Parathyroid exploration for primary hyperparathyroidism

INTRODUCTION — Primary hyperparathyroidism (PHPT) is most commonly diagnosed when hypercalcemia is detected incidentally on routine biochemical screening [1]. Hyperparathyroidism and hypercalcemia can lead to symptoms such as nephrolithiasis and osteoporosis. Parathyroidectomy provides definitive therapy for PHPT and is recommended for all patients with symptomatic and familial disease and selected patients with asymptomatic disease.

The surgical treatment for PHPT will be reviewed here. The medical management of hyperparathyroidism, surgical anatomy of the parathyroid glands, multiple endocrine neoplasia type 1, and role of preoperative localization and intraoperative parathyroid hormone assay are discussed elsewhere. (See "Surgical anatomy of the parathyroid glands" and "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism" and "Primary hyperparathyroidism: Management" and "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis" and "Intraoperative parathyroid hormone assays".)

INDICATIONS — Once a diagnosis of primary hyperparathyroidism (PHPT) has been made biochemically, a decision regarding surgical intervention versus observation must be made. That decision varies depending on whether the patient is symptomatic, is asymptomatic, or has familial disease. (See "Primary hyperparathyroidism: Management".)

Symptomatic PHPT — Surgical intervention is indicated for all patients with symptomatic PHPT [2]. Clinical manifestations of hyperparathyroidism include [2,3] (see "Primary hyperparathyroidism: Clinical manifestations"):

●Polydipsia and polyuria.

●Nephrolithiasis or nephrocalcinosis.

●Hypercalcuria (24 hour urine calcium level >400 mg/dL).

●Impaired renal function (glomerular filtration rate [GFR] <60 mL/minute).

●Osteoporosis (bone density score <-2.5), fragility fracture, or vertebral compression fracture.

●Pancreatitis, peptic ulcer disease, or gastroesophageal reflux.

●Neurocognitive dysfunction or neuropsychiatric symptoms attributable to PHPT.

Asymptomatic PHPT — Asymptomatic patients have a biochemical diagnosis of PHPT but no objective features of the disease (eg, osteoporosis or nephrolithiasis). However, completely asymptomatic PHPT is uncommon; many "asymptomatic" patients have nonspecific or subtle symptoms, such as fatigue, depression, irritability, anxiety, anorexia, difficulty with concentration, or memory impairment. These subjective symptoms are often difficult to quantify and are frequently not fully appreciated until successful surgical intervention unmasks an improvement in the complaints [4].

Indications for surgical intervention in patients with asymptomatic PHPT include [2,4-6] (see "Primary hyperparathyroidism: Management"):

●Age <50 years.

●Serum calcium level >1 mg/dL above normal range.

●Silent nephrolithiasis or nephrocalcinosis.

●Patients who are unable or unwilling to comply with surveillance protocols.

●Patients with high risk for cardiovascular disease who might benefit from mitigation of potential cardiovascular sequelae other than hypertension.

●Additionally, patients with clinical features such as muscle weakness, decreasing functional capacity, abnormal sleep patterns, and fibromyalgia may also be considered for parathyroidectomy.

Persistent or recurrent PHPT — After initial parathyroidectomy, some patients develop persistent (<6 months from initial exploration) or recurrent (>6 months from initial exploration) disease. If the diagnosis of persistent or recurrent PHPT is suspected, it should be confirmed biochemically and the indications for operation considered [2,7]. Because the risks of complications such as recurrent laryngeal nerve (RLN) injury, permanent hypoparathyroidism, and nontherapeutic re-exploration are higher, these operations should be performed by surgeons experienced with reoperative neck surgery [8]. It is generally recommended that two concordant imaging studies for localization be obtained prior to re-exploration. Another valuable technique for localization prior to re-exploration for persistent or recurrent PHPT is ultrasound-guided fine needle aspiration of a suspected gland(s) with both histology and parathyroid hormone (PTH) assay performed on the aspirate [9,10]. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism", section on 'Reoperation for recurrent or persistent hyperparathyroidism'.)

Due to increased risks, the indications for reoperation are more stringent than for initial surgery and limited to major manifestations of hypercalcemia, including [7]:

●Nephrolithiasis

●Osteoporosis

●Serum calcium level >12 mg/dL

●Hypercalciuria

●A 30 percent decrease in renal creatinine clearance

Familial PHPT — Hereditary forms of PHPT occur either as a part of a multiple endocrine neoplasia (MEN) syndrome or as isolated familial hyperparathyroidism (FHPT). MEN type 1-associated hyperparathyroidism usually has an earlier age of onset and is multiglandular. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2" and "Treatment of hypocalcemia", section on 'Hypoparathyroidism'.)

Surgical intervention is indicated for hereditary forms of PHPT. (See 'Familial disease' below.)

Normocalcemic PHPT — Normocalcemic PHPT is an increasingly recognized clinical entity that remains incompletely characterized. These patients have normal total and ionized calcium levels and inappropriately elevated PTH levels [11]. It is important to rule out causes of secondary HPT (eg, vitamin D deficiency) in these patients.

The indications for operative intervention for normocalcemic PHPT are not defined, and currently it is not recommended to use the same criteria used for patients with asymptomatic hypercalcemic PHPT [12]. Observational studies indicate that some of these patients will progress to hypercalcemic PHPT; therefore, it is important that they are followed over time [12,13]. (See "Primary hyperparathyroidism: Management", section on 'Normocalcemic hyperparathyroidism'.)

Parathyroid cancer — Parathyroid cancer is a rare cause of PHPT. It may be suspected preoperatively in a patient with markedly elevated serum calcium or PTH levels, hyperparathyroidism with a palpable or painful neck mass, imaging that shows an inhomogeneous or large mass, or local soft tissue invasion. Parathyroidectomy is indicated when there is suspicion for parathyroid cancer [2]. (See 'Parathyroid carcinoma' below and "Parathyroid carcinoma", section on 'Resectable disease'.)

Parathyroid cyst — Parathyroid cysts are uncommon but can cause hypercalcemia and other symptoms [14,15]. If noted before surgery, the cystic fluid (which is typically clear) should be tested for PTH. Occasionally, complete resolution of the cyst can occur with aspiration, although recurrence is likely. For patients who develop recurrences after aspiration, the optimal treatment is surgical resection. It is important to avoid spilling cystic fluid as this may lead to parathyroid cell seeding, also known as "parathyromatosis." (See "Parathyroid cysts".)

Parathyroid crisis — Parathyroid crisis is characterized by severe hypercalcemia with a serum calcium concentration >14 mg/dL (3.8 mmol/L) and dramatic symptoms including central nervous system dysfunction, nausea, and vomiting. Because PHPT is a progressive disease, most patients have slow, steady increases of calcium levels over time, rather than acute spikes. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Parathyroid crisis'.)

Emergency parathyroidectomy is indicated in patients with a parathyroid crisis. In a report of 43 patients who underwent emergency surgery for parathyroid crisis, 42 were normocalcemic in the immediate postoperative period [16]. Ninety-three percent of patients followed long-term remained normocalcemic; 7 percent developed recurrent hypercalcemia requiring further intervention.

CONTRAINDICATIONS — Relative and absolute contraindications to parathyroid surgery include:

●A known contralateral recurrent laryngeal nerve (RLN) injury or vocal cord dysfunction is a relative contraindication to neck exploration for parathyroidectomy, because bilateral RLN injury can be life-threatening. (See 'Recurrent laryngeal nerve injury' below.)

●Symptomatic cervical disc disease is a relative contraindication to neck exploration because of the mild neck extension necessary in positioning patients for thyroid and parathyroid surgery. Hyperextension may potentially cause spinal cord injury in patients with cervical disc disease. Thus, if cervical disc disease is present, it should be evaluated and in some cases corrected by an orthopedic surgeon or neurosurgeon prior to parathyroidectomy. (See "Evaluation of the adult patient with neck pain".)

