Parathyroid Surgery For Inherited Syndromes

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Parathyroid surgery for inherited syndromes

Parathyroid surgery for inherited syndromes
Authors:
Tina WF Yen, MD, MS
Tracy S Wang, MD, MPH
Section Editor:
Sally E Carty, MD, FACS
Deputy Editor:
Wenliang Chen, MD, PhD
Literature review current through: Feb 2022. | This topic last updated: May 23, 2020.
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
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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: Treatment" and "Approach to therapy in multiple endocrine neoplasia type 2" and
"Pathogenesis and etiology of primary hyperparathyroidism", 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]. (See "Multiple endocrine neoplasia
type 1: Treatment", section on 'Indications for surgery' and "Zollinger-Ellison syndrome
(gastrinoma): Clinical manifestations and diagnosis".)
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 [18-20]. 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 [21]. Given the high rates of persistent and recurrent HPT in
patients with MEN1, resections that are less than subtotal are not advised [22-28].
Choice of initial procedure — We typically perform a subtotal (removal of 3 to 3.5

parathyroid glands) rather than total parathyroidectomy with autotransplantation [16,29,30].
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 [31]. (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 [6,31].
Both subtotal and total parathyroidectomy have been shown to achieve high rates of
normocalcemia (>95 percent) [8,17,23-26,32-36]. 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) [8,17,23-26,32,33,35,36]. 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 [34]. 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 [22,33,37,38], 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: Treatment", section on 'Management of
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
[22-24,32,39]. 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 [2,40]. (See "Multiple endocrine neoplasia type 1: Treatment".)
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 [17,22,23,25-27,41-
44]. Reoperative surgery in the setting of an inherited syndrome (mostly MEN1) can achieve
surgical cure in 78 to 91 percent of cases [26,27,44-46].
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 [47]. 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 [48-51].
●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 [46]. 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 [52].
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 [46]. 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 [53].
●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 [15,22,54]. (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 [15,55]. (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 [56]. 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 [15,29]. 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 [5,6,57]. 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 [4-7,15,29,58]. (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 [59].
Currently, no guidelines exist on the management of MEN4-associated primary HPT, and
indications for parathyroidectomy are similar to those for MEN1 [60].
HPT-JT — Hypercalcemia in patients with hyperparathyroid-jaw tumor syndrome (HPT-JT)

is due to single gland disease in approximately 90 percent of cases [61,62]. 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 [8,29,61,63,64].
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 [61]. 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 [62,64]. 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
[64,65]. 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 [66]. 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 [67].
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 [8,66-68]. 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 [8,69,70]. Other experts advocate for treating
all FIHPT patients with aggressive surgery of subtotal or total resection [71].
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 [72-76].
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 [77,78]. 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 [79]. 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 [22].
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 [80].
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 [22]. Up to 40 percent of autografts
ultimately fail, leaving the patient with permanent hypoparathyroidism unless cryopreserved
parathyroid tissue is available [22,23,45].
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 [53].
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 [6,8,81]. 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
[30,45,46,82-88].
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 [22,44,89,90]. (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 less than 5 percent of patients.
Superior or recurrent laryngeal nerve injuries occur in less 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) [48,91-94]. 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.)
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Topic 15040 Version 6.0
References
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3 : Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type

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8 : Familial parathyroid tumors: diagnosis and management.
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10 : RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary
medullary thyroid cancer and associated endocrine tumors.
11 : Hyperparathyroidism-jaw tumour syndrome.
12 : Genetic analyses in patients with familial isolated hyperparathyroidism and

hyperparathyroidism-jaw tumour syndrome.
13 : Surgical therapy for familial hyperparathyroidism.
14 : Effect of parathyroidectomy in patients with hyperparathyroidism, Zollinger-Ellison syndrome,

and multiple endocrine neoplasia type I: a prospective study.
15 : Revised American Thyroid Association guidelines for the management of medullary thyroid
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neoplasia-type 1 and Zollinger-Ellison syndrome: long-term outcome of a more virulent form of HPT.
18 : Minimally invasive parathyroidectomy provides a conservative surgical option for multiple

