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Hyperparathyroidism

  • Author: Lawrence Kim, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
 
Updated: Jul 11, 2016
 

Overview

Through their secretion of parathyroid hormone (PTH), the parathyroid glands are primarily responsible for maintaining extracellular calcium concentrations. Hyperparathyroidism is a disease characterized by excessive secretion of parathyroid hormone, an 84–amino acid polypeptide hormone. The secretion of parathyroid hormone is regulated directly by the plasma concentration of ionized calcium. See the image below.

Normal parathyroid glands as seen during a thyroid Normal parathyroid glands as seen during a thyroidectomy. The large arrow points to the superior parathyroid. The thinner arrow points to the inferior parathyroid. The forceps points toward the recurrent laryngeal nerve. The patient's head is toward the right.

The main effects of parathyroid hormone are to increase the concentration of plasma calcium by increasing the release of calcium and phosphate from bone matrix, increasing calcium reabsorption by the kidney, and increasing renal production of 1,25-dihydroxyvitamin D-3 (calcitriol), which increases intestinal absorption of calcium. Thus, overproduction of parathyroid hormone results in elevated levels of plasma calcium. Parathyroid hormone also causes phosphaturia, thereby decreasing serum phosphate levels. Hyperparathyroidism is usually subdivided into primary, secondary, and tertiary hyperparathyroidism.

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Anatomy and Embryology

Usually, 4 parathyroid glands are situated posterior to the thyroid gland. A small number of patients have 3, 5, or, occasionally, more glands. The glands are identified based on their location as right or left and superior or inferior.

The inferior glands are derived from the third pharyngeal pouch. This structure is also the embryologic origin of the thymus. Therefore, the inferior glands originate more cephalad than the superior glands, but they migrate along with the thymus to finally become situated more inferiorly than the superior glands. Because of their embryologic association with the thymus, the inferior glands are often found adjacent to or within the thymus. They are usually located near the inferior pole of the thyroid.

The superior glands are more consistent in location, usually found just superior to the intersection of the inferior thyroid artery and the recurrent laryngeal nerve. The superior glands are derived embryologically from the fourth pharyngeal pouch. This structure also gives rise to the C cells of the thyroid gland. Because of their embryologic origin, the superior glands are occasionally found within the substance of the thyroid gland. Ectopic locations of parathyroid glands are discussed in more detail in Surgical care in Primary Hyperparathyroidism.

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Primary Hyperparathyroidism

Definition of problem

Primary hyperparathyroidism is the unregulated overproduction of parathyroid hormone (PTH) resulting in abnormal calcium homeostasis.

Frequency

US population-based data from Olmsted County, Minn, indicate that the prevalence of primary hyperparathyroidism is slowly decreasing.[1] The prevalence has been reported to be approximately 21 cases per 100,000 person-years. The mean age at diagnosis has remained between 52 and 56 years, and women have consistently made up the majority of cases (with a female-to-male ratio of 3:1).

Etiology

In approximately 85% of cases, primary hyperparathyroidism is caused by a single adenoma. In 15% of cases, multiple glands are involved (ie, either multiple adenomas or hyperplasia).[2] Rarely, primary hyperparathyroidism is caused by parathyroid carcinoma. The etiology of adenomas or hyperplasia remains unknown in most cases. Familial cases can occur either as part of the multiple endocrine neoplasia syndromes (MEN 1 or MEN 2a), hyperparathyroid-jaw tumor (HPT-JT) syndrome, or familial isolated hyperparathyroidism (FIHPT). Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism also belong to this category. The molecular genetic basis of MEN 1 is an inactivating mutation of the MEN1 gene, located on chromosome band 11q13. MEN 2a is caused by a germline mutation of the Ret proto-oncogene on chromosome 10.[3] Germline mutation of HRPT2 localized on chromosome arm 1q is responsible for HPT-JT, while FIHPT is genetically heterogeneous.

Pathophysiology

In primary hyperparathyroidism due to adenomas, the normal feedback on parathyroid hormone production by extracellular calcium seems to be lost, resulting in a change in the set point. However, this is not the case in primary hyperparathyroidism from parathyroid hyperplasia. An increase in the cell numbers is probably the cause.

The chronic excessive resorption of calcium from bone caused by excessive parathyroid hormone can result in osteopenia. In severe cases, this may result in osteitis fibrosa cystica, which is characterized by subperiosteal resorption of the distal phalanges, tapering of the distal clavicles, salt-and-pepper appearance of the skull, and brown tumors of the long bones. This is not commonly seen now. In addition, the chronically increased excretion of calcium in the urine can predispose to the formation of renal stones.

The other symptoms of hyperparathyroidism are due to the hypercalcemia itself and are not specific to hyperparathyroidism. These can include muscle weakness, fatigue, volume depletion, nausea and vomiting, and in severe cases, coma and death. Neuropsychiatric manifestations are particularly common and may include depression, confusion, or subtle deficits that are often characterized poorly and may not be noted by the patient. Increased calcium can increase gastric acid secretion, and persons with hyperparathyroidism may have a higher prevalence of peptic ulcer disease. Rare cases of pancreatitis have also been attributed to hypercalcemia.