●Familial hypocalciuric hypercalcemia (FHH) is an absolute contraindication to parathyroid surgery. These patients do not have primary hyperparathyroidism (PHPT), and surgical intervention does not result in cure. FHH is an autosomal dominant inherited disorder that often leads to unnecessary parathyroid surgery. The disease is suspected when persistent, mildly elevated serum calcium levels and a high-normal or mildly elevated parathyroid hormone (PTH) level are noted in association with normal renal function and low 24 hour urine calcium excretion (urine calcium/creatinine ratio <0.01). The low urinary calcium level (<100 mg/24 hours) is the mainstay of the diagnosis. FHH results from a higher renal set point for calcium excretion. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

PREOPERATIVE EVALUATION AND MANAGEMENT — Prior to parathyroid surgery, the surgeon must perform an initial evaluation that includes history, review of any medications that can cause hypercalcemia, review of systems, physical examination, and review of the biochemical diagnosis [17,18]. Error in diagnosis is a major cause of failed surgical exploration. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

Pertinent clinical history includes a family history of primary hyperparathyroidism (PHPT), exposure to head and neck radiation or nuclear fallout [19,20], and a history of prolonged lithium use [21,22]. A personal or family history of other endocrinopathies may suggest a familial form of hyperparathyroidism [2]. Genetic counseling should be offered to patients with PHPT who are <40 years of age, have multigland disease, or have a family history or syndromic manifestations [2]. In a case series of 939 patients referred for surgery for apparent sporadic hyperparathyroidism, multiple endocrine neoplasia type 1 was identified in 4.5 percent [23]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

For patients with asymptomatic PHPT, a review of systems should focus on gastrointestinal symptoms such as dyspepsia and constipation; cognitive symptoms such as depression, emotional lability, poor memory or concentration, and disturbed sleep (due to nocturia); and musculoskeletal symptoms such as generalized weakness, muscle aches, or easy fatigue.

Laboratory evaluation should include serum calcium, parathyroid hormone (PTH), 25-hydroxyvitamin D, and creatinine levels, as well as 24 hour urinary calcium and creatinine levels [2]. Because hyperthyroidism can complicate parathyroid exploration, a preoperative thyroid stimulating hormone (TSH) level and T4 level should also be obtained [24].

Imaging should focus on evaluation of potential end-organ damages caused or exacerbated by PHPT. Silent nephrolithiasis or nephrocalcinosis in patients with PHPT may be detected by renal ultrasound, noncontrast computed tomography (CT), or plain abdominal radiographs [2,25]. Dual-energy X-ray absorptiometry (DXA) should be performed to evaluate for osteopenia or osteoporosis. Bone density measurements should be obtained at the lumbar spine, hip, and distal one-third of the radius [25].

Cervical ultrasound is recommended to not only localize parathyroid disease but also assess for concomitant thyroid pathology [26]. Patients with thyroid disease may undergo concomitant thyroid resection at the time of parathyroidectomy after an appropriate workup [2].

Patients undergoing a focused parathyroidectomy for PHPT should undergo a preoperative parathyroid localization study. (See 'Preoperative localization' below and "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

Patients with PHPT who present with hypercalcemic crisis should be medically managed and then undergo parathyroidectomy [2]. With fluids and medications used to lower serum calcium, emergency parathyroidectomy is rarely indicated. (See "Treatment of hypercalcemia", section on 'Severe hypercalcemia'.)

Prior to parathyroidectomy, patients with PHPT who are vitamin D deficient can safely begin vitamin D supplementation, particularly those with serum markers suggestive of high bone turnover such as bone-specific alkaline phosphatase, N-terminal propeptide of type 1 procollagen (P1NP), and C-terminal cross-linking telopeptide of type 1 collagen (CTX) [2,27,28]. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Vitamin D replacement'.)

CHOICE OF PROCEDURE — Once the decision to perform a parathyroidectomy is made, the surgeon must decide whether a standard bilateral neck exploration or a more focused parathyroidectomy is appropriate. The goal of parathyroid surgery is durable biochemical cure. Although cure is technically defined as eucalcemia at six months postoperatively, in the vast majority of patients, lifelong eucalcemia is expected. In order to ensure the best postoperative outcome, careful considerations should be given to patient history when deciding on the operative approach. (See 'Preoperative evaluation and management' above.)

Approximately 15 percent of patients with primary hyperparathyroidism (PHPT) have hyperplasia or double adenoma. For patients with suspected or known multigland disease, bilateral neck exploration is the procedure of choice [2,29,30].

In a retrospective study of 5597 patients who underwent initial parathyroidectomy for PHPT by high-volume surgeons participating in the Collaborative Endocrine Surgery Quality Improvement Program (CESQIP), about 30, 60, and 11 percent of patients underwent bilateral exploration, focused exploration, and focused converted to bilateral exploration, respectively [31]. Despite localization of an apparent single parathyroid focus by ultrasound (87 percent), sestamibi (66 percent), and computed tomography (CT) scan (20 percent), bilateral neck exploration was required in 40 percent of patients. A quarter of focused explorations were converted to bilateral explorations, most commonly due to concern for failure and/or lack of intraoperative PTH drop; intraoperative PTH assay was used in over 90 percent of cases. Two or more glands were removed in 57 percent of bilateral exploration cases.

However, with experience and improved availability of excellent imaging modalities, focused parathyroidectomy has emerged as the procedure of choice for patients who have a localized single adenoma and is as effective as bilateral cervical exploration in select patients. In many high-volume centers, focused exploration remains common, aided by excellent imaging.

Bilateral parathyroid exploration — Bilateral parathyroid exploration is a standard technique in which all parathyroid glands are identified with exploration of the expected locations [2]. It has been well demonstrated to exclude or identify multigland disease with high surgical cure rates (95 to 99 percent). It is a time-tested standard of efficacy and safety in the definitive treatment of PHPT.

Bilateral parathyroid exploration is the preferred operative strategy when intraoperative parathyroid hormone (IOPTH) monitoring is not available or at the discretion of the surgeon. A low threshold to either begin with or convert to a bilateral parathyroid exploration is warranted in the following situations:

●When preoperative imaging studies fail to localize a single adenoma or detect bilateral foci. Such findings on preoperative imaging preclude a focused approach.

●When patients have familial PHPT. Such patients predictably have involvement of multiple glands. A bilateral parathyroid exploration should also be considered for young men with apparent sporadic PHPT as some of them may have undiagnosed multiple endocrine neoplasia (MEN) syndrome type 1 [23]. (See "Multiple endocrine neoplasia type 1: Management", section on 'Surgical approach'.)

●When concomitant thyroid disease requires surgical resection (eg, biopsy-proven papillary thyroid cancer). (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism", section on 'Imaging modalities'.)

●When the patient is pregnant and the available localization studies require radiation. However, if ultrasonography expertise is available and the results show an apparent single adenoma, a focused approach can be pursued. (See "Primary hyperparathyroidism: Management", section on 'Pregnancy'.)

●When the patient has lithium-associated hyperparathyroidism. Lithium-associated PHPT has a high chance of having multigland involvement [32,33]. However, if preoperative imaging localizes to a single adenoma and IOPTH monitoring is available, a focused approach may still be pursued [2,33].

Focused parathyroid exploration — Focused parathyroidectomy is ideally employed in patients who appear clinically and by imaging to have a single parathyroid adenoma. It is not recommended for patients with known or suspected multigland disease [2]. This approach is appropriate for patients with unequivocal imaging suggesting unilateral pathology, no suggestion of concomitant thyroid disease requiring surgical intervention, and no family history of MEN syndromes. When preoperative localization studies do not identify an adenoma or the adenoma cannot be found during focused parathyroid exploration, bilateral parathyroid exploration must be performed. Thus, focused parathyroidectomy should be performed by surgeons who are also experienced in performing bilateral neck exploration [34,35].

When performed with IOPTH monitoring, focused parathyroidectomy results in excellent outcomes that are comparable to those of the traditional bilateral cervical exploration [36-39]. The smaller incisions and less extensive dissection required for focused parathyroidectomy can also lead to less postoperative pain, less scar tissue, and a lower incidence of hypocalcemia from ischemia of other glands.

