Parathyroidectomy

Background

Successful parathyroidectomy requires an understanding of both the anatomy and the embryology of the parathyroid glands. The parathyroid glands arise from the dorsal endoderm of the third and fourth branchial pouches. The vast majority of patients have a total of 4 parathyroid glands: 2 superior and 2 inferior.

The inferior parathyroid glands, which arise from the third branchial pouch, initially migrate with the thymus until they separate to take their final position, usually at the level of the inferior pole of each thyroid lobe. The superior parathyroid glands (see the image below) arise from the fourth branchial pouch, follow the migration of the ultimobranchial bodies, and usually take their final position along the posterior part of the middle third of each thyroid lobe.[1] The superior parathyroid glands show less anatomic variation than the inferior thyroid glands do.

The parathyroid glands have a distinct, encapsulated, smooth surface that differs from the thyroid gland, which is has a more lobular surface, and lymph nodes, which are more pitted in appearance. The color of the parathyroid glands is typically light brown to tan, which relates to their fat content, vascularity, and percentage of oxyphil cells within the glands. The yellow color may be confused with surrounding fat. A distinct hilar vessel is also present that can be seen if the surrounding fat does not obscure the glands' hila.

For more information about the relevant anatomy, see Parathyroid Gland Anatomy.

Most parathyroidectomies are performed for primary hyperparathyroidism. The most common cause of primary hyperparathyroidism is parathyroid adenoma (see the image below), which accounts for 75–90% of cases. Most parathyroid adenomas are not genetic but sporadic, and they involve all parathyroid glands equally.

Between 5% and 25% of cases of primary parathyroid hyperplasia involve multi-gland disease. Historically, it was felt that this included dobule parathyroid adenomas and 4-gland hyperplasia. While most authors believe that double parathyroid adenomas do occur, it is unclear how prevalent they are. When individual patients with double adenomas are followed over a long period, some experience recurrence of hyperparathyroidism and are ultimately diagnosed with 4-gland hyperplasia. This is further complicated by the fact that 4-gland hyperplasia can be asymmetric with some glands being very large and other glands appearring closer to normal in size, shape, and appearance. In 2012, Norman et al. published on more than 15,000 parathyroid cases. In the cohort of 3000 patients that had bilateral operations, aproximately 75% had one gland removed, 17% had two glands removed, 5% had three glands removed, and about 3% had three and a half glands removed.[2]  Parathyroid cancer is rare and accounts for fewer than 1% of cases of primary hyperparathyroidism.

The parathyroid glands are involved in calcium homeostasis. They release parathyroid hormone (PTH) in response to low serum concentrations of ionized calcium, and the release of the hormone is inhibited by an increase in serum ionized calcium. PTH causes the kidneys to increase the tubular resorption of calcium and decrease the resorption of phosphorus.[3] PTH also acts on bone and the intestine to increase serum calcium levels.

Primary hyperparathyroidism occurs when the PTH level is inappropriately elevated in relation to the serum calcium level. In normal circumstances, a negative feedback loop exists in which the PTH level drops in response to an elevated serum calcium level. This does not occur in the setting of primary hyperparathyroidism.[4]

Secondary hyperparathyroidism occurs when the PTH is elevated as the result of another cause. Vitamin D deficiency and renal failure are the 2 most common causes of secondary hyperparathyroidism.

Tertiary hyperparathyroidism occurs when glands affected by secondary hyperparathyroidism become autonomous and are no longer controlled by the normal feedback mechanisms. An example would be a patient with secondary hyperparathyroidism from chronic renal failure who undergoes a renal transplant that corrects the renal failure but who continues to have inappropriate release of PTH.

Indications

Historically, patients with primary hyperparathyroidism presented with symptoms related to the effects of PTH on the bone and kidneys. However, with the advent of routine blood screening tests, most patients today are asymptomatic or with minimal and often nonspecific symptoms at presentation. Currently, only 10–20% have renal stones, and very few have osteitis fibrosis.[5]

Although patients may be referred with nothing more than elevated calcium and PTH levels, further questioning often reveals that they have nonspecific symptoms such as fatigue, musculoskeletal pains and aches, depression, constipation and abdominal discomfort, and decreased memory. These patients may be more accurately described as minimally symptomatic, rather than asymptomatic. Many of them will derive symptomatic benefit from parathyroid surgery, though such benefit cannot be guaranteed in advance.