Clinical presentation

History

The clinical syndrome of primary hyperparathyroidism can be easily remembered as "Bones, stones, abdominal groans, and psychic moans." With the introduction of routine measurement of blood calcium in the early 1970s, the clinical presentation of primary hyperparathyroidism changed from severe bone disease or kidney stones to asymptomatic hypercalcemia in most cases.[4]

Skeletal manifestations include selective cortical bone loss, which is common. Bone and joint pain, pseudogout, and chondrocalcinosis have also been reported. In the early clinical description of primary hyperparathyroidism, some patients developed a peculiar type of bone disease known as osteitis fibrosa cystica, characterized by increased generalized osteoclastic bone resorption, particularly involving the phalanges causing subperiosteal resorption, and the skull causing the radiologic appearance known as salt and pepper skull. This presentation is rarely seen today except in medically underserved populations.

Renal manifestations include polyuria, kidney stones, hypercalciuria, and rarely nephrocalcinosis.

Gastrointestinal manifestations include anorexia, nausea, vomiting, abdominal pain, constipation, peptic ulcer disease, and acute pancreatitis.

Neuromuscular and psychologic manifestations include proximal myopathy, weakness and easy fatigability, depression, inability to concentrate, and memory problems or subtle deficits that are often characterized poorly and may not be noted by the patient.

Cardiovascular manifestations include hypertension, bradycardia, shortened QT interval, and left ventricular hypertrophy.[5]

Physical

Physical examination findings are usually noncontributory. Examination may reveal muscle weakness and depression. A palpable neck mass is not usually expected with hyperparathyroidism, although in rare cases, it may indicate parathyroid cancer.

Diagnostic considerations

The causes of hypercalcemia that result in a concomitantly elevated parathyroid hormone level are few. These include familial benign (hypocalciuric) hypercalcemia (FHH) (see Related disorders), lithium-induced hypercalcemia, and tertiary hyperparathyroidism. A minority of patients (ie, 10-15%) with hyperparathyroidism have parathyroid hormone levels at the high end of the reference range, though inappropriately high in the presence of elevated serum calcium concentrations. A subset of patients have calcium levels within the reference range with elevated parathyroid hormone, so-called normocalcemic hyperparathyroidism. However, when considering this diagnosis, all potential causes of secondary hyperparathyroidism (eg, low calcium intake, gastrointestinal disorders, renal insufficiency, vitamin D deficiency, hypercalciuria of renal origin) should be excluded. Patients with normal calcium levels and elevated parathyroid hormone levels in the absence of an identifiable secondary cause should be monitored for progression to hypercalcemia. 

Secondary and tertiary hyperparathyroidism are typically diagnosed based on their clinical context. Cancer-induced hypercalcemia is usually associated with a low parathyroid hormone level but possibly a high parathyroid hormone-related peptide level.

Workup

Laboratory studies

Total serum calcium and albumin levels or ionized calcium levels should be measured. Hypercalcemia should be documented on more than one occasion before a diagnostic workup is undertaken.

Testing of the intact parathyroid hormone level is the core of the diagnosis. An elevated intact parathyroid hormone level with an elevated ionized serum calcium level is diagnostic of primary hyperparathyroidism. A 24-hour urine calcium measurement is necessary to rule out FHH.

Older assays measured fragments of the parathyroid hormone molecule, such as the C-terminal or mid region of parathyroid hormone. These first-generation assays are considered obsolete for the clinical practice. Second-generation parathyroid hormone assays, globally called "intact" parathyroid hormone assays, and third-generation parathyroid hormone assays called "whole" or "biointact" parathyroid hormone assays use two different antibodies against two different segments of parathyroid hormone. Second- and third-generation parathyroid hormone assays are producing far more clinically satisfying data than the first-generation assays but have some limitations that continue to be assessed in several studies.

Other laboratory findings in primary hyperparathyroidism include mild hyperchloremic acidosis, hypophosphatemia, and mild-to-moderate increase in urinary calcium excretion rate.

A study by Saliba et al evaluated the relationship between 25(OH)D levels and concomitant parathyroid hormone levels. The results revelaed that a 25(OH)D threshold of 50 nmol/L is sufficient for parathyroid hormone suppression and prevention of secondary hyperparathyroidism in persons with normal renal function. 25(OH)D levels that are greater than 75 nmol/L were not associated with additional changes in parathyroid hormone levels.[6]

Imaging studies

Imaging studies are not used to make the diagnosis of primary hyperparathyroidism (which is based on laboratory data) or to make a decision about whether to pursue surgical therapy (which is based on clinical criteria). Imaging studies are used to guide the surgeon once surgical therapy has been decided. If a limited parathyroid exploration is to be attempted, a localizing study is necessary. Other uses of imaging studies in the initial evaluation of a patient with primary hyperparathyroidism are controversial (see Choice of surgical treatment, below).

For many patients, the recommendation remains for complete parathyroid exploration with resection of all involved glands. Many surgeons agree that imaging studies are not required when this surgical treatment is chosen. However, in patients who have recurrent or persistent hyperparathyroidism after a previous surgical exploration, an imaging test to localize involved glands is definitely indicated.

Ultrasonography of the neck is a safe and widely used technique for localization of abnormal parathyroid glands. It is capable of a high degree of accuracy, but it is operatordependent and its reported accuracy has varied widely in the literature. One advantage of neck ultrasonography is that it can be performed rapidly by the clinician at the time of the initial evaluation. Studies of clinician-performed ultrasound show accuracy rates that compare favorably with the accuracy of traditional radiology departments, in the vicinity of 75-80%.[7, 8, 9, 10] Ultrasound, like nuclear medicine scanning, has not been reliable in detecting multigland disease.

Nuclear medicine scanning with radiolabeled sestamibi is also a widely used technique. Sestamibi is commonly used in cardiac imaging and was found serendipitously to accumulate in parathyroid adenomas. This radionuclide is concentrated in thyroid and parathyroid tissue but usually washes out of normal thyroid tissue in under an hour. It persists in abnormal parathyroid tissue. See the image below.

Hyperparathyroidism. Technetium-99m (99mTc) sestam Hyperparathyroidism. Technetium-99m (99mTc) sestamibi radionuclide scan. The early image (top left) shows uptake in the salivary glands and thyroid. The later images (right and bottom) show washout from the thyroid but persistence in the region of the right inferior thyroid lobe (arrows). This proved to be a right parathyroid adenoma.

On delayed images, an abnormal parathyroid is seen as a persistent focus of activity. The scan's sensitivity for detecting solitary adenomas has varied widely in the literature but generally is reported as 60-90%. The main weakness of this test is in diagnosing multiglandular disease. In this case, sensitivity drops to approximately 50%.[2] When combined with single-photon emission computed tomography (SPECT) scanning, it can be used effectively to localize parathyroid adenomas. The scan can include the mediastinum and, thus, is extremely useful in cases of an ectopic adenoma or previously failed surgical exploration.

CT scanning and magnetic resonance imaging (MRI) have also been used also to locate abnormal parathyroid glands. Standard CT scanning has inadequate sensitivity. Newer techniques of CT scanning with dynamic contrast images (4D-CT) have shown promise, with accuracy rates as high as 88%.[11, 12]  (A study by Ramirez et al suggested that two-phase CT scanning is as effective as the four-dimensional modality in localization of the parathyroids, including in cases of small adenomas, reoperation, and multiglandular disease, with less radiation exposure for the patient.[13] ) MRI can be useful, particularly in cases of recurrent or persistent disease and in ectopic locations such as the mediastinum.

Dual-energy radiographic absorptiometry is a useful tool to demonstrate the skeletal involvement in primary hyperparathyroidism. Note that hyperparathyroidism preferentially affects the cortical bone at the radius (distal third). In cases of severe primary hyperparathyroidism, skeletal radiographs show pathognomonic changes such as salt-and-pepper degranulation in the skull and subperiosteal bone resorption in the phalanges.

Procedures

Bilateral internal jugular vein sampling is used to help localize ectopic parathyroid adenomas; however, this technique should generally be reserved for centers with specialists and for selected patients.

Treatment

Surgical excision of the abnormal parathyroid glands (see below for details of surgical treatment) offers the only permanent, curative treatment for primary hyperparathyroidism. There is universal agreement that surgical treatment should be offered to all patients with symptomatic disease. Some controversy exists regarding the optimal management of asymptomatic patients.

A National Institutes of Health (NIH) Workshop on Asymptomatic Primary Hyperparathyroidism in 2002 revisited the key management issues addressed at the 1990 NIH Consensus Development Conference.[14] . They recommended new guidelines for surgery and the conservative approach of monitoring patients who do not meet the criteria for surgery. The indications for surgery as per the 2002 guidelines are as follows:

  • One mg/dL above the upper limit of the reference range for serum calcium
  • Twenty-four-hour urinary calcium excretion greater than 400 mg
  • A 30% reduction in creatinine clearance
  • Bone mineral density T-score below -2.5 at any site
  • Age younger than 50 years

For monitoring of patients with asymptomatic hyperparathyroidism who do not undergo surgery, the following are recommended: serum calcium and creatinine levels every 6 months and annual bone mineral density (all 3 sites).

Some clinicians advocate surgical therapy in all patients with primary hyperparathyroidism, modified only for those patients who are not able to tolerate surgery. They argue that the operation is generally well tolerated and such treatment prevents complications (eg, osteoporosis) and may reverse symptoms that patients often do not realize they have (eg, fatigue, mild depression). In addition, the monitoring of asymptomatic patients is expensive and cumbersome. This more liberal approach has been articulated by an expert group convened by the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons. They concluded that "...operative management should be considered and recommended for all asymptomatic patients with PHPT who have a reasonable life expectancy and suitable operative and anesthesia risk factors."[15]

Management of severe hypercalcemia in the acute setting

Reduction of elevated serum calcium can be accomplished by the use of intravascular volume expansion with sodium chloride and loop diuretics such as furosemide once the intravascular volume is restored. Drugs such as calcitonin and IV bisphosphonate have been used as a temporary measure prior to surgical treatment.

Nonsurgical care

Asymptomatic patients who choose not to have surgery should be carefully monitored. Patients should be assessed for overt signs and symptoms of primary hyperparathyroidism on an annual basis. Serum creatinine level and a 3-site dual-energy radiographic absorptiometry study should also be obtained on annual basis. Serum calcium should be checked every 6 months.

Patients with primary hyperparathyroidism should maintain a moderate daily elemental calcium intake of 800-1000 mg and a vitamin D intake appropriate for their age and sex. Maintaining good hydration, participation in regular exercise activity, and avoidance of immobilization and certain medications (such as thiazides, diuretics, and lithium) are desirable.

Pharmacotherapy

Estrogen therapy in postmenopausal women has been shown to cause a small reduction in serum calcium (0.5-1 mg/dL) without a change in parathyroid hormone. Estrogen also has beneficial effects of lumbar spine and femoral neck bone mineral density (BMD). However, due to risks associated with estrogen replacement, it should not be used for the sole purpose of treating primary hyperparathyroidism.

Selective estrogen receptor modulators such as raloxifene have been shown to cause a decrease in serum calcium of the same magnitude observed with estrogen.

Bisphosphonates, in particular alendronate, has been shown to improve the BMD at the spine and hip BMD in patients with primary hyperparathyroidism.[16, 17] No significant change in parathyroid hormone, calcium, or 24-hour urinary calcium has been reported. Treatment with a bisphosphonate such as alendronate can be considered in patients with primary hyperparathyroidism and low BMD who cannot, or will not, undergo surgery.

Calcimimetic drugs activate the calcium-sensing receptor and inhibit parathyroid cell function.[18, 19] Treatment with cinacalcet resulted in reduction without normalization of parathyroid hormone levels, reduction and even normalization of serum calcium, but no increase in BMD was observed.

Other treatments

Percutaneous alcohol injection, ablation with ultrasound energy, and other percutaneous ablation techniques of the parathyroid gland have been suggested as an alternative treatment in patients with primary hyperparathyroidism who cannot or will not undergo surgery. Percutaneous techniques have had high complication rates in small numbers of patients, however, mainly because of the close proximity to the recurrent laryngeal nerve, particularly for the superior glands. Routine use of these percutaneous techniques cannot yet be supported.

Surgical care

Surgical treatment should be offered to most patients with primary hyperparathyroidism. The historical criterion-standard operative approach is complete neck exploration with identification of all parathyroid glands and removal of all abnormal glands. Approximately 85% of cases of primary hyperparathyroidism are caused by a single adenoma. Therefore, most patients who undergo full neck exploration to evaluate all parathyroids endure some unnecessary dissection. Rather than explore all parathyroid glands, a newer technique, directed parathyroidectomy, has evolved. This technique relies on preoperative imaging studies to localize the abnormal gland. The surgeon then removes only that gland, without visualizing the other glands.

With either sestamibi scanning or ultrasonography, an abnormal parathyroid may be detected preoperatively in 70-80% of cases. However, neither technique is reliable for detecting multiple abnormal glands.[2] Therefore, an additional method is required to confirm that no other abnormal glands are present after excision of the imaged lesion. For this purpose, many centers have begun to use the intraoperative parathyroid hormone assay.[2, 20, 21] Because the plasma half-life of parathyroid hormone is only approximately 4 minutes, the level falls quickly after resection of the source. If the level fails to fall after resection of the identified abnormal gland, the procedure is extended to allow for further exploration. However, the intraoperative parathyroid hormone assay is usually available only in centers that perform a high volume of parathyroidectomies.

A few authors have advocated radio-guided parathyroidectomy, detecting the labeled sestamibi in the abnormal gland using a handheld probe. Most centers have abandoned this technique because if the gland labels well with sestamibi, allowing for adequate preoperative imaging, use of the handheld probe intraoperatively is unnecessary in most cases.

Use of directed parathyroidectomy results in a more limited operation for most patients, resulting in a more rapid recovery. However, it may yield a higher persistence rate than complete neck exploration, and it probably should be performed only in centers with the capability to perform the intraoperative parathyroid hormone assay.

Greene et al examined trends in surgeons' use of bilateral versus limited exploration for parathyroidectomy between 1998 and 2008.[22] Surveying 256 surgeons (members of the American Association of Endocrine Surgeons and the American College of Surgeons), who together accounted for 46% of parathyroid operations in the United States, the investigators found that in 2008, 10% of surgeons employed bilateral neck exploration, 68% used limited exploration, and 22% used both of these exploration techniques in their practice. In 1998, the statistics for surgeons using bilateral, limited, or both types of exploration were 74%, 11%, and 15%, respectively. The study indicated that the physicians who are most likely to use limited exploration are endocrine surgeons, surgeons with a high-volume practice, and surgeons whose mentors used limited exploration.

The authors also found that in 2008, half of the general surgeons surveyed never monitored parathyroid hormone intraoperatively (whether using bilateral or limited exploration), while the same held true for less than 10% of the endocrine surgeons. In addition, there was great variation "among subsets of surgeons in operative volumes, indications for bilateral neck exploration, [follow-up] care, expertise with [ultrasonography] and sestamibi, and perceptions of cure and complication rates." Greene and his coauthors concluded that because of the many differences that exist in the surgical management of hyperparathyroidism, best-practice guidelines may need to be defined.

For familial disease, such as MEN 1, total parathyroidectomy is performed with autotransplantation to the forearm and cryopreservation of some parathyroid tissue.[23]

Parathyroidectomy is usually well tolerated. The main risks are injury to the recurrent laryngeal nerves and hypoparathyroidism due to resection or devascularization of all parathyroid glands. Although local anesthesia has been used successfully for this procedure, especially in the directed approaches during which a single adenoma is localized preoperatively, general anesthesia is used most commonly. In patients in whom hypercalcemia (and, therefore, dehydration) has been severe, special attention must be directed to perioperatively restoring the fluid balance. Neck mobility must be assessed to ensure proper positioning in the operating room.

Technique for full neck exploration with identification of all parathyroid glands

The most critical aspect to ensure success in this operation is identification of all 4 parathyroid glands and removal of all abnormal glands. In the case of 4-gland hyperplasia, a 3.5-gland (subtotal) parathyroidectomy is performed. Approximately 50-70 mg of the most normal-appearing tissue is left behind. A nonabsorbable suture is left as a tag to identify the gland should reoperation be necessary.