Although there are few randomized trials comparing focused parathyroidectomy with the traditional bilateral approach, cure rates appear to be similar when the two procedures are performed by experienced endocrine surgeons [30,40-45]. Compared with bilateral exploration, focused parathyroidectomy had similar recurrence (0.8 versus 1.25 percent), persistence (2.4 versus 2.3 percent), and reoperation rates (1.3 versus 2.2 percent) but a shorter mean operative time (102.5 versus 64.2 minutes) and lower overall complication rates (17.1 versus 3.7 percent), according to a 2017 systematic review and meta-analysis of 19 comparative studies (over 12,000 patients) of the two approaches [46]. The lower complication rate was primarily driven by a lower transient hypocalcemia rate (13.2 versus 1.6 percent).

A 2020 Cochrane meta-analysis of five randomized trials found that similar percentages of patients are eucalcemic at six months (97.1 versus 99.2 percent based on five studies) and one year (89.5 versus 94.9 percent based on only one study) after focused as opposed to bilateral parathyroid exploration. Patients who underwent focused exploration had a lower incidence of symptomatic hypocalcemia (14.4 versus 26.5 percent) but a higher incidence of vocal cord paresis (3.8 versus 1.6 percent) [47].

Endoscopic or video-assisted parathyroidectomy — Video-assisted or endoscopic approaches for parathyroidectomy have been advocated by some for the management of PHPT (figure 1) [48,49]. Candidates for an endoscopic parathyroidectomy are patients with sporadic PHPT and unequivocal preoperative localization studies. Contraindications include prior extensive neck surgery, hereditary PHPT, large goiters, multigland disease, obesity, and suspicion of parathyroid carcinoma.

Except for a shorter length of incision, video-assisted parathyroidectomy does not offer significant advantages over open focused parathyroidectomy and should only be performed by surgeons who have first mastered the standard open operation. A randomized trial of 143 patients who underwent open parathyroidectomy (75 patients) or one of the two video-assisted approaches (68 patients) showed no significant difference in conversion rates or outcomes. The open surgery took less time than the video-assisted techniques (60 versus 84 minutes) [50].

Two approaches have been described for video-assisted parathyroidectomy [51]. One is a lateral endoscopic approach using 8 to 10 mmHg carbon dioxide. The other is a central gasless approach using a 30° 5 mm endoscope [48-53].

Surgeons should choose an operative approach that, in their hands, carries a high cure rate, low risk profile, and comparable cost to other available techniques [2].

SURGEON'S SAFETY CHECKLIST FOR PARATHYROID EXPLORATION

●Consent – The surgical consent should include the possibility of operative failure, transient or permanent paralysis of one or both vocal cords, a change in voice quality and strength, transient or permanent hypoparathyroidism, wound infection, and intraoperative or postoperative bleeding. (See 'Complications' below.)

●Medical records – Prior laboratory reports should be reviewed to confirm the diagnosis based on biochemical parameters. Available documentation of preoperative vocal cord evaluation and any prior neck surgery (eg, thyroidectomy, an anterior approach to cervical disc repair, or tracheostomy) should also be reviewed.

●Imaging studies – Imaging studies should be reviewed, and pertinent images should be immediately available to the surgeon in the operating room to confirm the location of the abnormal parathyroid glands. (See 'Preoperative localization' below.)

●Parathyroid hormone monitoring – If intraoperative parathyroid hormone (PTH) monitoring is employed, adequate peripheral access typically by peripheral intravenous catheter (or arterial line) should be secured for intraoperative blood draws. Alternatively, blood samples can be obtained from direct venipuncture of the ipsilateral internal jugular vein. Appropriate tubes and arrangements for transport of blood to the lab should be arranged prior to the start of the operation. (See 'Intraoperative parathyroid hormone monitoring' below.)

●Frozen section – Expert frozen section pathologic analysis should be available. (See "Thyroidectomy", section on 'Intraoperative frozen section analysis'.)

●Nerve monitoring – Preoperative voice evaluation should include specific inquiries about subjective voice changes. Patients who are hoarse, have a history of prior anterior cervical surgery, or have a suspected recurrent laryngeal nerve (RLN) dysfunction should undergo a formal evaluation with laryngoscopy. Intraoperative nerve monitoring is typically used for complex or reoperative cases or at the discretion of the operating surgeon [54]. (See "Thyroidectomy", section on 'Intraoperative nerve monitoring'.)

●Antibiotics – Parathyroid surgery is a clean procedure in a well-vascularized area; thus, postoperative infections are rare [55]. However, a dose of prophylactic antibiotic, such as cefazolin, can be given to patients who are immunocompromised or with comorbidities that could increase their risk of infection [56,57]. Prophylactic antibiotics should be administered within one hour prior to incision [58-60]. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults".)

●Anticoagulation – Most parathyroidectomies are elective. Thus, any bleeding diatheses, thrombocytopenia, or platelet dysfunction can be addressed prior to surgery. Additionally, medications such as warfarin, clopidogrel, aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and vitamin E should be discontinued prior to parathyroid surgery to minimize the risk of cervical hematoma. The perioperative management of anticoagulation is reviewed elsewhere. (See "Perioperative management of patients receiving anticoagulants".)

●Deep venous thrombosis prophylaxis – Patients undergoing general anesthesia should receive primary prophylaxis against deep venous thrombosis such as sequential compression devices. Patients should also be encouraged to ambulate the night of surgery. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

●Surgical timeout – A surgical timeout should be called with the participation of the entire operating room team (anesthesiologist, surgeon, nurse, scrub technician) to assure correct patient identity, laterality, and intended operation as well as to verify the informed consent.

SURGICAL MANAGEMENT — The challenges of parathyroidectomy include the wide variability in parathyroid gland anatomy between patients, the limitations of localization studies, and the possibility of having more than four parathyroid glands (supernumerary glands). Accordingly, judicious dissection informed by thorough knowledge of the wide anatomic and embryologic variations in gland locations is necessary to find an enlarged gland or glands, manage multigland disease, and deduce the presence of a supernumerary gland. The experienced endocrine surgeon can accurately recognize size and shape differences among parathyroid glands and reliably estimate their weights. In addition, the surgeon must be able to intraoperatively recognize and properly treat parathyroid carcinoma. (See "Surgical anatomy of the parathyroid glands" and "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

Parathyroidectomy is an operation that is well documented to exhibit high-volume expertise (ie, to have better outcomes when performed by surgeons who have a thorough understanding of the disease and distinct experience managing patients with sporadic adenomas, multigland disease, hereditary hyperparathyroidism [HPT], parathyroid carcinoma, and persistent or recurrent primary hyperparathyroidism [PHPT]). Several studies have demonstrated higher cure rates, fewer complications, lower cost, and shorter length of stay when parathyroid surgery is performed by high-volume surgeons and in high-volume centers [2,61-63]. It is the authors' recommendation that parathyroidectomy be performed by surgeons who perform no fewer than 10 procedures and ideally ≥50 procedures per year.

As follows, the techniques of bilateral parathyroid exploration and focused parathyroidectomy are described in detail separately. Steps common to both techniques are described in the bilateral parathyroid exploration section and not repeated in the focused parathyroidectomy section.

Bilateral parathyroid exploration

Anesthesia — Both general endotracheal anesthesia and local analgesia with monitored anesthesia care can be utilized for parathyroid exploration. The choice should be driven by the experience and comfort level of the surgical and anesthesia teams. An oral or nasogastric tube, an esophageal stethoscope, or a temperature probe may be placed in the esophagus to facilitate digital palpation of a gland deep in the tracheoesophageal groove. A tube in the esophagus provides a solid, consistent structure against which the mobile, enlarged parathyroid gland can be palpated.

