Parathyroid surgery for inherited syndromes

INTRODUCTION — Primary hyperparathyroidism (HPT) is a disorder of the parathyroid glands in which one or more of the glands secrete an excess amount of parathyroid hormone. Although most commonly a sporadic disease, primary HPT can be a part of an inherited genetic syndrome in a small subset of patients. These inherited syndromes include multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 4 (MEN4), hyperparathyroid-jaw tumor syndrome (HPT-JT), and familial isolated hyperparathyroidism (FIHPT). An inherited form of HPT should be suspected in younger patients, especially those with multiglandular disease, those with syndromic manifestations, and those with a family history of an endocrinopathy that is known to be associated with HPT [1].

Parathyroid surgery for the treatment of inherited syndromes will be reviewed here. The inherited syndromes are discussed in detail elsewhere. (See "Multiple endocrine neoplasia type 1: Management" and "Approach to therapy in multiple endocrine neoplasia type 2" and "Primary hyperparathyroidism: Pathogenesis and etiology", section on 'Familial hyperparathyroidism'.)

INDICATIONS — The indications for parathyroidectomy are the same for patients with either sporadic or inherited forms of primary hyperparathyroidism (HPT) [2-16]. Parathyroidectomy is required to treat HPT in symptomatic patients (eg, nephrolithiasis) and is the preferred treatment in asymptomatic patients who meet the Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism criteria (table 1). (See "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

In addition, the potential benefits of parathyroidectomy should be discussed with multiple endocrine neoplasia type 1 (MEN1) patients who have severe, medically refractory peptic ulcer disease or other symptoms due to a gastrinoma (ie, Zollinger-Ellison syndrome). Hypercalcemia worsens hypergastrinemia, which can exacerbate peptic ulcer disease. Successful parathyroidectomy may reduce gastrin secretion [14,17]. MEN1 patients with primary HPT may also have a greater reduction in both cortical and trabecular bone mass compared with patients with sporadic HPT [18]. (See "Multiple endocrine neoplasia type 1: Management", section on 'Symptomatic disease' and "Multiple endocrine neoplasia type 1: Management", section on 'Zollinger-Ellison syndrome'.)

SURGICAL APPROACHES — Surgical approaches to patients with inherited hyperparathyroidism (HPT) vary depending upon their individual syndromes [8]. The principles of parathyroid surgery, however, remain the same.

General principles — Since patients with an inherited form of primary HPT are at an increased risk of developing recurrent and persistent disease and may require multiple operations in their lifetime, the optimal surgical strategy requires a compromise between the relief of symptoms and avoidance of complications. The general principles include:

●Obtaining and maintaining eucalcemia for the longest possible duration

●Avoiding permanent hypoparathyroidism

●Minimizing other surgical complications, such as recurrent laryngeal nerve injury

●Facilitating future surgery for persistent/recurrent disease

MEN1 — For the initial treatment of multiple endocrine neoplasia type 1 (MEN1) patients with primary HPT, we perform a subtotal parathyroidectomy with intraoperative parathyroid hormone (PTH) monitoring. In patients who develop recurrent HPT, we perform either completion total parathyroidectomy with forearm autotransplantation or debulking of the parathyroid remnant.

Initial parathyroidectomy

Surgical options — For patients with MEN1, the choice of initial surgery includes subtotal (three and one-half glands) parathyroidectomy or total parathyroidectomy with nondominant forearm autotransplantation. Studies have evaluated the role of more limited initial resections (either resection of a single gland or unilateral clearance of both parathyroid glands) in patients for whom preoperative imaging demonstrates a concordant single focus of disease and intraoperative PTH levels drop adequately [19-21]. Although associated with short-term success, these studies have small sample sizes and limited long-term follow-up. One study with 89 patients and a median follow-up of 112 months reported a shorter time to recurrence and higher recurrence rate (21.3 versus 10.1 versus 4.4 percent, p = 0.03) among patients undergoing resection of one to two glands compared with those undergoing subtotal or total parathyroidectomy with autograft [22]. Given the high rates of persistent and recurrent HPT in patients with MEN1, resections that are less than subtotal are not advised [23-29].