The patient is placed in the lawn-chair position with the neck extended over a transversely placed shoulder roll. This position allows full exposure of anterior neck structures and improves venous drainage.

A low transverse incision placed within the skin creases provides the best cosmetic result. The length of the incision must be adequate to allow thorough exploration of all potential locations of the parathyroid glands; however, given the elasticity of the neck skin flaps, a 3- to 5-cm incision allows safe identification of important structures.

After hemostasis of the skin incision is obtained, subplatysmal flaps are developed superiorly to the notch of the thyroid cartilage and inferiorly to the flat portion of the manubrium. The sternohyoid and sternothyroid (strap) muscles are separated in the midline to expose the thyroid gland. If preoperative localization studies suggest a parathyroid adenoma, that side is approached first.

Frequently, a middle thyroid vein may require ligation to ensure adequate mobilization of the thyroid lobe. The thyroid lobe is elevated off the common carotid artery and retracted medially. The inferior thyroid artery is identified after blunt and sharp dissection of the areolar tissue anteriorly and medially to the common carotid artery and posteromedially to the thyroid lobe. The recurrent laryngeal nerve is identified next, inferior and lateral to the lower lobe of the thyroid gland.

The intersection of the inferior thyroid artery and the recurrent laryngeal nerve is an important landmark because most parathyroid glands, superior and inferior, are located within 2 cm of this area. The superior parathyroid glands are located dorsal to the upper two thirds of the thyroid lobe and posterior to the recurrent laryngeal nerve. The inferior glands, which are less consistent in location, can usually be found inferior to the inferior thyroid artery and ventral to the recurrent laryngeal nerve. They are usually within 1 cm of the inferior lobe of the thyroid gland.

Occasionally, all parathyroid glands cannot be identified. In such instances, the usual locations are reexamined first because most parathyroid glands are located in typical areas. If parathyroid glands are not identified in those locations, then a systematic search is performed, taking into consideration the path of descent of superior and inferior parathyroid glands.

Inferior glands may be located in the thyrothymic ligament. They may be difficult to identify, especially after division of the inferior thyroid vein, a maneuver that allows the gland to retract into the superior mediastinum. Another location for ectopic inferior parathyroid glands is the thymus. The thymus can be visualized through a transverse cervical incision by retracting the innominate vein dorsally with a sponge-stick while elevating the manubrium anteriorly.[24] Division of the interclavicular ligament improves visualization in the superior mediastinum.

Superior parathyroid glands are usually dorsal to the upper two thirds of the thyroid gland. Occasionally, these glands are adjacent to the superior thyroid vessels. Other locations include the carotid sheath or posterior to the esophagus or pharynx (retroesophageal). Finally, both superior and inferior parathyroid glands may be located aberrantly within the capsule of the thyroid gland. Some surgeons perform a thyroid lobectomy on the side harboring the abnormal gland after an exhaustive search is made in the aforementioned locations. Median sternotomy is rarely required during the initial neck exploration for hyperparathyroidism.

Abnormally enlarged glands are excised after confirmation of the normal size of other glands. During excision, avoiding capsular rupture of the abnormal gland is important because this may be associated with implantation of parathyroid cells in the operative site and subsequent parathyromatosis. Parathyroids may be identified by highly experienced surgeons based on appearance and location. In most cases, identification of the parathyroid glands should be confirmed histologically by frozen section examination. In cases of subtotal or total parathyroidectomy with autotransplantation, parathyroid tissue should be cryopreserved for future autotransplantation in case the initial transplant does not function adequately.

Technique for directed parathyroidectomy

In many respects, the operative technique is similar to that described above for a complete parathyroid exploration. Differences are noted below.

Adequate imaging of the abnormal gland prior to surgery is essential. In addition, arrangements for intraoperative measurement of parathyroid hormone should be confirmed.[2] A line for sampling of peripheral venous blood should be established. Often, the distal saphenous vein provides the most convenient access.

Some surgeons modify the location of the incision based on the preoperative location of the adenoma. This author prefers a small incision (ie, ~1-2 cm) in the standard location for a collar incision. This incision can be readily extended should a complete exploration prove necessary.

A baseline parathyroid hormone level is drawn immediately prior to skin incision. Following identification and dissection of the adenoma, a preexcision level is drawn. Manipulation of the gland occasionally causes significant increases in the parathyroid hormone level. Following excision of the gland, parathyroid hormone levels are drawn at 5 minutes and 10 minutes postexcision. Criteria for adequate excision are either a 50% drop in parathyroid hormone from the baseline level to the 10-minute postexcision level or a 50% drop in parathyroid hormone from the preexcision level at 10 minutes and a postexcision level below the baseline level[25] .

The incision may be closed while the last parathyroid hormone levels are being processed, but the patient should remain under anesthesia, and the sterile field maintained until the parathyroid hormone assay results are known.

If a directed parathyroidectomy is performed successfully, most of these patients may be safely discharged the day of surgery. Some practitioners routinely supplement with oral calcium postoperatively.

Complications and postoperative care

For a full parathyroid exploration, calcium levels must be monitored postoperatively every 12 hours until stabilization. The nadir of serum calcium usually occurs 24-72 hours postoperatively. Many patients become hypocalcemic, but few become symptomatic. Reserve treatment for hypocalcemia unless it is severe or the patient becomes symptomatic.

Hypocalcemia after parathyroid surgery may be due to hungry bone syndrome where calcium and phosphorus are rapidly deposited in the bone. This is characterized by hypoparathyroidism and transient, but occasionally severe, hypocalcemia until the normal glands regain sensitivity.