Positioning — The patient is positioned on the operating table in the semi-Fowler position with both arms tucked. A roll can be placed transversely under the scapulae to put the neck in mild extension, which increases exposure of the region posterior to the tracheoesophageal groove (figure 2). Care should be taken to prevent overextension of the neck, which can lead to vertigo, headache, and postoperative nausea. The head of the operating table is tilted up by approximately 30 degrees (reverse Trendelenburg).

The skin should be prepped from the lower lip/angle of the mandible to the anterior chest. Mediastinal exploration, though rarely needed, should only be performed after preoperative discussion with the patient and operating room staff. If it is contemplated, the entire chest should be prepped into the operative field.

Incision — If a bilateral exploration is planned, a 3 to 5 cm transverse incision is usually made 2 cm above the clavicular head. Efforts should be made to place this incision in a skin crease, if possible. A longer incision may be needed if the patient has obesity, the gland is large, or the neck is foreshortened as with kyphoscoliosis (figure 3). Preemptive analgesia with a local anesthetic before incision is helpful in postoperative management of pain.

Dissection — The platysma is divided transversely and the median raphe longitudinally. The strap muscles on the side of dissection are elevated off the thyroid lobe. In planned bilateral exploration, the initial laterality of dissection may be guided by thyroid pathology or surgeon preference.

Parathyroid exploration begins after inspection of the ipsilateral thyroid lobe. The lobe is retracted anterior-medially. At all times, the surgeon should be cognizant of the course of the recurrent laryngeal nerve (RLN) and strive to maintain excellent hemostasis of the surgical field (figure 4).

Exploration — The lateral, inferior, and posterior surfaces of the thyroid lobe, and the tracheoesophageal groove, are palpated to search for an enlarged gland (picture 1). Normal and enlarged parathyroid glands are usually soft, have a yellow-brown color, and can be found nested within a lobule of surrounding yellow adipose or thymic tissue. A single hilar vascular pedicle is frequently a visual clue to the gland and must be carefully preserved.

While parathyroid adenomas are classically described with respect to their superior, inferior, or supernumerary embryologic origin, a classification scheme that utilizes details of preoperative imaging and intraoperative anatomic findings has been described [64].

The most common locations of parathyroid adenomas should be explored in a logical order, from superficial to deep. Areolar tissue between the thyroid and carotid sheath is gently swept laterally (figure 5). To find an enlarged superior parathyroid gland, the undersurface of the superior pole of the thyroid lobe is also inspected. Exploration continues until the first enlarged parathyroid gland is identified, while taking note of the locations of normal/suppressed parathyroid glands as well.

First gland — Once identified, a first enlarged parathyroid gland is dissected circumferentially and isolated on its vascular pedicle, with great care not to rupture its capsule. Manipulating the connective tissue around the enlarged gland is preferable to direct handling of the parathyroid as capsular rupture is a cause of parathyromatosis or seeding of hyperfunctioning parathyroid tissue in the soft tissues of the neck and/or mediastinum. Overgrowth of spilled parathyroid tissue can cause recurrent hyperparathyroidism [65,66].

Starting dissection from the lateral aspect of an adenoma helps the surgeon appreciate the full extent and size of an adenoma visually as "the tip of the iceberg." Prior to division and ligation of the vascular pedicle, it is imperative to confirm safety of the ipsilateral RLN (figure 6). Enlarged parathyroid glands can sometimes be wedged between the RLN and the trachea at the ligament of Berry and must be freed by gentle dissection.

Upon excision and inspection of the suspected adenoma, all resected parathyroid tissue should be measured and weighed. In evaluating the first resected gland, a weight of <200 mg is likely associated with both multigland disease and operative failure [67]. When in doubt, frozen section analysis may be utilized to confirm that the specimen is in fact parathyroid tissue. Ectopic thyroid tissue, thyroid nodules, and lymph nodes can easily resemble an enlarged parathyroid gland, especially in a reoperative case or when the patient has concomitant thyroiditis. In vivo or ex vivo parathyroid hormone (PTH) aspiration may also be used to confirm the tissue origin of the specimen. Direct fine needle aspiration of the excised gland's parenchyma can be performed with a 21 to 24 gauge needle attached to a small syringe. The aspirate is sent for intraoperative PTH assessment in a small amount of saline, usually 1 cc, and values that are exceedingly high or above the upper limit of the assay are highly suggestive of parathyroid tissue.

Second gland — After resecting the first enlarged gland, many surgeons search for the second ipsilateral parathyroid gland. A normal parathyroid gland weighs 35 to 50 mg. In primary hyperparathyroidism, a "suppressed" normal gland can be even smaller. Routine biopsy of normal glands is not recommended. When in doubt, shave or hemi-biopsy of the second ipsilateral gland can be accomplished by gently applying a titanium clip to the distal edge of the gland opposite the vascular pedicle and sharply excising a 5 to 15 mg fragment, which is then weighed and assessed by pathology. Care should be taken not to disrupt the vascular pedicle or to devascularize the gland.

Multigland disease — If the second parathyroid gland ipsilateral to the first is enlarged, the diagnosis of multigland disease is made, and multigland resection should be performed after a four-gland exploration [2]. Double adenomas are rare (<6 percent) but do occur. Inspection of all four glands allows for double adenomas to be distinguished from four-gland hyperplasia. Double adenomas can be treated with removal of just two glands.

For patients who have multiple enlarged glands, it is important to visualize all the glands before a final decision is made on which glands are to be removed. In patients with four-gland hyperplasia, all but a portion of one enlarged gland is removed, leaving a well-vascularized parathyroid remnant of 50 to 100 mg size. This is referred to as a subtotal or three-and-half-gland resection. The parathyroid remnant should be marked with a titanium clip or Prolene in case reoperation is required. Viability of the intended remnant is checked before the remaining enlarged glands are resected. (See "Parathyroidectomy in end-stage kidney disease", section on 'Subtotal parathyroidectomy'.)

Another approach, which has fallen into disuse in familial PHPT but is still used by some experts in dialysis patients with secondary/tertiary HPT, is to remove all four glands and autotransplant parathyroid tissue into the forearm, where it is more accessible in case of recurrent disease [68]. Total parathyroidectomy with autotransplantation can lead to temporary vitamin D and calcium dependency due to a lack of functional PTH [69]. It is not recommended for first-time operations in familial PHPT, secondary, or tertiary HPT patients, because it can result in severe hypocalcemia that is extremely difficult to manage and life-threatening. (See "Parathyroidectomy in end-stage kidney disease", section on 'Total parathyroidectomy with heterotopic autotransplantation'.)

Some centers cryopreserve parathyroid tissue in the event that the remnant or autotransplanted tissue becomes devascularized or dysfunctional, which renders the patient aparathyroid. Cryopreservation, however, requires preoperative planning for tissue transport and storage and is costly. With regard to tissue maintenance, there is no role for cryopreservation in primary operations. (See "Parathyroidectomy in end-stage kidney disease", section on 'Cryopreservation'.)

Missing gland — A missed parathyroid adenoma is the most common cause for persistent hyperparathyroidism. During bilateral parathyroid exploration, the surgeon must use their knowledge of the embryology and anatomy of the parathyroid glands to determine whether a superior or an inferior gland is missing, or a supernumerary gland is present (figure 7), and use that information to conduct an orderly search for the missing gland.

Missing superior gland — For a missing superior gland, the surgeon should explore the middle and posterior neck compartments, particularly the paraesophageal spaces and the tracheoesophageal groove, extending the dissection caudad into the middle and posterior mediastinal planes (figure 8).

The surgeon must confirm that there is not an enlarged gland in the paraesophageal or retroesophageal space, which is the most common place for missed superior glands. Such glands can often descend in the avascular plane to reside in a location inferior to the inferior gland and are posteriorly located along the lateral border of the esophagus. Digital palpation along the lateral border of the esophagus is an excellent way to identify the gland, which can be appreciated as a subtle bulge.

The superior thyroid vessels can be followed superiorly to assess for a partially undescended gland, palpating the piriform sinus and angle of the jaw cranial to the superior pole of the thyroid. The missing superior gland may also be found in the posterior retropharyngeal space. The majority of mediastinal parathyroid glands (over 90 percent) are accessible via a cervical approach. A partial median sternotomy or thorascopic approach should be reserved for reoperation after localization studies have identified a mediastinal gland.