Choice of initial procedure — We typically perform a subtotal (removal of 3 to 3.5 parathyroid glands) rather than total parathyroidectomy with autotransplantation [16,30,31]. The parathyroid gland remnant left in situ should be the smallest, most normal-appearing parathyroid gland and/or the gland that would be most accessible (eg, an anteriorly located inferior gland) at the time of reoperative surgery [32]. (See 'Extent of resection' below.)

We perform all parathyroid surgeries with intraoperative PTH monitoring. If, after subtotal resection, the intraoperative PTH value remains high, we preferentially resect additional tissue from the remaining remnant, if possible, rather than proceeding with total parathyroidectomy. If the intraoperative PTH value is <10 pg/mL (in an assay whose normal range is approximately 10 to 72 pg/mL), we perform an immediate forearm autograft to prevent permanent hypoparathyroidism [6,32].

Both subtotal and total parathyroidectomy have been shown to achieve high rates of normocalcemia (>95 percent) [8,17,24-27,33-37]. Total parathyroidectomy with immediate autotransplantation results in a higher rate of postoperative hypoparathyroidism than subtotal parathyroidectomy (10 to 45 percent versus 10 to 25 percent) [8,17,24-27,33,34,36,37]. However, subtotal parathyroidectomy predisposes patients to a greater risk of complications associated with reoperative cervical exploration in cases of recurrent HPT.

In a small trial, 32 patients with MEN1 were randomly assigned to undergo either subtotal parathyroidectomy or total parathyroidectomy with autotransplantation [35]. After a mean follow-up of 7.5 years, similar proportions of patients in each group had transient (6 out of 17 versus 6 out of 15) or permanent hypoparathyroidism (2 out 17 versus 1 out of 15), developed recurrent HPT (4 out of 17 versus 2 out of 15), or required reoperation (4 out 17 versus 1 out of 15).

Timing — The timing of parathyroid surgery in young, asymptomatic MEN1 patients is controversial. Early parathyroidectomy could decrease the long-term detrimental effects of HPT, such as bone loss and nephrolithiasis [23,34,38,39], but predisposes patients to potential recurrences and reoperations. Delaying parathyroidectomy until the glands are more enlarged could make the surgery simpler and decrease the likelihood of persistent or recurrent disease that would necessitate reoperative surgery. The timing of surgery in MEN1 patients is reviewed elsewhere. (See "Multiple endocrine neoplasia type 1: Management", section on 'Asymptomatic disease'.)

Thymectomy — In MEN1 patients with <4 parathyroid glands identified at the time of surgery, the initial parathyroidectomy should include bilateral transcervical thymectomy, given the relatively high prevalence of supernumerary glands residing in the thymus in such patients [23-25,33,40]. Because transcervical thymectomy does not remove the entire thymus, patients are still at risk of developing neuroendocrine tumors, such as thymic carcinoid, after the procedure [2,41]. (See "Multiple endocrine neoplasia type 1: Management".)

Management of recurrent disease — Recurrent HPT is detected in 20 to 70 percent of MEN1 patients within 8 to 14 years after their initial surgery [17,23,24,26-28,42-45]. Reoperative surgery in the setting of an inherited syndrome (mostly MEN1) can achieve surgical cure in 78 to 91 percent of cases [27,28,45-47].

For patients who have a neck recurrence after subtotal parathyroidectomy, we perform either completion total parathyroidectomy with forearm autotransplantation or debulking of the parathyroid remnant. For patients who have a forearm recurrence from a previous autotransplantation, we perform excision or debulking of the forearm autograft. (See 'Reoperative management' below.)

Localization of hyperfunctioning parathyroid tissue — For patients with recurrent disease, identification of the source of disease is mandatory prior to reoperation. HPT can originate from one or more of three potential sources:

●Growth of remnant tissue in the neck following subtotal parathyroidectomy

●Supernumerary or ectopic gland in the neck or mediastinum

●Forearm autograft hyperfunction

Casanova test — For patients with a forearm autograft, we perform the Casanova test to rule out recurrence in the forearm autograft [48]. In this test, a baseline PTH value is drawn from the nongrafted arm. The grafted arm is then rendered ischemic for 10 minutes by using an Esmarch bandage before another PTH value is drawn from the nongrafted arm. Comparison of the two PTH values determines the source(s) of recurrent HPT as follows:

●Positive (arm recurrence) – Patients with forearm autograft-dependent recurrence demonstrate a drop in systemic PTH of more than 50 percent after 10 minutes of grafted arm ischemia. Recurrence attributed to autonomous function of parathyroid autografts occurs in 3 to 67 percent of patients, with the higher rate seen in inherited HPT patients [49-52].