If hypoparathyroidism persists, oral supplementation with calcium and vitamin D is required. Calcium citrate or calcium carbonate may be started at 2 tablets 4 times per day. Some patients require substantially more. Calcitriol is started at 0.5 mcg twice daily and increased as required. Patients in whom total parathyroidectomy and autotransplantation is performed can be expected to require temporary calcium supplementation.

If a recurrent laryngeal nerve is transected during parathyroidectomy, immediate repair is indicated. If the recurrent nerve is not known to be injured intraoperatively but dysfunction is suggested because the patient has developed new hoarseness, expectant management is chosen initially since most patients recover nerve function over a few weeks to months. Laryngoscopy is indicated to document both dysfunction and recovery of function.

A potential life-threatening emergency in the postoperative period is the development of an expanding hematoma in the pretracheal space. This complication must be recognized and treated immediately by opening the wound and evacuating the hematoma. If untreated, laryngeal edema may progress rapidly, causing airway obstruction.

Most small hematomas do not require treatment. A subplatysmal fluid collection may occasionally form, and these are usually treated adequately with a single aspiration. In a few cases, aspiration may need to be repeated. Rarely, a drain may need to be placed for recurrent fluid collections.

Follow-up

Patients are seen 1-2 weeks postoperatively, and serum calcium, 25 hydroxy vitamin D levels, and parathyroid hormone levels are obtained. Parathyroid hormone levels may be elevated postoperatively in some patients, but if the serum calcium remains within the reference range, it does not indicate persistent disease in most patients. Many of these patients have vitamin D deficiency and replacement may correct the elevated PTH concentration.[26] Vitamin D deficiency is particularly common in patients with hyperparathyroidism. Many practitioners routinely add calcium and vitamin D supplementation postoperatively to help restore bone loss and supplement poor dietary intake.

After the immediate postoperative period, follow-up is limited to periodic determinations of serum calcium levels to detect the persistence or recurrence of disease or hypoparathyroidism.

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Secondary Hyperparathyroidism

Definition of problem

Secondary hyperparathyroidism is the overproduction of parathyroid hormone secondary to a chronic abnormal stimulus for its production. Typically, this is due to chronic renal failure.[27] Another common cause is vitamin D deficiency. A study by Bleskestad et al found that more than 50% of patients who undergo kidney transplantation have elevated levels of intact PTH more than 1 year after transplantation. If these elevated levels are associated with mortality, it may have a major impact on future guidelines.[28]

Frequency

Secondary hyperparathyroidism (SHPT) develops early in chronic kidney disease (CKD), before dialysis is required. Consequently, most patients with chronic kidney disease stage 5 or end-stage renal disease (ESRD) have elevated parathyroid hormone and secondary hyperparathyroidism of variable severity. Vitamin D deficiency is common and is underdiagnosed.

Etiology

In chronic kidney disease, overproduction of parathyroid hormone occurs in response to hyperphosphatemia, hypocalcemia, and impaired 1,25-dihydroxyvitamin D production by the diseased kidneys. Hyperphosphatemia appears to be particularly important; it can directly stimulate parathyroid hormone synthesis and parathyroid hyperplasia and indirectly promotes secondary hyperparathyroidism by decreasing free calcium level.

Pathophysiology

Chronic overproduction of parathyroid hormone in patients with renal failure contributes to the spectrum of bone disease observed in patients on dialysis (eg, osteitis fibrosa cystica and mixed uremic osteodystrophy).[29] Nonskeletal consequences include cardiovascular calcification, soft tissue calcification, endocrine disturbances, compromised immune system, neurobehavioral changes, and altered erythropoiesis.

Clinical presentation

Because virtually all patients with renal failure have hyperparathyroidism to some degree, the clinical presentation is often that of renal failure. In patients with secondary hyperparathyroidism due to vitamin D deficiency, the symptoms are mainly due to the vitamin deficiency (eg, osteomalacia with increased fracture risk, myopathy [rarely]). In advanced cases of secondary hyperparathyroidism, some patients may have bone pain.

Workup

Laboratory studies

Serum level of parathyroid hormone, calcium, phosphorus, and 25- hydroxyvitamin D should be measured. Patients with secondary hyperparathyroidism usually have a low-normal calcium and elevated parathyroid hormone. The phosphate level may vary based on the etiology, trending towards high values in renal insufficiency and low values in vitamin D deficiency.

Vitamin D deficiency is defined by most experts as a 25-hydroxyvitamin D level of less than 20 ng per milliliter (50 nmol per liter). A level of 21-29 ng per milliliter can be considered to indicate relative insufficiency of vitamin D and a level of 30 ng per milliliter or greater can be considered to indicate sufficient vitamin D.

Imaging studies

Radiographic evaluation is limited to assessments of the bone disease. Obtain radiographs of sites of bone pain. Hand radiographs may show characteristic subperiosteal erosions. Imaging of the parathyroid glands is not indicated unless primary hyperparathyroidism is suggested.

Treatment

Medical care

Unlike primary hyperparathyroidism, medical management is the mainstay of treatment for secondary hyperparathyroidism.

Correcting vitamin D deficiency can be achieved using 50,000-IU capsule of vitamin D-2 once a week for 8 weeks and repeating the course for another 8 weeks if needed to achieve vitamin D sufficiency.