Missing inferior gland — For a missing inferior gland or supernumerary gland, the surgeon should explore the ipsilateral thymus and upper cervical region, dissecting into the anterior, superior mediastinum via a cervical approach. Missing inferior glands may sometimes be palpated by sweeping a finger from lateral to medial on the periosteum behind the manubrium.

Many missing inferior parathyroid glands will be located within the thymus, and most intrathymic enlarged glands can be removed with a cervical approach. A cervical thymectomy may need to be performed. The thyrothymic ligament must be carefully handled in order to prevent fracture division or retraction of the thymus into the mediastinum. The resected thymus should be manually inspected and palpated in an ex vivo fashion and further evaluated with frozen section because a normal or enlarged parathyroid gland may not be readily visible.

If exploration is still unrevealing, the carotid sheath is entered sharply and meticulously explored to assess for an undescended parathyroid gland (figure 9). Care should be taken to avoid damage to the vagus nerve. Exploration of the carotid sheath should extend from the clavicle to the bifurcation of the common carotid artery. Although rarely indicated, an ipsilateral thyroid lobectomy may be performed if an intrathyroidal parathyroid gland is suspected; approximately 1 percent of inferior gland adenomas are intrathyroidal.

Missing supernumerary gland — Most supernumerary parathyroid glands are within the thymus [70,71]. In the search for a missing enlarged gland, a cervical thymectomy should be performed. Supernumerary glands can also be found along the anterior surface of the carotid sheath and near the tubercle of Zuckerkandl. The surgeon should explore the bilateral carotid sheaths and palpate the piriform sinuses. Preoperative or intraoperative thyroid ultrasound can also help identify an intrathyroidal parathyroid adenoma. (See "Overview of the clinical utility of ultrasonography in thyroid disease".)

When an enlarged gland cannot be located in any of the normal or ectopic positions despite a systematic and thorough search, the surgeon must concede that a curative operation is not possible, and the surgical procedure should be concluded. Before that, PTH levels can be obtained via bilateral jugular venous sampling and used to lateralize the missing gland to one side of the neck [72]. If a reoperation is contemplated, the diagnosis of PHPT should be reconfirmed biochemically and additional localization studies performed. (See 'Intraoperative parathyroid hormone monitoring' below.)

Compromised gland — Although only one normal parathyroid gland is necessary for maintaining calcium homeostasis, removal of normal parathyroid glands should be avoided. If a normal parathyroid gland becomes severely ischemic during dissection or is excised accidentally, immediate autotransplantation is recommended [2].

If there is uncertainty about the tissue of origin, the surgeon should send a 1 mm sliver of tissue for frozen section analysis and store the remainder of the specimen in chilled Tis-U-Sol or normal saline solution in the interim.

To perform parathyroid autotransplantation, a small pocket is created in the designated muscle, either the nondominant forearm or the ipsilateral sternocleidomastoid muscle, using a right angle clamp. After ensuring hemostasis, the parathyroid tissue is minced into multiple 1-mm-sized fragments and inserted into the single muscle pocket. Two small hemoclips can be used to tag and close the pocket.

Alternatively, cryopreservation is available at some centers and is useful in some patients to avoid permanent hypoparathyroidism, particularly in the setting of reoperative parathyroid surgery [73,74].

Familial disease — For patients with hereditary forms of PHPT, the amount of parathyroid tissue removed varies with the cause of hyperparathyroidism [75-77]:

●For patients with multiple endocrine neoplasia (MEN) type 1-associated PHPT, the initial surgical procedure usually includes resection of three-and-one-half hyperplastic parathyroid glands (subtotal resection) with strong consideration for concomitant cervical thymectomy [2].

●For patients with MEN type 2A-associated PHPT, parathyroid hyperplasia is heterogeneous. Thus, although bilateral exploration is usually performed as the initial procedure, only the visibly enlarged glands are resected [2]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

For patients with MEN type 2A-associated recurrent hyperparathyroidism, a complete parathyroidectomy with forearm autotransplant is typically performed. This more aggressive surgical approach is warranted because patients with MEN type 2A may develop medullary thyroid carcinoma with cervical metastases. Autotransplanting the parathyroid tissue to a distant site eliminates the risk of devascularization, should another cervical reoperation be needed. Recurrent hyperparathyroidism due to overgrowth of a forearm autograft can be tested by measurement of PTH in the antecubital vein. This can then be treated by graft removal under local anesthesia after localization of the site with ultrasound imaging. However, if the autograft fails to function, the patient may have permanent hypoparathyroidism (or aparathyroidism). The risk of hypoparathyroidism is higher with autotransplantation than with leaving the parathyroid gland in situ.

Parathyroid carcinoma — Parathyroid carcinoma is a rare cause of primary hyperparathyroidism. It is difficult to distinguish from parathyroid adenoma based on preoperative evaluation but may be suggested by one of the following findings during parathyroid exploration:

●A solitary tumor greater than 3 cm in diameter [78].

●A firm, irregular, lobulated mass [79].

●A dense, fibrous capsule surrounding the tumor producing a white or gray-brown tint [79,80].

●Invasion of or adhesion to surrounding structures, including the ipsilateral thyroid lobe, strap muscles, RLN, esophagus, or trachea [78,81,82].

●Lymph node metastasis (present in <5 percent of parathyroid cancer cases) [83].

●Cystic features.

The presence of these operative findings in patients with preoperative calcium levels greater than 14 mg/dL and parathyroid hormone levels >3 times the normal value is a reason for suspicion of parathyroid carcinoma [81,84].

A suspected parathyroid carcinoma should be completely resected, which may require en bloc resection of the ipsilateral thyroid lobe and adherent tissues. Although formal bilateral central lymph node dissection is not recommended, clearance of the ipsilateral central neck may allow for optimal clearance of soft tissues of the side of the carcinoma. The RLN can be preserved unless it is circumferentially involved [78,79,85,86]. It is important to avoid capsular violation or tumor spillage (eg, with biopsy) [78,79,83,84,87-90]. Because lymph node involvement is uncommon, a modified lateral neck dissection is not required in the absence of clinical nodal involvement, which is rare [2,83]. The diagnosis of parathyroid carcinoma relies on the histologic identification of unequivocal angioinvasion and can be assisted by biomarkers.

A complete surgical resection (R0 resection) is the only cure for parathyroid cancer and has been shown to reduce complications and improve quality of life [79,81,91-93]. Adjuvant external beam radiation should be reserved for palliation and is not routinely given after surgical resection of a parathyroid carcinoma [2,94]. (See "Parathyroid carcinoma", section on 'Resectable disease'.)

Closure — The strap muscles are reapproximated with interrupted absorbable sutures to cover the trachea by some surgeons. The platysma is then reapproximated with interrupted absorbable suture. The skin is typically closed with a running subcuticular absorbable suture. A drain is not required.

Documentation — The operative report should detail the findings and events of parathyroidectomy. It is useful to have lateralized templates or drawings of cervical structures on which to place an excised gland to show its location at the time of surgery. The excised gland can be photographed on this template, made a permanent part of the medical record, and be available for future reference in the event of persistent or recurrent disease. Alternatively, the surgeon can include a drawing of the operative findings in the written operative report [64].

Focused parathyroidectomy — The success of a focused parathyroidectomy is predicated upon preoperative localization studies that permit the surgeon to limit the operative field to the region where a single radiologic focus has been identified and combined with intraoperative PTH monitoring that is suggestive that no other hyperfunctional parathyroid tissue remains. In other words, localization results inform the surgeon where to start looking for the adenoma, and intraoperative PTH results can suggest to them when to stop looking. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism" and 'Intraoperative assessment' below.)