The diagnosis of primary hyperparathyroidism requires, minimally, an increased serum total calcium level with an increased intact PTH level—or, at least, an inappropriately high normal PTH level. Serum calcium levels can fluctuate somewhat over time, but patients with primary hyperparathyroidism should have a documented increase in serum total or ionized calcium sometime during the course of the condition.  

Patients with an elevated intact PTH level and a calcium concentration in the normal range often have secondary hyperparathyroidism. Secondary hyperparathyroidism can result from insufficient calcium or vitamin D intake, decreased intestinal calcium absorption, vitamin D malabsorption, or renal hypercalciuria.

Depending on the cause of secondary hyperparathyroidism, surgery may or may not be an appropriate treatment option;[6] therefore, it is important to distinguish primary from secondary hyperparathyroidism before deciding on surgery for presumed primary hyperparathyroid disease.

For this reason, vitamin D levels should be checked preoperatively to rule out vitamin D deficiency, which can be a cause of elevated PTH. Sometimes patients may present with a high PTH, low vitamin D, and a calcium within the high normal range. Often in this case, once the low vitamin D is corrected the patient will develop an elevated calcium, and if the PTH remains elevated, now fit the classic presentation for primary hyperparathyroidism.[7]  A 24-hour urine calcium and creatinine test should also be administered to rule out familial hypocalciuric hypercalcemia (FHH).

To further complicate matters, a new clinical entity called normocalcemic primary hyperparathyroidism has been introduced. Normocalcemic primary hyperparathyroidism is when the calcium is normal and the PTH is persistently elevated and secondary causes of hyperparathyroidism, such as chronic kidney diease, vitamin D insufficiency, malabsorbtion syndromes, and side effects from medications such as lithium and thiazides have been excluded.[8, 9, 10] Some of these patients may also benefit from surgery. 

As a result of the large number of patients being diagnosed with primary hyperparathyroidism on the basis of laboratory testing, the National Institutes of Health (NIH) consensus panel has come up with the guidelines for recommending surgery in asymptomatic patients.[11, 12, 13] The guidelines were first introduced in 1990 and then amended in 2002 and again in 2008.[14, 15]

• Blood calcium > 1 mg/dL above normal

• Bone density by DXA < -2.5 at any site (lumbar spine, hip, or forearm)

• History of kidney stones or evidence of kidney stones or calcifications in the kidney by imaging (e.g., X-ray, ultrasound, CT scan). Evidence for stone risk by 24-hour urine with excessive calcium and other stone risk factors.

• A fracture resulting from relatively little force, such as a fall from a standing or sitting position (a fragility fracture)

• Age < 50 years

Although not included in the criteria, there is some conflicting evidence to suggest that primary hyperparathyroidism contributes to cardiovascular disease.[16, 17, 18] Some authors believe that the cardiovascular risks, as well as other nonspecific symptoms, can improve in patients with primary hyperparathyroidism who do not meet the above cirteria.[17, 14]  It must be kept in mind that these guidelines are for asymptomatic patients. They do not apply, for example, to patients with a history of painful kidney stones for whom surgery is automatically indicated. The decision whether to provide surgical therapy for asymptomatic patients and those with minimal symptoms can be complicated. Often, the patient’s wishes, the surgeon’s experience, and the results of localization studies exert a substantial influence on this decision.

Contraindications

Parathyroid surgery is contraindicated in patients with familial hypocalciuric hypercalcemia (FHH). Patients who have this disorder can present with elevated calcium and PTH levels, mimicking the serum biochemical characteristics of primary hyperparathyroidism. However, FHH is not treated surgically.

In patients with FHH, 24-hour urine calcium excretion is lower than expected in comparison with the serum calcium level. The ratio of 24-hour urinary calcium to creatinine clearance is usually lower than 0.01 in these patients, whereas it is typically higher than 0.01 in patients with primary hyperparathyroidism.[19, 20] In addition, FHH patients typically have normal or mildly elevated PTH levels. Calcium excretion over 24 hours is less than 100 mg in 75% of FHH patients but usually more than 200 mg in patients with primary hyperparathyroidism.[21]

Thiazide diuretics and lithium excess can cause elevated PTH and serum calcium levels, mimicking primary hyperparathyroidism. Therefore, it is important to consider these medications when taking a history and to carry out further investigation if necessary before proceeding with surgery.