For patients with chronic kidney disease, the National Kidney Foundation (NKF) published clinical practice guidelines as part of its Kidney Disease Outcomes Quality Initiative (KDOQI). In general, it has been recommended to reduce parathyroid hormone levels to within a range that supports normal bone turnover and minimizes ectopic calcification.

The following is a list of current nonsurgical treatment options for management of secondary hyperparathyroidism in chronic kidney disease:

  • Dietary phosphate restriction can be initiated if parathyroid hormone is elevated despite sufficient 25-hydroxyvitamin D (>30 ng/mL).
  • Phosphate binders can be used if hyperphosphatemia persists despite dietary phosphate restriction. These include calcium-based phosphate binders such as calcium carbonate or calcium acetate and non-calcium-based phosphate binders such as sevelamer hydrochloride or lanthanum carbonate.
  • Calcium supplementation should be limited to less than 2 g/d.
  • Vitamin D and its analogs may be used, including calcitriol and analogs of calcitriol, including calcifediol, paricalcitol, doxercalciferol, maxacalcitol, and falecalcitriol. Newer vitamin D analogs have been suggested to be less calcemic than calcitriol, although definite data in humans are still lacking. Trials indicate that early intervention in stage 3 and 4 chronic kidney disease can correct parathyroid hormone levels and could prevent renal bone disease and prolong patient survival. Treatment with calcimimetics such as cinacalcet leads to significant improvements in biochemical parameters, but patient-based benefits have not yet been demonstrated.
  • The EVOLVE (EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events) trial was one of the first large-scale, randomized controlled trials in patients with ESRD to examine the treatment of secondary hyperparathyroidism with cinacalcet vs placebo along with standard of care phosphorous binders and Vitamin D analogs. Hyperphosphatemia and hyperparathyroidism have been associated with increased risk of death in ESRD patients and this trial was designed to see if there was a mortality benefit in the use of the non-calcium/non-Vitamin D analog cinacalcet in the ESRD population. The results of the trial demonstrated that cinacalcet did not result in improved mortality or improve cardiovascular endpoints. The use of cinacalcet did reduce the need for parathyroidectomy for refractory hyperparathyroidism. Of note, there was an increased risk of serious adverse events, namely hypocalcemia, with the use of cinacalcet. In conclusion, despite aggressive management of secondary hyperparathyroidism thatis associated with increased mortality in ESRD patients, cinacalcet did not offer a cardiovascular or mortality benefit in this population of patients. [30]

Surgical care

Indications for surgery include bone pain or fracture, pruritus, calciphylaxis (see Related Disorders), and extraskeletal nonvascular calcifications with elevated parathyroid hormone levels despite appropriate medical therapy.

Parathyroidectomy can be considered in patients with severe hyperparathyroidism (persistent serum levels of intact parathyroid hormone greater than 800 pg/mL [88.0pmol/L]), associated with hypercalcemia and/or hyperphosphatemia that is refractory to medical therapy.

All 4 glands must be exposed, and biopsies are taken if needed to ensure correct identification. In most cases, diffuse hyperplasia is encountered, although the size of the glands can be significantly heterogeneous.

The procedure of choice is either total parathyroidectomy with autotransplantation or 3.5-gland parathyroidectomy. In either case, a thymectomy must be included. A 1991 article by Rothmund et al reported a randomized controlled trial of total versus subtotal parathyroidectomy for secondary hyperparathyroidism. The authors found that 4 of 17 subjects treated with subtotal parathyroidectomy developed recurrent hypercalcemia, and 2 required reexploration. None of the subjects treated by total parathyroidectomy developed recurrent hypercalcemia. Therefore, several authors prefer total parathyroidectomy with autotransplantation.[31]

Briefly, parathyroid tissue is cut into approximately 16-20 pieces, each of which measures 1 X 1 mm. These are inserted in pockets in the forearm musculature, and each piece is marked with a polypropylene suture on the fascia. Parathyroid tissue must also be cryopreserved in case the primary autotransplant fails.

Postoperative care follows the routine described above in Postoperative care for primary hyperparathyroidism.

If total parathyroidectomy and autotransplantation are performed, the patient requires a period of maintenance with calcium and calcitriol supplementation.

A study by Hsu et al indicated that in patients with severe secondary hyperparathyroidism resulting from end-stage renal disease, parathyroidectomy reduces the risk of peripheral arterial disease. In the end-stage renal disease patients who underwent parathyroidectomy (947 patients, 5.08-year follow-up), the incidence density rate of peripheral arterial disease was 12.26 per 1000 person-years, compared with 24.09 per 1000 person-years in those who did not undergo the surgery (3746 patients, 4.52-year follow-up).[32]

Outcome and prognosis

Medical treatment of secondary hyperparathyroidism is successful in most patients. Patients who require parathyroidectomy have approximately a 10% risk of recurrent or persistent disease. This may be due to a hyperfunctioning or missed neck gland or hyperplasia of the autograft. Occasionally, a patient has persistent hypoparathyroidism after operation. If tissue has been cryopreserved, transplantation may reverse hypoparathyroidism. If hypoparathyroidism is permanent, lifelong calcium and calcitriol supplementation is necessary.

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Tertiary Hyperparathyroidism

Definition of problem

Tertiary hyperparathyroidism is a state of excessive secretion of parathyroid hormone after longstanding secondary hyperparathyroidism and resulting in hypercalcemia. Some authorities reserve the term for secondary hyperparathyroidism that persists after successful renal transplantation.