Preoperative localization — Parathyroid localization studies are an integral part of a focused parathyroid exploration. Localization studies should only be performed to help plan an intended operation after the biochemical diagnosis has been confirmed. The role of the imaging is to suggest where to start the surgical dissection, rather than to make the diagnosis or decide whether to intervene with parathyroidectomy. (See 'Preoperative evaluation and management' above.)

Commonly used localization studies include cervical ultrasound, sestamibi scan, and multiphase contrast-enhanced computed tomography (CT) of the neck (commonly referred to as four-dimensional CT). Patients who are candidates for parathyroidectomy should be referred to expert clinicians to decide which imaging studies to perform based on their knowledge of local imaging capabilities. The expertise of the local radiologist in study selection is also important since interpretation of studies is often user dependent. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

Patients who are candidates for surgery based on a complete biochemical workup and who have negative or discordant imaging should always be referred to a parathyroid surgeon for evaluation. Because capsular fracture can potentially cause histologic changes similar to those of atypia, preoperative parathyroid fine needle aspiration is not recommended except in unusual, difficult cases of PHPT and should not be performed if parathyroid cancer is suspected [2]. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

If a bilateral parathyroid exploration is planned, then there is little role for preoperative localization studies since all parathyroid glands will be visualized. However, cervical ultrasound is frequently used to identify concomitant thyroid abnormalities that may need to be addressed at the same operation. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism" and 'Preoperative evaluation and management' above.)

Intraoperative assessment — Intraoperative parathyroid hormone (IOPTH) monitoring provides real-time confirmation of surgical cure. In the past, a radioguided approach was advocated by a select few to enhance focused dissection and allow ex vivo confirmation that a sestamibi-avid gland had been removed [95]. IOPTH monitoring and the radioguided probe may be used in tandem.

Intraoperative parathyroid hormone monitoring — IOPTH monitoring provides a useful tool to indicate when all hyperfunctioning parathyroid tissue has been adequately excised. When focused parathyroidectomy is planned, the use of IOPTH is suggested to avoid high operative failure rates [2]. In a systematic review and meta-analysis of 12 studies of minimally invasive parathyroidectomy, the use of IOPTH was associated with a higher cure rate (odds ratio 3.88, 95% CI 2.12-7.10) and a lower reoperation rate (odds ratio 0.40, 95% CI 0.19-0.86) compared with no IOPTH [96].

IOPTH monitoring takes advantage of the short plasma half-life of PTH (three to five minutes) and a rapid assay that produces measurements while the patient is still in the operating room [34,97-99]. A baseline PTH value is obtained at the start of the procedure, prior to skin incision. PTH levels are then measured following removal of the suspected adenoma [72]. A reduction of at least 50 percent in PTH level from the baseline (the ">50 percent PTH drop criteria") is an accepted standard for intraoperative confirmation of success, although a number of centers further require that the postexcision PTH level also be within the normal range (the "Dual criteria") [2,100,101]. The combination of a post-resection IOPTH that is within the normal range and has dropped by >50 percent of baseline does not define cure but has been shown to be a strong predictor of cure [102]. Surgeons utilizing IOPTH monitoring should employ a sampling protocol that is reliable in the local environment and should be familiar with the interpretation of PTH decay dynamics [2]. (See "Intraoperative parathyroid hormone assays".)

Blood sample for IOPTH monitoring may be obtained from a peripheral vein or an arterial line. For localization of a missing gland, samples from bilateral jugular veins can be assayed at the time of exploration; a unilateral elevation is suspicious for a missing hyperfunctioning gland on that side, while comparable PTH levels from both sides may suggest hyperfunctioning parathyroid disease in the mediastinum. (See 'Missing gland' above.)

False-positive IOPTH results (ie, a >50 percent decrease intraoperatively) followed by recurrent hyperparathyroidism should raise suspicion for hereditary PHPT. In a series of 269 patients, six had decreases in IOPTH values that were consistent with a cure but later recurred [103]. Three of the six patients had germline mutations in the MEN gene (MEN1), and two had mutations in the RET proto-oncogene (MEN2). (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

Radioguided parathyroidectomy — In the past, a radioguided approach was advocated by some to serve as an adjunct to parathyroid exploration. The technique involves intravenous administration of technetium-99m-labeled sestamibi approximately two hours preoperatively [104,105]. Using sestamibi uptake as an indirect measure of parathyroid gland hyperfunction, the surgeon uses a handheld gamma probe in conjunction with preoperative imaging results to focus the incision over the site of greatest radioactivity. Once the suspected offending gland or glands are removed, intraoperative PTH monitoring is typically used to attempt to confirm adequate parathyroidectomy. The gamma probe is also used to survey the surgical bed (background radioactivity). An ex vivo radioactivity count of >20 percent of the background radioactivity is a suggested threshold for completion of the exploration.

Use of the gamma probe alone, however, may not reliably ensure operative cure. The probe detects sestamibi uptake as a surrogate for hyperfunctioning parathyroid tissue, a method that is unreliable for definitively excluding multigland disease [98,106,107]. Furthermore, thyroid nodules often retain isotope, which can potentially lead to false positive results and resection of healthy thyroid tissue. Additionally, concentration of radioactivity in the heart can lead to misinterpretations if the probe is angled below the clavicle. Finally, the timing and dosing requirements for isotope injection can cause delays in the operating room schedule.

Near-infrared autofluoresence and indocyanine angiography — Parathyroid tissue exhibits a unique autofluorescence signature when excited at the near-infrared (NIR) wavelength of 785 nm, reemitting at a wavelength between at 820 to 830 nm, with an intensity that is two to 11 times greater than that of the surrounding tissues, thereby allowing for the improved detection and the precise localization of the parathyroid glands. A meta-analysis reported an area under the curve (AUC) of near-infrared autofluorescence of 0.99, demonstrating that near-infrared autofluorescence is an excellent tool to identify parathyroids in parathyroid surgical exploration and that it could be a complementary tool for cases in which preoperative images failed to detect them [108].

Despite these benefits, autofluorescence is neither able to analyze the perfusion status of the parathyroid tissues nor the vitality of parathyroid glands, with the properties of autofluorescence preserved even after gland resection. The use of indocyanine green (ICG) to enhance fluorescence imaging enables the real-time assessment and direct imaging of tissue perfusion and vascularization [109].

Anesthesia — Focused parathyroidectomy can be performed under general anesthesia or superficial cervical plexus block anesthesia with monitored conscious sedation. The latter is most appropriate when a single gland has been well localized and the procedure is expected to have a short duration [110,111]. Compared with general anesthesia, cervical plexus block may reduce postoperative pain, nausea, and vomiting [112]. However, cervical plexus block anesthesia should be avoided in patients with obesity or claustrophobia. (See "Anesthesia for patients with thyroid disease and for patients who undergo thyroid or parathyroid surgery", section on 'Choice of anesthetic technique'.)

In a report of 441 patients undergoing focused parathyroidectomy under cervical plexus block anesthesia, 10 percent required conversion to general anesthesia [112]. Reasons for conversion included concomitant thyroid disease (34 percent), multigland parathyroid hyperplasia (failure of PTH levels to drop, 32 percent), technical considerations (17 percent), patient discomfort (11 percent), intraoperative diagnosis of parathyroid carcinoma (4 percent), and a purported reaction to locally administered lidocaine with seizure (2 percent). (See "Allergic reactions to local anesthetics".)

Incision — A 2 cm incision is made on the anterior aspect of the mid-neck. Guided by preoperative imaging, the incision may be lateralized to the side of the predicted parathyroid adenoma. If IOPTH monitoring is used, a pre-excision baseline PTH level is obtained just prior to the incision. (See 'Intraoperative parathyroid hormone monitoring' above.)

Dissection — The platysma is divided transversely and the median raphe longitudinally. The strap muscles on the side of dissection are elevated off the thyroid lobe ipsilateral to the suspected adenoma localized by preoperative imaging studies.

If imaging predicts a laterally or posteriorly located gland, a "backdoor" initial approach may be useful. In this setting, the lateral border of the strap muscles is separated from the medial border of the sternocleidomastoid muscle, exposing the lateral edge of the thyroid gland as the plane where parathyroid exploration begins.