As localization studies become more frequent, patients may be directly referred for surgery by their primary doctors with a presumed indication based on such studies. In this situation, it is important to rule out not only FHH but also forms of secondary hyperparathyroidism in which surgery may not be appropriate. Furthermore, all localization studies have some false positives, and these can further confuse the picture. Negative localization studies, however, are not a contraindication for surgery. If the patient clearly meets the criteria for primary hyperparathyroidism based on blood and urine tests, then they should be referred to an experienced surgeon for consultation regardless of the localization tests. Given surgeon preference for imaging, it may be most efficient to hold off on ordering localization studies and simply refer the patient to an appropriate surgeon who can then arange for imaging.  

Approach considerations

Historically, a comprehensive 4-gland parathyroid exploration has been the traditional standard. With the introduction of the Sestamibi scan in the 1990s surgeons started to move towards doing unilateral and targeted surgery. The proponents of this approach argued that operating time and hospital stay can be decreased by performing targeted or unilateral parathyroid surgery. Proponents of this approach argued that this allows for smaller incisions, regional anesthesia, and same-day hospital discharge[22] and that it may also reduce the risk of laryngeal nerve injury and postoperative hypocalcemia.

These presumed advantages notwithstanding, not all surgeons favor 1-gland or unilateral surgery. Some experienced surgeons advocate the return of bilateral parathyroid surgery.[23, 24, 2]  However, even though these authors argue in favor of bilateral surgery, they still use technetium Tc 99m sestamibi scintigraphy before the operation and parathyroid hormone (PTH) assays or a gamma probe during the operation.

Intraoperative PTH assay is often employed to predict surgical cure in patients with primary hyperparathyroidism.[25, 26, 27, 28, 29, 30, 31] Guidelines for its use are available from the National Association of Clinical Biochemistry.[32] Some authors measure preincision PTH levels, and some measure preexcision levels after the abnormal gland has been identified but before it is removed. Some authors check postexcision levels at 5 minutes, 10 minutes, 15 minutes, and 20 minutes after removal of the abnormal gland.

In most situations, 10-15 minutes after the abnormal gland is removed, the PTH sample should be within normal limits and should have decreased by more than 50% from the initial baseline value.[33, 29] If the PTH level does not decrease by 50% and fall into the normal range, the surgeon should continue with 4-gland exploration, or, at least, should continue exploring until additional abnormal parathyroid glands are identified and removed and the PTH level is in the normal range and 50% or more below the starting value.

 

 

In patients with diffuse 4-gland hyperplasia, PTH levels should decrease further with each gland removal. After 3.5 glands have been removed, the PTH level should be in the normal range and at least 50% below the starting level. If the PTH level falls below the lower limit of normal autotransplantation, the use of some previously removed parathyroid tissue should be considered.[34]

However, making a patient hypoparathyroid is often worse than having the patient be mildly hyperparathyroid. This is where surgical experience and judgment becomes critical. The pictures above are from a 4-gland parathyroid exploration. The smallest gland, which looked to be normal in size and shape, was left intact given that the PTH had already come down from 111 to 17. If all four glands look equally enlarged, three-and-a-half-gland surgery is sometimes necessary. In this situation, rather than removing three glands, and then trying to remove half of the remaining gland, it may be best to try to remove half of a gland first and see if the remaining half still looks like it has an intact blood supply. Technically, it can be difficult to remove half of a gland without disturbing the blood supply. If all glands look the same, you have more than one chance to do this if you attempt this before removing all but one gland.  