Etiology

Tertiary disease is characterized by the development of autonomous hypersecretion of parathyroid hormone causing hypercalcemia. The etiology is unknown but may be due to monoclonal expansion of parathyroid cells (nodule formation within hyperplastic glands). A change may occur in the set point of the calcium-sensing mechanism to hypercalcemic levels. Four-gland involvement occurs in most patients.

Pathophysiology

Tertiary hyperparathyroidism is observed most commonly in patients with chronic secondary hyperparathyroidism and often after renal transplantation. The hypertrophied parathyroid glands fail to return to normal and continue to oversecrete parathyroid hormone, despite serum calcium levels that are within the reference range or even elevated. In these cases, the hypertrophied glands become autonomic and cause hypercalcemia, even after withdrawal of calcium and calcitriol therapy. They also may become resistant to calcimimetic treatment.[33, 34] This type of tertiary disease is particularly dangerous because the phosphate level is often elevated. If the calcium value multiplied by the phosphate value yields a high product, diffuse calcinosis may occur.

Clinical presentation

The clinical manifestations of tertiary hyperparathyroidism include persistent hyperparathyroidism after renal transplantation or new hypercalcemia in the setting of chronic secondary hyperparathyroidism.

Treatment

Total parathyroidectomy with autotransplantation or subtotal parathyroidectomy is indicated.

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Related Disorders

Familial benign (hypocalciuric) hypercalcemia

Familial benign (hypocalciuric hypercalcemia (FHH) is caused by a loss-of-function mutation of one allele of the gene for the calcium-sensing receptor (CaR). It causes hypercalcemia, hypophosphatemia, and hypermagnesemia. The parathyroid hormone level is usually within the reference range or is mildly elevated. It can be distinguished from primary hyperparathyroidism by low 24-hour urinary calcium excretion. Persons with FHH are asymptomatic. Parathyroidectomy is not indicated.

Hypercalcemia of malignancy

This disorder is usually caused by tumor release of a hormone called parathyroid hormone -related peptide. Less commonly, hypercalcemia of malignancy is caused by local osteolytic lesions and, rarely, by overproduction of 1,25-dihydroxyvitamin D. This disorder is the most common cause of hypercalcemia in hospitalized patients. The hypercalcemia of malignancy results in a low or undetectable intact parathyroid hormone level. Usually, it is easily distinguished from hyperparathyroidism. Only a few cases of ectopic production of true parathyroid hormone are reported in the literature.

Calciphylaxis

Calciphylaxis, also known as uremic gangrene syndrome, is a rare disorder observed in patients with renal failure and secondary or tertiary hyperparathyroidism. It is characterized by ischemic necrosis of the skin due to calcium phosphate crystal deposition and subsequent inflammation in small-to-medium–sized vessels. The exact mechanism is unknown because the product of the calcium value multiplied by the phosphate value is often near the reference range. The disease is often fatal. In many cases, total parathyroidectomy appears to reverse the course of the disease.

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Contributor Information and Disclosures
Author

Lawrence Kim, MD Professor, Department of Surgery, Division of Surgical Oncology, University of North Carolina at Chapel Hill School of Medicine

Lawrence Kim, MD is a member of the following medical societies: Association for Academic Surgery, Association of VA Surgeons, International Association of Endocrine Surgeons, Society of Surgical Oncology, Society of University Surgeons, American Association of Clinical Endocrinologists, American Association of Endocrine Surgeons, American College of Surgeons, Southwestern Surgical Congress

Disclosure: Received income in an amount equal to or greater than $250 from: Affinergy, LLC.

Coauthor(s)

Michelle Whittier Krause, MD, MPH Associate Professor of Medicine, Division of Nephrology, University of Arkansas for Medical Sciences

Michelle Whittier Krause, MD, MPH is a member of the following medical societies: American Society of Nephrology, International Society of Nephrology, National Kidney Foundation

Disclosure: Nothing to disclose.

Elizabeth H Harris, MD, FACE Clinical Assistant Professor, Division of Endocrinology, Department of Medicine, University of North Carolina at Chapel Hill School of Medicine

Elizabeth H Harris, MD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Additional Contributors

Daniel Einhorn, MD, FACP, FACE Medical Director, Scripps/Whittier Diabetes Institute; Associate Clinical Professor of Medicine, University of California, San Diego, School of Medicine

Daniel Einhorn, MD, FACP, FACE is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, Phi Beta Kappa, Society of Nuclear Medicine and Molecular Imaging

Disclosure: Nothing to disclose.

Acknowledgements

Vitaly Kantorovich, MD Assistant Professor and Director of the UAMS Weight Control Program, Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences and Staff Physician, Central Arkansas Veterans Healthcare System

Vitaly Kantorovich, MD is a member of the following medical societies: The Endocrine Society

Disclosure: Nothing to disclose.

Antoine Makdissi, MD Assistant Professor of Medicine, University of Arkansas for Medical Sciences College of Medicine

Disclosure: Nothing to disclose.

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Normal parathyroid glands as seen during a thyroidectomy. The large arrow points to the superior parathyroid. The thinner arrow points to the inferior parathyroid. The forceps points toward the recurrent laryngeal nerve. The patient's head is toward the right.
Hyperparathyroidism. Technetium-99m (99mTc) sestamibi radionuclide scan. The early image (top left) shows uptake in the salivary glands and thyroid. The later images (right and bottom) show washout from the thyroid but persistence in the region of the right inferior thyroid lobe (arrows). This proved to be a right parathyroid adenoma.
 
 
 
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