Exploration — (See 'Exploration' above.)

First gland — Following resection of the first enlarged and presumable localized gland, either blood draws are sent for IOPTH assay after 5 and 10 minutes, or exploration continues if bilateral exploration is planned. If the intraoperative PTH level does not drop appropriately after excising the first gland, the diagnosis of multigland disease is made, and multigland resection should be performed [2]. Procedures that begin as a focused parathyroid exploration should be promptly converted to a bilateral exploration, and all four glands should be inspected, prior to excision of additional parathyroid tissue. (See 'Multigland disease' above.)

Closure — (See 'Closure' above.)

Documentation — (See 'Documentation' above.)

PERCUTANEOUS PARATHYROID ABLATION — In centers with the appropriate expertise, percutaneous parathyroid ablation is an acceptable treatment for patients who need treatment for primary hyperparathyroidism (PHPT) but are not surgical candidates or have an inoperable mediastinal gland [113-115]. Percutaneous parathyroid ablation is discussed in the setting of complex recurrent PHPT after a failed parathyroidectomy in an inoperable patient.

The parathyroid gland can be percutaneously ablated angiographically or by ethanol injection under ultrasound guidance. Success rates of 66 percent at up to four years have been reported for angiographic ablation [113]. Ethanol ablation was successful in restoring eucalcemia in 82 percent of patients who failed subtotal parathyroidectomy for multiple neoplasia syndrome type 1-associated hyperparathyroidism [116]. However, recurrent hypercalcemia requiring repeat treatments is common after percutaneous ablation.

POSTOPERATIVE CARE — After parathyroid surgery, patients with reoperation, extensive exploration, subtotal resection, profound vitamin D deficiency, or a lack of social support should be admitted for overnight observation. Other patients may be discharged following "outpatient" parathyroid surgery at the surgeon's discretion [2]. However, all patients must be examined to exclude bleeding and confirm that esophageal swallowing is normal, pain is controlled, and no allergic reaction to medication has occurred prior to hospital discharge. An examination is recommended at a minimum of four to six hours after the procedure. Evidence of compressive hematoma should prompt emergency decompression. (See "Thyroidectomy", section on 'Hematoma'.)

Patients can remove the surgical dressing and shower on the day following the operation. Pain is usually modest and controllable with mild analgesics such as acetaminophen. In general, opiate narcotics should be avoided. Oversedation brought on by narcotics can potentiate an airway emergency if there is a clinically significant cervical hematoma.

At one to two weeks postoperatively, patients should be seen in the office by the surgical team to inspect the wound, review pathology, and obtain a baseline postoperative biochemical assessment.

At six months postoperatively, patients should have a repeat clinic visit with biochemical assessment. For most patients, cure after parathyroidectomy is defined as the reestablishment of normal calcium homeostasis lasting a minimum of six months. For patients with normocalcemic PHPT, the PTH level must also normalize at six months after surgery to indicate cure [2,117].

At six months to one year following documented cure (ie, 12 to 18 months following parathyroidectomy), we also suggest a follow-up visit along with a repeat biochemical assessment and a comparative bone mineral density study [2,118]. (See "Overview of dual-energy x-ray absorptiometry".)

COMPLICATIONS — Complications following parathyroidectomy are uncommon. However, the patient should be counseled about them preoperatively, and the surgeon should be knowledgeable about their presentation and management.

Operative failure — Failure to achieve durable cure of hypercalcemia is the most common complication of parathyroid surgery (reported at rates of 1 to 5 percent). (See 'Outcomes' below.)

Symptomatic hematoma — The incidence of symptomatic hematoma following neck exploration is 0.3 to 1 percent [119]. Symptoms include anxiety, respiratory distress, dysphagia, fullness, and persistent or increasing pain. On examination, a large anterior cervical mass is often visible. Although rare, this complication can result in life-threatening airway compromise. Cervical hematoma results in venous congestion of airway structures, creating significant laryngeal edema and subsequent airway compromise. In addition, oropharyngeal swelling creates a narrow window for reintubation. With rare exceptions, the presence of hematoma indicates urgent surgical evaluation and treatment. Early recognition and immediate intervention are crucial to minimizing mortality [119,120]. (See "Thyroidectomy", section on 'Complications'.)

Postoperative hypocalcemia — Hypocalcemia is an important potential complication of parathyroid exploration. After a focused parathyroid exploration, low serum calcium may be the result of suppression of the other glands, which require the stimulus of hypocalcemia to resume function. If a bilateral exploration or prior contralateral exploration has taken place, the hypocalcemia may be caused by inadvertent injury to or loss of function of the remaining parathyroid glands. Thus, it is prudent to confirm function of the residual parathyroid tissue with a parathyroid hormone (PTH) assessment. The classic calcium nadir occurs within the first 24 to 48 hours after a parathyroidectomy, and a serum PTH value can be obtained on the first postoperative day prior to discharge. Preoperative assessment of vitamin D status, along with repletion of deficiency if present, is safe [121] and is routine in many high-volume practices today.

Mild hypocalcemia — Mild postoperative hypocalcemia may be due to bone hunger or functional hypoparathyroidism resulting from suppression of the remaining normal parathyroid tissue. Symptoms, including perioral or acral paresthesias and anxiety, can be exacerbated by hyperventilation. Mild hypocalcemia generally responds well to a short course of oral calcium supplementation, starting with 1500 to 2000 mg of elemental calcium daily in divided doses, given as calcium carbonate or calcium citrate. (See "Hypoparathyroidism", section on 'Acute hypoparathyroidism: Postsurgical'.)

Transient postoperative hypocalcemia is more common in patients with severe preoperative hypercalcemia and in those with chronic vitamin D deficiency (<15 ng/mL). For this reason, preoperative ergocalciferol (vitamin D2, 1000 IU daily or more depending on vitamin D level) is desirable in vitamin-D-deficient patients whose urinary calcium levels are not elevated. If hypercalciuria limits the ability to replete vitamin D preoperatively, it is important to provide adequate calcium and ergocalciferol after surgical correction of primary hyperparathyroidism (PHPT). (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Coexisting primary hyperparathyroidism'.)

Severe hypocalcemia — Symptoms of severe hypocalcemia include tetany, electrocardiogram (EKG) changes, papilledema, and seizures. A patient with severe, symptomatic postoperative hypocalcemia may require intravenous and oral calcium supplementation as well as correction of concomitant hypomagnesemia [122]. (See "Clinical manifestations of hypocalcemia" and "Treatment of hypocalcemia", section on 'Intravenous calcium dosing'.)

Appropriate treatment for severe hypocalcemia also depends in part on the phosphate and PTH levels:

●Hypophosphatemia – If prolonged hypocalcemia is accompanied by low or normal phosphate levels and normal or high PTH levels, hungry bone syndrome is diagnosed. Hungry bone syndrome is caused by rapid deposition of serum calcium into demineralized bone following a drop in PTH. Treatment for hungry bone syndrome is discussed elsewhere. (See "Hungry bone syndrome following parathyroidectomy in patients with end-stage kidney disease".)

●Hyperphosphatemia – If hypocalcemia is accompanied by hyperphosphatemia and low PTH levels, hypoparathyroidism is diagnosed, requiring treatment with calcitriol. (See "Etiology of hypocalcemia in adults" and "Hypoparathyroidism", section on 'Management'.)

Permanent hypoparathyroidism — Permanent hypoparathyroidism may occur with resection or devascularization of normal parathyroid glands, especially in patients who have had previous neck surgeries. It may also occur following a subtotal parathyroidectomy if the parathyroid remnant is not viable.

After an apparently successful parathyroidectomy, calcium intake should follow the Institute of Medicine (IOM) Dietary Reference Intakes, and patients who are vitamin D deficient should receive vitamin D supplementation [2]. If calcitriol and calcium supplementation cannot be tapered off over several months following surgery, the hypoparathyroidism may be permanent. An undetectable or markedly low serum PTH level when serum calcium level is low confirms the diagnosis and indicates the permanent need for treatment. (See "Hypoparathyroidism", section on 'Chronic hypoparathyroidism'.)