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type 1.
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256-patient series from Groupe D'etude des Néoplasies Endocriniennes Multiples Study Group.
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review.
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37 : Osteoporosis in multiple endocrine neoplasia type 1: severity, clinical significance, relationship

to primary hyperparathyroidism, and response to parathyroidectomy.
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neoplasia type 1.
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up of serum calcium levels after parathyroidectomy.
42 : The outcome of subtotal parathyroidectomy for the treatment of hyperparathyroidism in multiple

endocrine neoplasia type 1.
43 : Long-term biochemical results after operative treatment of primary hyperparathyroidism

associated with multiple endocrine neoplasia types I and IIa: is a more or less extended operation
essential?
44 : Reoperative parathyroid surgery in the era of sestamibi scanning and intraoperative

parathyroid hormone monitoring.
45 : Reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1.
46 : Reoperative Surgery in Patients with Multiple Endocrine Neoplasia Type 1 Associated Primary
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47 : Secondary hyperparathyroidism: diagnosis of site of recurrence.
48 : Results of heterotopic parathyroid autotransplantation: a 13-year experience.
49 : Recurrent hyperparathyroidism due to parathyroid autografts: incidence, presentation, and

management.
50 : Autogenous parathyroid grafts for generalized primary parathyroid hyperplasia: contrasting

outcome in sporadic hyperplasia versus multiple endocrine neoplasia type I.
51 : Long-term evaluation of patients with primary parathyroid hyperplasia managed by total

parathyroidectomy and heterotopic autotransplantation.
52 : Surgical Management of Multiple Endocrine Neoplasia 1 and Multiple Endocrine Neoplasia 2.
53 : Recurrent hyperparathyroidism and forearm parathyromatosis after total parathyroidectomy.
54 : The calcimimetic cinacalcet normalizes serum calcium in subjects with primary

55 : Surgical approach to the patient with familial hyperparathyroidism.
56 : Management of the Parathyroid Glands During Preventive Thyroidectomy in Patients With

56 : Management of the Parathyroid Glands During Preventive Thyroidectomy in Patients With

Multiple Endocrine Neoplasia Type 2.
57 : Primary hyperparathyroidism in patients with multiple endocrine neoplasia syndromes. Surgical

experience.
58 : Efficacy of 4D-CT preoperative localization in 2 patients with MEN 2A.
59 : Clinical Features of Multiple Endocrine Neoplasia Type 4: Novel Pathogenic Variant and
Review of Published Cases.
60 : Familial Hyperparathyroidism - Disorders of Growth and Secretion in Hormone-Secretory

Tissue.
61 : Hyperparathyroidism-jaw tumor syndrome: a report of three large kindred.
62 : Long-Term Outcomes of Parathyroidectomy in Hyperparathyroidism-Jaw Tumor Syndrome:

Analysis of Five Families with CDC73 Mutations.
63 : Hyperparathyroidism-jaw tumor syndrome: Results of operative management.
64 : Clinical Features, Treatment, and Surveillance of Hyperparathyroidism-Jaw Tumor Syndrome:

An Up-to-Date and Review of the Literature.
65 : Surgical approach in hereditary hyperparathyroidism.
66 : New Concepts About Familial Isolated Hyperparathyroidism.
67 : Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is

more aggressive and has a lesser rate of biochemical cure.
68 : Genetic screening for MEN1 mutations in families presenting with familial primary
69 : Genetic analyses in familial isolated hyperparathyroidism: implication for clinical assessment
and surgical management.
70 : Parafibromin expression, single-gland involvement, and limited parathyroidectomy in familial

isolated hyperparathyroidism.
71 : Familial hyperparathyroidism: surgical outcome after 30 years of follow-up in three families with
germline HRPT2 mutations.
germline HRPT2 mutations.
72 : Randomized clinical trial comparing regional and general anaesthesia in minimally invasive
video-assisted parathyroidectomy.
73 : Minimally invasive parathyroidectomy using cervical block: reasons for conversion to general
anesthesia.
74 : A prospective, randomized comparison between combined (deep and superficial) and

superficial cervical plexus block with levobupivacaine for minimally invasive parathyroidectomy.
75 : Local/cervical block anesthesia versus general anesthesia for minimally invasive

parathyroidectomy: what are the advantages?
76 : 1112 consecutive bilateral neck explorations for primary hyperparathyroidism.
77 : Lateralization of parathyroid adenomas by intra-operative parathormone estimation.
78 : The utility of intraoperative bilateral internal jugular venous sampling with rapid parathyroid
hormone testing.
79 : Intraoperative parathyroid aspiration and parathyroid hormone assay as an alternative to frozen

section for tissue identification.
80 : Parathyroid autotransplantation in primary parathyroid hyperplasia.
81 : Intraoperative parathormone measurement in patients with multiple endocrine neoplasia type I

syndrome and hyperparathyroidism.
82 : Impact of intraoperative parathyroid hormone monitoring on the prediction of multiglandular

parathyroid disease.
83 : Detection of multiple gland primary hyperparathyroidism in the era of minimally invasive

parathyroidectomy.
84 : Utility of intraoperative PTH for primary hyperparathyroidism due to multigland disease.
85 : Predicting the success of limited exploration for primary hyperparathyroidism using ultrasound,
sestamibi, and intraoperative parathyroid hormone: analysis of 1158 cases.
86 : Retrospective analysis of sequential changes in serum intact parathyroid hormone levels