●Negative (neck recurrence) – If the PTH value after 10 minutes of grafted arm ischemia remains unchanged or decreases by no more than 20 percent, the source of recurrent disease is not in the arm and therefore presumed to be in the neck.

●Indeterminate – In the group of patients who have a PTH drop between 20 and 50 percent, the test is inconclusive. In this setting, imaging studies are needed to determine whether to re-explore the neck, the forearm autograft, or both.

Imaging — In patients who do not have a forearm autograft or who have a negative or indeterminant Casanova test, we perform imaging studies to localize all hyperfunctioning parathyroid tissue in the neck or chest prior to reoperative parathyroid surgery [47]. If a forearm autograft is present and the Casanova test is negative or indeterminate, the forearm should be included in a 99 Tc-labeled sestamibi scan to evaluate for hyperplasia of the autograft [53].

Available imaging modalities include 99 Tc-labeled sestamibi scan with single photon emission computed tomography (SPECT), ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), as well as invasive localization procedures such as angiography with venous sampling for PTH gradients or fine needle aspiration of suspected parathyroid tissue for PTH levels.

We typically obtain at least two imaging studies, including a cervical ultrasound. The best imaging study or combination of studies for persistent disease, however, varies with the institution and surgeon preference, and a significant percentage of enlarged glands may be missed by conventional imaging [47]. Two studies with concordant localization findings would be ideal prior to re-exploration. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

Reoperative management — Reoperative parathyroid surgery is challenging to perform and therefore should be reserved for surgeons who have experience managing patients with familial hyperparathyroidism. Prior to performing the reoperation, the surgeon must reconfirm the diagnosis of HPT and review all available operative reports, pathology reports, and imaging studies.

●Neck – For patients who have undergone an initial subtotal parathyroidectomy, we perform either completion total parathyroidectomy with forearm autotransplantation or debulking of the parathyroid remnant [6,15]. Debulking of the parathyroid remnant avoids the potential complications of forearm autografting [54].

●Forearm – Patients with hyperfunctioning forearm autografts should undergo excision or debulking of their hyperfunctioning autograft under local anesthesia guided by intraoperative PTH monitoring.

Nonoperative management — Patients with persistent or recurrent HPT who are not surgical candidates due to comorbidities, multiple prior surgeries, or a lack of demonstrable disease on imaging are managed nonoperatively, which is discussed elsewhere [15,23,55]. (See "Primary hyperparathyroidism: Management", section on 'Poor surgical candidates'.)

MEN2A — Because many patients with multiple endocrine neoplasia type 2A (MEN2A) develop medullary thyroid cancer (MTC) early in life, they often have had prophylactic or therapeutic total thyroidectomy before they develop hyperparathyroidism. The best approach to parathyroid surgery in MEN2A patients depends upon whether they have had prior thyroid surgery.

Patients with MEN2A must be biochemically screened for pheochromocytoma prior to surgery. In patients with a diagnosed pheochromocytoma, adrenalectomy should be performed before thyroid or parathyroid surgery [15,56]. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Symptomatic disease'.)

Parathyroid preservation during prophylactic thyroidectomy — Many patients with MEN2A have repeated neck operations (eg, thyroidectomy, central neck lymphadenectomy) for MTC, during which normal parathyroid glands can be removed or devascularized. In this setting, we typically autograft any devascularized or accidentally removed normal parathyroid tissue to prevent the development of hypoparathyroidism [57]. Parathyroid tissue can be autografted to the nondominant forearm or the sternocleidomastoid muscle, depending upon the patient's risk of developing primary HPT as follows (see "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Primary hyperparathyroidism'):

●For patients who have a high risk of developing HPT (MEN2A with a ret proto-oncogene [RET] mutation associated with a high incidence of HPT), parathyroid tissue should be autografted into the forearm. The forearm location simplifies the diagnosis and management of recurrent disease due to autograft hypertrophy [15].

●For patients who have a low risk of developing HPT (sporadic MTC, multiple endocrine neoplasia type 2B [MEN2B], or MEN2A with a RET mutation that is rarely associated with HPT), parathyroid tissue can be autografted into the sternocleidomastoid muscle [15].

Parathyroidectomy with thyroidectomy — In patients with MEN2A undergoing an initial prophylactic or therapeutic thyroidectomy with a known diagnosis of HPT, we suggest exploring all four parathyroid glands but removing only grossly enlarged glands, guided by intraoperative PTH monitoring [15,30]. If all four glands are enlarged, then we perform a subtotal parathyroidectomy (removal of 3 to 3.5 glands) with a forearm autograft. In patients who require repeated neck surgeries for MTC, early forearm parathyroid gland autografting may reduce the risk of subsequent permanent hypoparathyroidism [15].

Given the relatively mild course of HPT in MEN2A patients, many surgeons prefer a conservative resection in order to minimize postoperative hypocalcemia [5,6,58]. They avoid total parathyroidectomy unless preservation of a parathyroid remnant in situ is not possible or is not desirable because all four glands are obviously abnormal [7,15]. Other experts favor total parathyroidectomy because of its low recurrence rate. In a study of 119 MEN2A patients, persistent or recurrent HPT occurred in 9, 14, and 0 percent of patients who underwent selective, subtotal, and total parathyroidectomy, respectively, at five years [3]. In this study, total parathyroidectomy was not associated with a higher rate of postoperative hypocalcemia (20 percent with total resection versus 29 percent with selective or subtotal resection).

Parathyroidectomy after thyroidectomy — In MEN2A patients with prior thyroidectomy who develop primary HPT, we suggest performing a focused neck exploration guided by preoperative localization studies and resecting only hyperfunctioning parathyroid gland(s) aided by intraoperative PTH monitoring [4-7,15,30,59]. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism" and "Intraoperative parathyroid hormone assays".)

MEN4 — There is a paucity of reports on cases with MEN4, which may represent a more restrictive phenotype (primary HPT and pituitary neuroendocrine tumors) similar to MEN1 but without a mutation in the MEN1 gene [60]. Mutations have been reported in the CDKN genes, most commonly CDKN1B. The clinical phenotype includes a high frequency of primary HPT and may also include functional and nonfunctional pituitary, gastrointestinal, and pancreatic neuroendocrine tumors [61,62]. Currently, no guidelines exist on the management of MEN4-associated primary HPT, and indications for parathyroidectomy are similar to those for MEN1 [63].

HPT-JT — Hypercalcemia in patients with hyperparathyroid-jaw tumor syndrome (HPT-JT) is due to single-gland disease in approximately 90 percent of cases [64,65]. Thus, we suggest performing bilateral neck exploration and selective parathyroidectomy with the removal of only grossly enlarged parathyroid gland(s), guided by intraoperative PTH monitoring, particularly if there are concordant preoperative localization findings [8,30,64,66,67].

In one study, only 18 percent of patients who underwent selective parathyroidectomy developed recurrent disease due to metachronous single gland involvement after a mean disease-free interval of 13.7 years [64]. In such cases, the diagnosis of primary hyperparathyroidism should be confirmed biochemically, and indications for surgery should be reevaluated. Accurate localization studies are mandatory in patients undergoing reoperative surgery. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism", section on 'Reoperation for recurrent or persistent hyperparathyroidism'.)

HPT-JT patients are at risk (15 to 20 percent) of developing parathyroid carcinoma [65,67]. When parathyroid carcinoma is suspected, an en bloc resection of the affected gland with adjacent involved tissues, including the ipsilateral thyroid lobe, should be performed when necessary [67,68]. The treatment of parathyroid carcinoma is discussed separately. (See "Parathyroid carcinoma", section on 'Resectable disease'.)

FIHPT — The extent of parathyroidectomy for familial isolated hyperparathyroidism (FIHPT) is controversial as FIHPT is comprised of a spectrum of disease due to incomplete expression of MEN1, HPT-JT, or familial hypercalciuric hypercalcemia, or due to an activating GCM2 mutation [69]. Patients with GCM2-associated primary HPT may have higher rates of multiple gland disease and parathyroid carcinoma and lower cure rates compared with those with sporadic disease [70].

In our practice, all patients known to have the disorder preoperatively undergo a bilateral neck exploration. We treat patients with FIHPT linked to mutations in the MEN1 or GCM2 genes in a similar manner to MEN1 patients, with subtotal or total resection [8,69-71]. We treat patients with FIHPT linked to mutations in the cell division cycle 73 (CDC73/HRPT2) gene or unknown mutations similarly to HPT-JT patients, with selective resections of grossly enlarged parathyroid glands, guided by intraoperative PTH monitoring [8,72,73]. Other experts advocate for treating all FIHPT patients with aggressive surgery of subtotal or total resection [74].

SURGICAL TECHNIQUES

Anesthesia — Since bilateral neck exploration is typically planned, the majority of parathyroidectomies are performed under general anesthesia. Focused exploration of a single parathyroid adenoma localized preoperatively can be carried out under local or regional anesthesia with sedation [75-79].

Initial exposure — Patient position, skin incision, and initial exposure in a standard parathyroidectomy are discussed elsewhere. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Positioning' and "Parathyroid exploration for primary hyperparathyroidism", section on 'Incision' and "Parathyroid exploration for primary hyperparathyroidism", section on 'Dissection'.)

Exploring for missing glands — Standard steps to explore for missing (fewer than four) parathyroid glands are discussed separately. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Missing gland'.)

For patients with multiple endocrine neoplasia type 1 (MEN1) who typically have four-gland disease and a high risk of recurrence, it is important that all glands be identified. If visual exploration is unsuccessful, intraoperative differential venous parathyroid hormone (PTH) sampling of both internal jugular veins may help lateralize a hyperfunctioning gland to one side of the neck [80,81]. Venous sampling is typically performed with a 23 or 25 gauge needle and analyzed in real-time using an intraoperative PTH assay. Lateralization is defined by a greater than 5 percent difference between the two PTH values. Venous sampling is more sensitive for identifying hyperfunctioning superior parathyroid glands.

If a parathyroid gland is deduced or suspected to be intrathyroidal, a portion of the putative gland can be sent for frozen section, or an aspirate of the tissue can be diluted in a syringe containing 1 mL of saline for intraoperative PTH measurement. The presence of parathyroid tissue is confirmed if the parathyroid hormone value is greater than 1500 pg/mL [82]. If possible, empiric thyroidectomy should not be performed routinely without first confirming the presence of parathyroid tissue within the thyroid gland, as thyroidectomy significantly increases central neck scarring and risks devascularization of the remaining parathyroid glands.

If a hyperfunctioning parathyroid gland remains elusive despite all efforts, the procedure should be terminated. Reevaluation of the initial diagnosis and further imaging studies to localize a possible unidentified cervical or mediastinal parathyroid gland should be performed before attempting a reexploration at a later date. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism", section on 'Reoperation for recurrent or persistent hyperparathyroidism'.)

Extent of resection — At the time of parathyroidectomy, care should be taken to avoid seeding the neck with parathyroid tissue, which can cause parathyromatosis. Complete removal of a parathyroid gland without damaging the capsule can be achieved by gentle dissection and clipping of the vascular pedicle. Placing a large metallic clip across the parathyroid gland before cutting into the gland minimizes the risk for seeding when creating a parathyroid remnant [23].

Subtotal parathyroidectomy — Subtotal parathyroidectomy removes three (or more) parathyroid glands and leaves a remnant of the fourth (or the last remaining) gland. The remnant size may depend on the size of the remaining in situ gland, but we prefer to leave an approximately 40 to 60 mg remnant. The remnant gland should be devoid of any nodules, if possible, to avoid recurrent hyperparathyroidism (HPT). The technique of subtotal parathyroidectomy is described elsewhere. (See "Parathyroidectomy in end-stage kidney disease", section on 'Subtotal parathyroidectomy'.)

Total parathyroidectomy — Total parathyroidectomy resects all (four or more) glands. The technique of total parathyroidectomy is described elsewhere. (See "Parathyroidectomy in end-stage kidney disease", section on 'Total parathyroidectomy with heterotopic autotransplantation'.)

Transcervical thymectomy — Up to 30 percent of patients with inherited HPT have enlarged supernumerary glands often found within the thymus. Thus, bilateral transcervical thymectomy should be performed in patients undergoing parathyroid surgery for inherited HPT when fewer than four parathyroid glands are identified. Transcervical thymectomy is performed with blunt dissection through the existing cervical incision without the need for a sternotomy. After mobilization of the cervical portion of the thymic tongue, traction can be applied to allow for resection of at least the upper part of the thymus bilaterally.