Norman et al advocate radio-guided parathyroid gland identification and removal.[35, 2] In this technique, patients receive an injection of Tc 99m sestamibi in the morning about 2 hours before the procedure. A hand-held gamma probe is used to confirm which gland or glands are concentrating Tc 99m sestamibi. The abnormal gland or glands are removed, and the tissue is assessed against background radiation levels with the probe. Parathyroid adenomas should exceed background activity by at least 20% (on average, closer to 60%).[36]

Some surgeons perform intraoperative laryngeal nerve monitoring with special endotracheal tubes that have electromyographic (EMG) capability. This may be particularly helpful in revision cases, in which the recurrent laryngeal nerve may be involved with surrounding scar tissue. Like many newer technologies, intraoperative laryngeal nerve monitoring has encountered varying degrees of acceptance, depending on the institution. It is certainly not possible in operations using local anesthesia with sedation or laryngeal mask airway anesthesia.

Parathyroidectomy

As in thyroid surgery, a low cervical incision, usually between 2 and 4 cm long, is made approximately 2 fingerbreadths above the suprasternal notch; this is known as a Kocher incision. Dissection continues through the platysmal muscle, and the subplatysmal flaps are raised. If a localization study suggests a unilateral abnormality (see the images below), then the thyroid is mobilized first on that side.

Dissection continues along the thyroid capsule, and the thyroid gland is rotated anteriorly and medially. If a preoperative localization study suggested either a superior or inferior gland, the corresponding area is examined first. However, the standard parathyroid Tc 99m sestamibi scans may be misleading. For example, what looks like an inferior parathyroid adenoma on the scan may in fact be a superior gland that has descended posteriorly and inferiorly along the tracheoesophageal groove.

The location of the superior parathyroid gland is sought on the posterior and lateral aspect of the thyroid gland. The middle thyroid veins are ligated, and the gland is rotated. The superior gland should be located deep to the plane of the recurrent laryngeal nerve and superior to the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. The superior gland is often within 1 cm of the cricothyroid cartilage articulation. Blunt dissection of the fibroareolar tissue in this area facilitates finding both normal and abnormal parathyroid glands.

Care should be taken to maintain excellent hemostasis, because blood that stains the tissue makes identifying the parathyroid glands harder and increases the risk of injury to the recurrent laryngeal nerve. Often, there is a covering layer of fascia just superficial to the parathyroid gland; once this is divided, the parathyroid gland generally presents itself with gentle blunt palpation in this area.

The clefts within the thyroid gland are carefully examined to confirm that the parathyroid gland is not within a cleft and to make sure that the parathyroid gland has not been accidentally caught within the retractor and is not being retracted with the thyroid. If the superior gland is still not found, exploration proceeds to the common ectopic locations.

Although identification of the recurrent laryngeal nerve is not always necessary, it is important and often helpful in cases in which a gland cannot be found. The superior gland is posterior to the plane of the recurrent laryngeal nerve and can often be found in the tracheoesophageal groove, in the posterior mediastinum, or adjacent or posterior to the esophagus. If additional exposure is needed, the superior thyroid artery can be ligated as it enters the superior aspect of the thyroid, and the thyroid gland can be further rotated anteromedially.

In addition, it is sometimes helpful to divide the sternothyroid muscle. Often, an abnormal gland can be palpated before it can be seen. This is especially true of the superior glands, which migrate to posterior and deep locations. Finger palpation along the tracheoesophageal groove and along the esophagus down into the posterior mediastinum may lead to the area where dissection is needed to find the abnormal gland.

Most normal parathyroid glands are light brown in color; this coloration helps distinguish them from the surrounding fat, which is more yellow. The parathyroid glands can often be teased out of the fat by means of gentle palpation with a Kittner or peanut dissector.

The search for the inferior gland begins at the inferior and posterior aspect of the thyroid lobe and should include the thyrothymic ligament and the superior aspect of the thymus. The inferior gland is typically anterior to the plane of the recurrent laryngeal nerve and is often found just medial and anterior to the intersection of the recurrent laryngeal nerve and the inferior thyroid artery. With gentle retraction, the ectopic inferior gland can usually be pulled up into the neck and removed (see the image below).

It is essential to proceed in a systematic fashion, fully understanding and carefully documenting what was found and what was not. The surgeon must know which gland is missing because each missing gland has its own likely ectopic sites.

If a normal parathyroid gland is inadvertently devascularized during the dissection, it should be set aside in saline for later reimplantation. The gland should be cut into 1 mm cubes and placed in 1 or more small pockets that are made within the sternocleidomastoid muscle. The area should be marked with nonabsorbable suture (eg, polypropylene) and with staple clips; this facilitates imaging and intraoperative identification should the patient becomes hyperparathyroid again in the future.