Wound infection — Parathyroid surgery is a clean procedure in a well-vascularized area; wound infection is a rare complication. Redness and inflammation at the incision are more likely to be caused by skin reactions to tape or suture materials.

Recurrent laryngeal nerve injury — Recurrent laryngeal nerve (RLN) injury is a rare complication that occurs in <1 percent of initial operations in the hands of experienced parathyroid surgeons. Reoperations are associated with a higher risk of RLN injuries due to scarring and distorted anatomy.

To minimize the risk of RLN injury, the surgeon should review the patient's prior operative and pathology reports to gain information regarding the extent of prior dissection. Preoperative laryngoscopy is also recommended in the reoperative setting to assess any preexisting RLN compromise (see 'Preoperative evaluation and management' above). Intraoperative neuromonitoring can be helpful in high-risk reoperative cases but should augment, rather than circumvent, the need for meticulous surgical techniques, including intraoperative visual identification of the RLN. (See "Thyroidectomy", section on 'Intraoperative nerve monitoring'.)

The diagnosis and treatment of RLN injuries are discussed separately. (See "Thyroidectomy", section on 'Nerve injury/vocal cord paresis or paralysis'.)

Hyperthyroidism — Hyperthyroidism is an underappreciated consequence of thyroid gland manipulation (also referred to as palpation thyroiditis) at the time of parathyroid surgery [24,123]. Biochemical evidence and symptoms (eg, mild thyrotoxicosis) of hyperthyroidism were found in 31 to 43 percent and 15 to 27 percent of patients, respectively [24]. Thus, patients with symptoms of hyperthyroidism should be monitored for biochemical or clinical evidence of hyperthyroidism in the early postoperative period after parathyroidectomy. Those with symptoms can be treated with thionamides and/or beta blockers as indicated. In general, the hyperthyroidism is transient and self-limited, with thyroid function studies normalizing within a few weeks to months. (See "Overview of the clinical manifestations of hyperthyroidism in adults" and "Thionamides in the treatment of Graves' disease" and "Beta blockers in the treatment of hyperthyroidism".)

OUTCOMES — The surgical cure rate for primary hyperparathyroidism (PHPT) should be ≥95 percent [30,40,124]. Operative management is more effective and less costly than either long-term observation or pharmacologic therapy [2]. However, the overall survival of patients treated successfully for PHPT is uncertain; increased mortality due to persistent cardiovascular disease after surgical cure of PHPT has been reported [125]. (See "Primary hyperparathyroidism: Clinical manifestations".)

Persistent or recurrent disease may be the result of surgeon inexperience, supernumerary glands, or unrecognized multigland disease. Reoperation is technically challenging with higher rates of morbidity [126-128] and higher incidences of recurrent laryngeal nerve (RLN) injury and permanent hypoparathyroidism as well as higher rates of failure to cure [126-128]. Thus, indications for reoperations are more stringent than for initial surgery. (See 'Indications' above.)

Patients with persistent or recurrent PHPT should be evaluated by an experienced parathyroid surgeon for possible reoperation. The evaluation should include confirmation of biochemical diagnosis, assessment of indications for surgery, review of prior records if available, and evaluation of RLN function. Some surgeons prefer to have two concomitant, concordant imaging studies before performing reoperation. Precise description of gland location using a standardized nomenclature system is particularly useful for reoperative surgery [129]. A targeted approach based on preoperative imaging should be used for reoperations [2].

In the majority of reoperations for persistent or recurrent PHPT, the hyperfunctional parathyroid gland is identified in a usual and expected anatomic location, such as the deep tracheoesophageal groove or superior portion of the cervical thymus [130]. Ectopic parathyroid glands, such as undescended glands or those deep within the mediastinum, are uncommon. The cure rate of reoperations may be by the use of intraoperative parathyroid hormone monitoring to confirm excision of all hyperfunctioning tissue and, in some cases, to guide laterality of dissection [131]. (See 'Intraoperative assessment' above.)

Although surgical removal of the hyperfunctional parathyroid tissue is the only definitive therapy for persistent or recurrent PHPT, patients who refuse surgery or have a parathyroid gland that cannot be found may be managed medically [132]. (See "Primary hyperparathyroidism: Management".)

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" and "Society guideline links: Primary hyperparathyroidism".)

SUMMARY AND RECOMMENDATIONS

●Primary hyperparathyroidism – Primary hyperparathyroidism (PHPT) is typically diagnosed when hypercalcemia is detected incidentally on routine biochemical screening tests. Clinical manifestations of PHPT include polydipsia and polyuria, nephrolithiasis, nephrocalcinosis, osteoporosis, fragility fractures, vertebral compression fractures, pancreatitis, peptic ulcer disease, gastroesophageal reflux, fatigue, depression, and significant neurocognitive dysfunction. Although some patients are completely asymptomatic, many have nonspecific and often subtle symptoms, such as fatigue, depression, irritability, anxiety, anorexia, difficulty with concentration, or memory impairment. (See 'Introduction' above and 'Indications' above.)

●Surgical indications – Parathyroidectomy is the definitive therapy for PHPT and is indicated for all patients with symptomatic PHPT, patients with familial PHPT (multiple endocrine neoplasia [MEN] type 1 and 2A, or familial hyperparathyroidism), and patients with asymptomatic disease who have decreased renal function (glomerular filtration rates <60 mL/minute), hypercalciuria (24 hour urine calcium level >400 mg/dL), osteoporosis, serum calcium >1 mg/dL above normal, age <50 years, or who prefer surgery to observation. Parathyroid exploration is also indicated for patients with parathyroid cancer or parathyroid crisis and for selected patients with persistent or recurrent PHPT after a previous parathyroid surgery. (See 'Indications' above.)

●Contraindications – Contralateral recurrent laryngeal nerve (RLN) injury and symptomatic cervical disc disease are relative contraindications to parathyroidectomy. Patients with familial hypocalciuric hypercalcemia do not have a primary parathyroid disorder and should not undergo parathyroidectomy. (See 'Contraindications' above.)

●Focused parathyroidectomy – For selected patients who have unilateral pathology as localized by preoperative imaging, no concomitant thyroid disease, and no family history of MEN, we suggest focused parathyroidectomy, rather than bilateral cervical exploration (Grade 2B). The success of focused parathyroidectomy is dependent upon both preoperative localization studies that limit the operative field to the region where a presumed single adenoma is and the use of intraoperative parathyroid hormone (PTH) monitoring to confirm that no other hyperfunctioning gland remains in situ. (See 'Choice of procedure' above and 'Focused parathyroid exploration' above.)

●Bilateral neck exploration – Initial bilateral neck exploration should still be performed when a single hyperfunctioning gland cannot be identified on preoperative imaging, when a focused approach fails, when the preoperative or intraoperative findings suggest multigland disease, for most forms of familial diseases, and when there is concomitant thyroid pathology (see 'Choice of procedure' above and 'Bilateral parathyroid exploration' above). Intraoperative parathyroid hormone monitoring is necessary in virtually all cases.

●Outcomes – For most patients, cure after parathyroidectomy is defined as the reestablishment of normal calcium homeostasis lasting a minimum of six months. For patients with normocalcemic PHPT, the PTH level must also normalize at six months after surgery to indicate cure. In experienced hands, surgical cure is achieved in ≥95 percent of initial parathyroidectomies; the recurrence rate is higher with reoperations. During exploration for primary hyperparathyroidism, expert understanding of the embryology and anatomy of the parathyroid glands is essential to achieve surgical cure. A missed parathyroid adenoma is the most common cause for a failed initial parathyroid operation and persistent hyperparathyroidism. (See 'Missing gland' above and 'Outcomes' above.)

●Complications – Major complications after parathyroidectomy include failure to achieve durable cure of hypercalcemia, hematoma with airway compromise, hypoparathyroidism, and RLN injury. (See 'Complications' above.)