Autotransplantation — For inherited HPT patients who require autotransplantation, autografts are typically placed into the brachioradialis muscle of the nondominant forearm, rather than the sternocleidomastoid muscle. Forearm autotransplantation avoids a potential cervical reoperation in case the autograft becomes the source of recurrent HPT [83].

The parathyroid autograft is prepared by taking nonnodular parathyroid tissue (40 to 80 mg) and cutting it into approximately 20 pieces of 1 mm³ sized fragments. A longitudinal incision is made over the brachioradialis muscle of the patient's nondominant arm, and the parathyroid fragments are placed within the muscle pocket(s) created by blunt dissection of the muscle. Each muscle pocket is then closed with nonabsorbable sutures after complete hemostasis.

Autografts can take up to two to four years to function [23]. Up to 40 percent of autografts ultimately fail, leaving the patient with permanent hypoparathyroidism unless cryopreserved parathyroid tissue is available [23,24,46].

Other complications of forearm autografting include parathyromatosis secondary to iatrogenic spillage of parathyroid tissue. Parathyromatosis can make debulking a forearm remnant technically difficult. An en bloc resection of the remnant potentially increases the risk of damaging the brachioradialis muscle and/or surrounding neurovascular bundles [54].

Cryopreservation — Approximately 10 to 15 percent of patients develop postoperative hypoparathyroidism due to either ischemic necrosis of the parathyroid remnant or early failure of an autograft. Permanent hypoparathyroidism can potentially be prevented if cryopreservation of parathyroid tissue at the time of the initial subtotal or total parathyroidectomy is performed.

There are several methods of cryopreservation. The traditional method is to place all excised parathyroid tissue in normal saline solution at 4°C until the end of the operation. Tissue from the smallest and most normal-appearing (least nodular) gland is then divided into pieces of 1 mm³. Approximately 20 to 30 pieces are then stored in vials containing 1 mL of carrier medium (80 percent culture medium [RPMI-1640], 10 percent patient serum, and 10 percent dimethyl sulfoxide). Using a programmable freezer, the vials are then cooled to -70°C to -80°C at a rate of 1° per minute and then further cooled to -196°C at a rate of 20°C per minute. Other methods of gradually decreasing the temperature of the parathyroid fragments have also been described. The parathyroid tissue is stored at -70°C in a freezer or at -196°C in liquid nitrogen.

When delayed autografting is performed, the vials containing the cryopreserved parathyroid fragments are placed in a 37°C water bath until the carrier medium is thawed. The fragments are then washed several times in RPMI-1640 at a temperature of 37°C to eliminate the toxicity of dimethyl sulfoxide. Typically, 20 fragments of parathyroid tissue are placed within brachioradialis muscle pockets after one such piece has been submitted for pathologic confirmation.

Intraoperative PTH monitoring — We favor the use of intraoperative PTH monitoring for all patients undergoing parathyroid surgery. While many patients with inherited forms of HPT require bilateral exploration, intraoperative PTH monitoring may help guide the extent of resection and may indicate the presence of supernumerary and/or ectopic parathyroid glands [6,8,84]. Intraoperative PTH monitoring can also allow for immediate autotransplantation of parathyroid tissue when PTH levels become too low (<10 pg/mL). In addition, intraoperative PTH monitoring is helpful in reoperative parathyroid surgery [31,46,47,85-91].

When properly followed, an established intraoperative monitoring protocol can provide assurance that all hyperfunctioning parathyroid tissue has been adequately excised before the surgical procedure is concluded. The optimal protocol in patients with inherited HPT syndromes is not defined. A 70 to 90 percent reduction in PTH levels has been proposed to indicate the removal of all hyperfunctioning glands in this patient population, which is more stringent than the Miami criterion (50 percent reduction) commonly used for patients with sporadic primary HPT [23,45,92,93]. (See "Intraoperative parathyroid hormone assays", section on 'Intraoperative PTH monitoring protocols'.)

POSTOPERATIVE CARE — Standard postoperative care after a parathyroidectomy has been described elsewhere. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Postoperative care'.)

Patients undergoing parathyroidectomy for inherited forms of hyperparathyroidism (HPT) should undergo long-term follow-up for surveillance of persistent or recurrent HPT and the development of associated endocrinopathies by a multidisciplinary team of endocrinologists, surgeons, and genetic counselors. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors' and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Screening for MEN2-associated tumors'.)

COMPLICATIONS — Technical complications of parathyroid surgery (eg, bleeding, hematoma, or wound infection) typically occur in fewer than 5 percent of patients. Superior or recurrent laryngeal nerve injuries occur in fewer than 1 percent of patients. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Complications'.)

After parathyroid surgery, 10 to 15 percent of patients develop hypoparathyroidism that persists for more than six months. In these patients, any available cryopreserved parathyroid tissue should be transplanted, although delayed autotransplantation has a lower success rate compared with immediate autotransplantation (70 versus 100 percent) [49,94-97]. If cryopreserved parathyroid tissue is not available, calcium with vitamin D supplementation must be administered indefinitely. (See 'Cryopreservation' above and "Parathyroid exploration for primary hyperparathyroidism", section on 'Postoperative hypocalcemia'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Parathyroid surgery".)

SUMMARY AND RECOMMENDATIONS

●Primary hyperparathyroidism (HPT) is most commonly a sporadic disease but can be a part of inherited genetic syndromes, such as multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 4 (MEN4), hyperparathyroid-jaw tumor syndrome (HPT-JT), or familial isolated hyperparathyroidism (FIHPT). (See 'Introduction' above.)

●The indications for parathyroidectomy are the same for patients with both sporadic and inherited forms of primary HPT. (See 'Indications' above and "Primary hyperparathyroidism: Management", section on 'Symptomatic' and "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

●Surgical approaches to inherited HPT vary depending upon the individual syndromes.

•For patients who have MEN1, we suggest performing initial subtotal rather than total parathyroidectomy (Grade 2C). Bilateral transcervical thymectomy may be performed when fewer than four parathyroid glands are identified at the time of the initial surgery.

•For patients with MEN1 who have a neck recurrence after subtotal parathyroidectomy, we perform either completion total parathyroidectomy with forearm autotransplantation or debulking of the parathyroid remnant. For patients who have a forearm recurrence from a previous autotransplantation, we perform excision or debulking of the forearm autograft. (See 'Management of recurrent disease' above.)

•For patients who have MEN2A with a known diagnosis of HPT who are undergoing an initial prophylactic or therapeutic thyroidectomy, we suggest exploring all four parathyroid glands but removing only grossly enlarged glands, rather than performing a subtotal or total parathyroidectomy (Grade 2C). (See 'Parathyroidectomy with thyroidectomy' above.)

•For MEN2A patients with prior thyroidectomy who develop primary HPT, we suggest performing a focused neck exploration with resection of only abnormal parathyroid gland(s) rather than performing a subtotal or total parathyroidectomy (Grade 2C). Preoperative parathyroid localization studies and intraoperative parathyroid hormone assays can be used to guide the focused neck exploration. (See 'Parathyroidectomy after thyroidectomy' above and "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

•For patients who have HPT-JT, we suggest performing bilateral neck exploration but removing only grossly enlarged parathyroid gland(s), rather than performing a subtotal or total parathyroidectomy (Grade 2C). Patients with HPT-JT are at risk of developing parathyroid carcinoma, a condition that can require more extensive resection. (See 'HPT-JT' above.)

•The extent of parathyroid surgery for patients who have FIHPT is controversial and is influenced by the mutation each individual patient carries. (See 'FIHPT' above.)

●We prefer to use intraoperative parathyroid hormone monitoring for all patients undergoing parathyroid surgery for inherited HPT. (See 'Intraoperative PTH monitoring' above.)

●Patients with MEN2A should be biochemically screened for pheochromocytoma prior to parathyroid surgery. Adrenal surgery should precede parathyroid surgery in patients with a diagnosed pheochromocytoma. (See "Approach to therapy in multiple endocrine neoplasia type 2", section on 'Symptomatic disease'.)

●Many patients with MEN2A have repeated neck operations for medullary thyroid cancer, during which normal parathyroid glands can be removed or devascularized. In this setting, we typically autograft any devascularized or accidentally removed normal parathyroid tissue to prevent the development of hypoparathyroidism. (See 'Parathyroid preservation during prophylactic thyroidectomy' above.)