As noted (see above) in Equipment, if a localization scan indicates a single parathyroid adenoma (the most common cause of primary hyperparathyroidism), many surgeons choose to terminate the procedure after the intraoperative PTH assay yields a level that is at least 50% lower than the starting PTH level and is within the normal range. The reported success rate with this method exceeds 95% and is comparable with that of traditional bilateral parathyroid surgery.[26, 13, 29] However, this does not guarantee the the patient will not have persistent or recurrent disease.[2]  The patient is much less likley to have persisent or recurrent disease if the PTH falls to the low normal level and/or continues to fall with subsequent PTH levels.   

If the patient has 4-gland hyperplasia or secondary hyperparathyroidism, then either 3.5 glands are removed or 4 glands are removed and autotransplantation subsequently performed.

Alternatively, if there is a well-localized parathyroid adenoma on preoperative scanning (see the images below), a 2.0-2.5 cm incision may be made directly over the location of the gland. Dissection proceeds between the strap muscles and the sternocleidomastoid muscle and then directly toward the abnormal gland. However, if a parathyroid adenoma is not found or if the PTH does not drop sufficiently after the removal of the gland, the incision must be extended to allow a more formal operation of the type described above.

Most surgeons today practice limited exploration for parathyroidectomy, using Tc 99m sestamibi scans and ultrasonography with intraoperative PTH assays.[37] However, others have achieved excellent results with a radio-guided approach that uses a gamma probe during surgery done within 2 hours of obtaining a Tc 99m sestamibi scan.[23] Overall, fewer than 1% of parathyroid surgeons employ this approach.[37]

Parathyroid carcinoma is a very rare disease that accounts for fewer than 1% of cases of primary hyperparathyroidism. To provide the best chance of survival, a wide local excision should be done in the initial procedure. The parathyroid cancer should be removed en bloc with the adjacent tissue, and the surrounding lymph nodes should be removed. No indication exists for a prophylactic lateral neck dissection.[38]

Complications of the procedure

With parathyroidectomy, as with all surgical procedures, bleeding and infection are potential complications. Because parathyroidectomy is a clean operation and because meticulous homeostasis is crucial to its performance, both of these complications should be rare.

As with thyroid surgery, there is a risk of injury to the recurrent and superior laryngeal nerves. In difficult cases, where the abnormal gland is not easily found easily, it is important to identify the recurrent laryngeal nerve, both to protect it from injury and to have it available as a landmark during the dissection.

Failure to cure the hyperparathyroidism, persistent or recurrent hypercalcemia, and postoperative hypocalcemia are also potential adverse results of parathyroidectomy.

Preprocedural planning

If patients are receiving anticoagulants, these agents should be discontinued before surgery. If patients have significant medical problems, their medical status should be optimized before surgery.

Preoperative parathyroid localization studies should also be planned and carried out.

Parathyroid localization

When parathyroid localization studies were first introduced, many surgeons maintained that the only localization necessary was locating an experienced parathyroid surgeon.[37] At that time, a comprehensive 4-gland bilateral exploration was the standard of care.

The technique of 4-gland bilateral exploration is still fundamental to parathyroid surgery and remains the standard by which all other more limited operations are measured. However, the development of preoperative parathyroid localization studies has allowed more focused exploration of the neck for primary hyperthyroidism, and such studies are now the standard of care in cases of reexploration for persistent or recurrent hyperparathyroidism.[39, 40, 41, 22]

Technetium Tc 99m sestamibi was first discovered to have persistent uptake in parathyroid tissue during myocardial perfusion studies.[42] Because it is quickly absorbed and retained by abnormal parathyroid tissue but quickly washed out from thyroid tissue, it is useful in the assessment of abnormal parathyroid tissue; the faster clearance from thyroid tissue facilitates identification of abnormal parathyroid tissue on delayed imaging. This technique allows identification of parathyroid adenomas both in normal and in ectopic locations.

It is important to keep in mind that thyroid nodules can reduce the accuracy of this test.[22] The accuracy of Tc 99m sestamibi scanning can be improved by combining it with single-photon emission computed tomography (SPECT).[43, 44] Some believe that Tc 99m sestamibi scintigraphy with hybrid SPECT/computed tomography (CT) is the best study for evaluating patients with hyperparathyroidism and concomitant nodular goiter.[45, 46]

Ultrasonography can also be used to localize abnormal parathyroid glands. Although it is the most noninvasive and least costly localization study,[13] it is highly operator-dependent and yields variable results. The use of a 7.5-10 MHz transducer is mandatory.[47] Abnormal parathyroid glands are usually hypoechoic compared with the thyroid because of the uniform hypercellularity of the lesions. About 15-20% are isoechoic compared with the thyroid gland or have a cystic component; about 90% demonstrate a hypervascular pattern.[47]

Ultrasonography often misses retroesophageal or mediastinal adenomas as a result of the shadowing effect of the laryngeal-tracheal complex and the sternum. It identifies 95% of adenomas weighing more than 1000 mg but fewer than 50% of adenomas weighing less than 200 mg.[13]  Many surgeons are now doing their own preoperative ultrasounds.

Currently, both ultrasonography and Tc 99m sestamibi scintigraphy (with or without SPECT) are commonly performed preoperatively during the evaluation of patients with primary hyperparathyroidism.[48, 22, 24, 49]

CT and magnetic resonance imaging (MRI) can also be helpful in localizing abnormal parathyroid glands. CT scanning is useful for localizing ectopic glands in the mediastinum. In one study, the use of preoperative thin-cut (2.5 mm) CT scanning has been used to locate abnormal parathyroid glands in patients with primary hyperparathyroidism and negative Tc 99m sestamibi scans allowed a focused neck exploration in 66% of patients with a negative sestamibi scan.[50]

Equipment

In addition to the basic equipment used to perform the operation itself, materials and devices for performing preoperative localization studies (see above) and intraoperative guidance studies (eg, intraoperative parathyroid hormone [PTH] assay; see Technique) may be required.

If 4-gland parathyroid exploration is going to be performed, no special equipment for intraoperative assessment is needed. However, if more targeted parathyroid surgery is going to be performed, additional equipment may be required, such as a gamma probe (for radio-guided parathyroid gland identification and removal) or and intra-operative PTH assay.  

Other intraoperative equipment, such as tissue fusion devices (eg, LigaSure; Covidien, Boulder, CO) or ultrasonic dissectors, is used by some surgeons but certainly is not required. Some surgeons also use special endotracheal tubes with electromyographic (EMG) capablilities for intraoperative laryngeal nerve monitoring. 

Patient preparation

Patient preparation includes adequate anesthesia and appropriate patient positioning.

Anesthesia

Surgery for primary hyperparathyroidism can be performed with either local or general anesthesia.[51] Patients with localized scans who are at high risk with general anesthesia may be better off under local anesthesia with sedation.

However, preoperative imaging does not always correlate with intraoperative findings and therefore the surgeon should always be prepared to do 4-gland exploration surgery. In such patients, and at times in patients who are under local anesthesia for targeted parathyroid adenoma removal, intraoperative conversion to general anesthesia is carried out.

In a survey of surgeons, 90% of the respondents reported that they prefer to use general anesthesia with intubation for parathyroid surgery.[37] Of those who prefer to use local anesthesia, half use only local anesthetic infiltration with monitored sedation, and half use both local anesthetic infiltration and cervical nerve blocks with monitored sedation.[37]

Local anesthesia eliminates the risk of intubation, shortens the recovery time, permits same-day discharge, and reduces cost.[29] However, many surgeons who use general anesthesia with intubation for parathyroidectomy also find that they can discharge their patients home the same day after performing a targeted 1-gland or unilateral parathyroid operation.[37]  Many patients are also currently being discharged home the same day after having bilateral surgery.  

Positioning

The patient is positioned with the neck extended to provide improved access to the lower neck. The arms are positioned along the sides to allow the surgeon and an assistant to stand on either side of the patient and operate comfortably. If intraoperative PTH levels will be checked, an accessible intravascular site (either venous or arterial) should be available. Using the reverse Trendelenburg position or simply elevating the back of the bed decreases venous congestion and helps minimize venous bleeding during the operation.