during conventional parathyroid exploration.
87 : Role of intraoperative parathormone monitoring during parathyroidectomy in patients with

discordant localization studies.
88 : Pitfalls of intraoperative quick parathyroid hormone monitoring and gamma probe localization in
surgery for primary hyperparathyroidism.
89 : Relative contributions of technetium Tc 99m sestamibi scintigraphy, intraoperative gamma

probe detection, and the rapid parathyroid hormone assay to the surgical management of
90 : Utility of intraoperative parathyroid hormone monitoring in patients with multiple endocrine

neoplasia type 1-associated primary hyperparathyroidism undergoing initial parathyroidectomy.
91 : Long-term functionality of cryopreserved parathyroid autografts: a 13-year prospective

analysis.
92 : Parathyroid autotransplantation.
93 : Deferred parathyroid autografts with cryopreserved tissue after reoperative parathyroid surgery.
94 : Parathyroid autotransplantation at the time of reoperation for persistent hyperparathyroidism.

Parathyroid Surgery For Inherited Syndromes - Uptodate 2022

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Parathyroid surgery for inherited syndromes - Uptodate Free 20/10/22 20:24

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Why What's Patient Calculators Drug

INTRODUCTION — Primary hyperparathyroidism (HPT) is a disorder of

be associated with HPT [1].

INDICATIONS — The indications for parathyroidectomy are the same for

In addition, the potential benefits of parathyroidectomy should be discussed with multiple

SURGICAL APPROACHES — Surgical approaches to patients

●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

Choice of initial procedure — We typically perform a subtotal (removal of 3 to 3.5

Timing — The timing of parathyroid surgery in young, asymptomatic MEN1 patients is

Management of recurrent disease — Recurrent HPT is detected in 20

Localization of hyperfunctioning parathyroid tissue — For patients with

●Growth of remnant tissue in the neck following subtotal parathyroidectomy

●Supernumerary or ectopic gland in the neck or mediastinum

●Forearm autograft hyperfunction

PTH values determines the source(s) of recurrent HPT as follows:

●Positive (arm recurrence) – Patients with forearm autograft-dependent recurrence

Reoperative management — Reoperative parathyroid surgery is challenging to

●Forearm – Patients with hyperfunctioning forearm autografts should undergo excision or

Nonoperative management — Patients with persistent or recurrent HPT who are

Parathyroid preservation during prophylactic

Parathyroidectomy with thyroidectomy — In patients with MEN2A

Parathyroidectomy after thyroidectomy — In MEN2A patients with

HPT-JT — Hypercalcemia in patients with hyperparathyroid-jaw tumor syndrome (HPT-JT)

FIHPT — The extent of parathyroidectomy for familial isolated hyperparathyroidism

Initial exposure — Patient position, skin incision, and initial exposure in a

Exploring for missing glands — Standard steps to explore for

If a parathyroid gland is deduced or suspected to be intrathyroidal, a portion of the putative

Extent of resection — At the time of parathyroidectomy, care should be taken

Subtotal parathyroidectomy — Subtotal parathyroidectomy removes three

Total parathyroidectomy — Total parathyroidectomy resects all (four or more)

Transcervical thymectomy — Up to 30 percent of patients with

bilateral transcervical thymectomy should be performed in patients undergoing parathyroid

Autotransplantation — For inherited HPT patients who require

Other complications of forearm autografting include parathyromatosis secondary to iatrogenic

Cryopreservation — Approximately 10 to 15 percent of patients develop

Intraoperative PTH monitoring — We favor the use of

When properly followed, an established intraoperative monitoring protocol can provide

POSTOPERATIVE CARE — Standard postoperative care after a

Patients undergoing parathyroidectomy for inherited forms of hyperparathyroidism (HPT)

COMPLICATIONS — Technical complications of parathyroid surgery (eg,

After parathyroid surgery, 10 to 15 percent of patients develop hypoparathyroidism that persists

SOCIETY GUIDELINE LINKS — Links to society and

SUMMARY AND RECOMMENDATIONS

●Patients with MEN2A should be biochemically screened for pheochromocytoma prior to

Oncol 2007; 14:1525.

24. Goudet P, Cougard P, Vergès B, et al. Hyperparathyroidism in multiple endocrine neoplasia

hormone assay to the surgical management of hyperparathyroidism. Arch Surg 2000;

Topic 15040 Version 6.0

1 : Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International

2 : Guidelines for diagnosis and therapy of MEN type 1 and type 2.

3 : Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type

5 : Primary hyperparathyroidism in multiple endocrine neoplasia type 2A.

6 : Surgical management of familial hyperparathyroidism.

7 : Surgical management of MEN-1 and -2: state of the art.

8 : Familial parathyroid tumors: diagnosis and management.

9 : Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship.