is restored within the first 24 hours after a successful parathyroidectomy, and this may be accompanied by mild paresthesias circumorally and/or in the extremities. Symptoms may occur while the serum calcium level is within the normal range, reflecting the rapidity of change; however, this is usually transient and does not require treatment. Symptomatic hypocalcemia is more common in the elderly, in those with more severe preoperative primary HPT, or in patients with evidence of high-turnover bone disease. Restoration of normocalcemia can be achieved with calcitriol in combination with supplemental calcium. It is sufficient to maintain the serum calcium within the lower part of the reference range in order to control symptoms.
The rationale for parathyroidectomy is supported by evidence that in about 80% of patients, the clinical manifestations of primary HPT improve after successful parathyroidectomy. Thus, fatigue, weakness, polydipsia, polyuria, bone and joint pain, constipation, nausea, and depression regress in most patients. This is also true for associated conditions—renal stones usually stop forming, osteoporosis stabilizes or improves, pancreatitis becomes less likely, and peptic ulcer disease often resolves. In most patients, fracture risk and weakness also improve, and objective increase in muscular strength has been documented. In addition, neurocognitive impairments, confusion, spatial learning deficits, and depression have been shown to improve after successful operative intervention. Patients can resume a regular diet with or without calcium supplementation, and hypercalcemia is not a concern when these patients are hospitalized for other medical conditions.
Another important reason for recommending parathyroidectomy is that patients with primary HPT appear to be at risk for premature death primarily because of cardiovascular disease and cancer. More importantly, the increased death rate, even in patients with mild primary HPT, can be reversed by successful parathyroidectomy. Patients between the ages of 55 and 70 years seem to receive the greatest survival benefit.
Case Conclusion
After appropriate medical management of acute hypercalcemia, including intravenous hydration, bisphosphonate and furosemide therapy, the patient’s serum calcium decreased to 10.8 mg/dL and her mental status returned to baseline. She underwent a sestamibi scan with SPECT, which revealed increased uptake in the right inferior anterior neck. After adequate medical evaluation, she underwent a minimally invasive parathyroidectomy with excision of a right inferior parathyroid adenoma. Intraoperative rapid PTH measurement documented adequate resection with a decline from her baseline of 250 to 35 pg/mL at ten minutes postresection. The patient returned home the following day with a normal serum calcium level of 9.8 mg/dL, and a postoperative regimen of oral calcium supplementation. At 6 months postoperatively, she remained eucalcemic and did not have any further episodes of nephrolithasis.
TAKE HOME POINTS
· In the outpatient setting, primary HPT is the most common reason for hypercalcemia. In the inpatient population, hypercalcemia often is secondary to malignancy
· Imaging modalities to localize hyperfunctioning abnormal parathyroid glands should be undertaken only after the diagnosis of primary HPT has been confirmed biochemically.
· An understanding of the embryology of the parathyroid glands and the ability to distinguish between a normal and an abnormal parathyroid gland are essential for successful parathyroid surgery. A systematic approach knowing the routine and unusual locations for parathyroid glands results in successful parathyroidectomy in more than 95% of patients with primary HPT.
· Permanent hypoparathyroidism, injury to the recurrent laryngeal nerves, and postoperative bleeding (with possible airway compromise) are some of the more serious complications that occur after parathyroidectomy.
· The increased death rate associated with primary HPT can be reversed by successful parathyroidectomy. In the hands of a high-volume parathyroid surgeon, cure rates of up to 98% have been documented with both minimally invasive and conventional techniques.
SUGGESTED READINGS
Adami S, Marcocci C, Gatti D. Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res. 2002;17(S2):N18–N23.
Akerstrom G, Rudberg C, Grimelius L, et al. Causes of failed primary exploration and technical aspects of re-operation in primary hyperparathyroidism. World J Surg. 1992;16:562–568.
Bilezikian JP, Potts JT Jr, Fuleihan GEH, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab. 2002;87:5353–5361.
Bonjer HJ and Bruining HA. Technique of parathyroidectomy. In: Clark OH, Duh QY, Kebebew E, eds. Textbook of Endocrine Surgery. 2nd ed. Philadelphia, PA: Elsevier Saunders, 2005:439–448.
Cannon J, Lew JI, Solorzano CC. Parathyroidectomy for hypercalcemic crisis: 40 years’ experience and long-term outcomes. Surgery. 2010;148:807–813.
Chen H, Mack E, Starling JR. Radioguided parathyroidectomy is equally effective for both adenomatous and hyperplastic glands. Ann Surg. 2003;238:332–338.
Diamond TW, Botha JR, Wing J, et al. Parathyroid hypertension: a reversible disorder. Arch Int Med. 1986;146:1709–1712.
Hedback G and Oden A. Increased risk of death from primary hyperparathyroidism – an update. Eur J Clin Invest. 1998;28:271–276.
Hruska KA, Teitelbaum SL. Renal osteodystrophy. N Engl J Med. 1995;333:166.
Irvin GL, Prudhomme Dl, Deriso GT, et al. A new approach to parathyroidectomy. Ann Surg. 1994;219:574–579.
Lew JI and Solorzano CC. Surgical management of primary hyperparathyroidism: state of the art. Surg Clin North Am. 2009;89:1205–1225.
Lo Gerfo P. Bilateral neck exploration for parathyroidectomy under local anesthesia: a viable technique for patients with coexisting thyroid disease with or without sestamibi scanning. Surgery. 1999;126:1011–1014.
Lowe H, McMahon DJ, Rubin MR, et al. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab. 2007;92:3001–3005.
Miccoli P, Bendinelli C, Vignali E, et al. Endoscopic parathyroidectomy: report on an initial experience. Surgery. 1998;124:1077–1079.
Mittendorf EA and McHenry CR. Persistent parathyroid hormone elevation following curative parathyroidectomy for primary hyperparathyroidism. Arch Otolaryngol Head Neck Surg. 2002;128:275–279.
NIH Consensus Development Conference Panel. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development state. Ann Intern Med. 1991;114:593–597.
Norenstedt S, Ekbom A, Brandt L, et al. Postoperative mortality in parathyroid surgery in Sweden during five decades: improved outcome despite older patients. Eur J Endocrinol. 2009;160:295–299.
Peacock M, Bilezikian JP, Klassen PS, et al. Cinacalcet hyperochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2003;90:135–141.
Rodgers SE, Hunter GJ, Hamberg LM, et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery. 2006;140:932–941.
Rodgers SE, Lew JI, Solorzano CC. Primary hyperparathyroidism. Curr Opin Oncol. 2008;20:52–58.
Rodgers SE, Perrier ND. Parathyroid carcinoma. Curr Opin Oncol. 2006;18:16–22.
Roman SA and Sosa JA. Psychiatric and cognitive aspects of primary hyperparathyroidism. Curr Opin Oncol. 2007;19:1–5.
Roman SA, Sosa JA, Mayes L et al. Parathyroidectomy improves neurocognitive deficits in patients with primary hyperparathyroidism. Surgery. 2005;138:1121–1128.
Roman SA, Sosa JA, Pietrzak R, et al. The effects of serum calcium and parathyroid hormone changes on psychiatric and cognitive function in patients undergoing parathyroidectomy for primary hyperparathyroidism. Ann Surg. 2010 (in press).
Sheldon DG, Lee FT, Neil NJ, et al. Surgical treatment of hyperparathyroidism improves health-related quality of life. Arch Surg. 2002;137:1022–1028.
Silverberg SJ, Lewiecki EM, Mosekilde L, et al. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the Third International Workshop. J Clin Endocrinol Metab. 2009;94:351–365.
Solorzano CC, Carneiro-Pla DM, Irvin Gl. Surgeon-performed ultrasonography as the initial and only localizing study in sporadic primary hyperparathyroidism. J Am Coll Surg. 2006;202:18–24.
Sosa JA, Power NR, Levine MA, et al. Profile of a clinical practice: Thresholds for surgery and surgical outcomes for patients with primary hyperparathyroidism: a national survey of endocrine surgeons. J Clin Endocrinol Metab. 1998;83(8):2658–2665.
Tamura Y, Araki A, Chiba Y, et al. Remarkable increase in lumbar spine bone mineral density and amelioration in biochemical markers of bone turnover after parathyroidectomy in elderly patients with primary hyperparathyroidism: a 5-year follow-up study. J Bone Miner Metab. 2007;25:226–231.
Udelsman R. Primary hyperparathyroidism. Curr Treat Options Oncol. 2001;2:365–372.
Udelsman R, Aruny JE, Donovan PI, et al. Rapid parathyroid hormone analysis during venous localization. Ann Surg. 2003;237:714–721.
Udelsman R, Lin Z, Donovan P. The superiority of minimally invasive parathyroidectomy based on 1,650 consecutive patients with primary hyperparathyroidism. Ann Surg. 2011;253(3):585-591.
Udelsman R, Pasieka JL, Sturgeon C, et al. Surgery for asymptomatic primary hyperparathyroidism: Proceedings of the Third International Workshop. J Clin Endocrinol Metab. 2009;94:366–372.
Uludag M, Isgor A, Yetkin G, et al. Supernumerary ectopic parathyroid glands: persistent hyperparathyroidism due to mediastinal parathyroid adenoma localized by preoperative single photon emission computed tomography and intraoperative gamma probe application. Hormones. 2009;8:144–149.