Version July 2025
INTRODUCTION —
Primary hyperparathyroidism is usually caused by a solitary benign adenoma (80 to 85 percent) but can also be due to multiple adenomata (2 to 5 percent), diffuse or nodular hyperplasia (10 to 15 percent), or parathyroid carcinoma (<1 percent) [1]. Surgery is the gold standard for treating patients with primary hyperparathyroidism and options include either four-gland parathyroid exploration or a focused, minimally invasive approach to parathyroid surgery, which has been adopted at many centers [2,3]. (See "Parathyroid exploration for primary hyperparathyroidism".)
Parathyroid imaging is primarily used to identify patients who are candidates for a minimally invasive approach. It is also important in patients who have persistent or recurrent disease, or who have had prior cervical exploration and require reoperative surgery.
Localization studies, in conjunction with intraoperative parathyroid hormone testing, can help minimize the extent of surgical dissection, identify concurrent thyroid pathology, and detect ectopic parathyroid tissue, the latter being a particular advantage for patients who had prior failed parathyroid exploration. However, localization studies have no role in the diagnosis or confirmation of the diagnosis of primary hyperparathyroidism, which is based on biochemical profile. Similarly, imaging does not determine the need for surgery. Finally, the use of localization studies does not override the recommendation that parathyroid surgery should only be performed by highly experienced surgeons [2,4]. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Indications'.)
The techniques and role of preoperative localization in patients with primary hyperparathyroidism will be reviewed here. Patients who require surgery for secondary or tertiary hyperparathyroidism usually undergo subtotal or total parathyroidectomy, which requires four-gland exploration. Thus, preoperative localization may not be as essential in those cases. (See "Parathyroidectomy in end-stage kidney disease".)
Because of the high likelihood of multiglandular disease, patients with syndromic hereditary primary hyperparathyroidism in particular generally undergo bilateral parathyroid exploration, even in the event of a positive localizing study. This is discussed elsewhere. (See "Parathyroid surgery for inherited syndromes".)
CHOICE OF IMAGING MODALITIES —
The diagnosis of primary hyperparathyroidism should be made based on biochemical findings. Imaging studies are not used as a diagnostic tool; rather, preoperative localization studies help plan the operative approach in patients who have a biochemically confirmed diagnosis of primary hyperparathyroidism and in whom other pathologies have been appropriately ruled out (eg, familial hypocalciuric hypercalcemia) [2].
Minimally invasive parathyroidectomy — For patients undergoing initial parathyroid surgery for primary hyperparathyroidism, preoperative localization studies are predominantly used to determine whether or not a patient is a candidate for a minimally invasive approach [5-7]. Preoperative localization is required if a minimally invasive procedure is contemplated, and can reduce operative time in unilateral parathyroid surgery [8,9].
Ultrasound of the parathyroid glands is endorsed as the initial imaging study for primary hyperparathyroidism by both the American Head and Neck Society Endocrine Surgery Section [10] and the American Association of Endocrine Surgeons [2], noting the advantage of concomitant thyroid evaluation. (See 'Ultrasound' below.)
Sestamibi scintigraphy (technetium-99-sestamibi scanning) combined with sestamibi single photon emission computed tomography (SPECT) has the highest positive predictive value of the available imaging techniques (table 1), and some prefer this as the localizing procedure of choice for initial surgery [11,12]. However, SPECT is not available at all centers, and some use planar sestamibi or 4D CT as the initial localizing study. (See 'Sestamibi scintigraphy' below and 'Four-dimensional computed tomography' below.)
Reoperation for recurrent or persistent hyperparathyroidism — Because of fibrosis from the previous surgery and alterations in parathyroid gland location, the rate of complications, such as recurrent laryngeal nerve injury, permanent hypoparathyroidism, and persistent disease, is typically higher than initial parathyroid surgery [13]. The risk of complication may be even higher without clear preoperative localization. Thus, accurate localization studies are mandatory in patients undergoing reoperative parathyroid surgery [14].
At least one preoperative imaging study should localize hyperfunctional parathyroid tissue before proceeding with re-exploration [2,13,15]. The success rate of reoperative surgery without preoperative localization is only 60 percent. Several observational studies have reported success rates of 95 percent or more with positive preoperative localization before reoperation [16,17].
The best imaging study or combination of studies for persistent or recurrent disease has not been determined and is often dependent on local, institutional expertise (table 2). The following is a common clinical algorithm (figure 1):
●In most reports assessing different imaging modalities, sestamibi with SPECT/CT often is the first imaging study utilized in the reoperative setting and can detect 60 to 80 percent of the abnormal glands [18,19]. Clinical algorithms suggest performing two noninvasive procedures prior to reoperation, one of which should be sestamibi imaging; the other is often ultrasonography, but may vary by available expertise at the center where the study is performed [20,21].
●If the results of the first two studies are concordant, surgery is performed.
●If the results are discordant or inconclusive, the next step depends upon the expertise of the center and may include either surgery with intraoperative parathyroid hormone monitoring or additional testing [20,21]. Further testing includes additional imaging (four-dimensional computed tomography, magnetic resonance imaging [MRI], positron emission tomography [PET]/CT) or possible invasive procedures (eg, selective venous sampling). (See 'Imaging modalities' below.)
Several observational studies showed that this step-wise approach allowed the identification of the offending parathyroid gland or glands in 92 to 97 percent of reoperated cases [20,22,23].
IMAGING MODALITIES —
Imaging modalities that have been used successfully for localizing parathyroid glands prior to surgery include sestamibi scintigraphy with optional three-dimensional imaging (SPECT/CT), neck ultrasound, four-dimensional computed tomography (4D-CT), MRI, and positron emission tomography (PET) combined with CT or MRI [24-27]. The sensitivity and positive predictive value (PPV) of these imaging modalities are summarized in these tables (table 1 and table 2).
Sestamibi scintigraphy — Technetium-99m-methoxyisobutylisonitrile (99mTc-sestamibi or MIBI) was first used for cardiac scintigraphy and was noted to concentrate in parathyroid adenomas. 99mTc-sestamibi is taken up by the mitochondria in thyroid and parathyroid tissue; however, the radiotracer is retained by the mitochondria-rich oxyphil cells in parathyroid glands longer than in thyroid tissue [28]. Planar images are typically obtained shortly after injection of 99mTc-sestamibi and again at approximately two hours to identify foci of retained radiotracer activity consistent with hyperfunctioning parathyroid tissue.
A negative 99mTc sestamibi scan does not negate the diagnosis of primary hyperparathyroidism, since it occurs in 12 to 25 percent of patients with disease [29,30]. Sestamibi scanning is often unrevealing, or misleading, in patients with parathyroid hyperplasia, multiple parathyroid adenomas, and coexisting thyroid disease [31-33]. Thyroid disease requiring surgery significantly increases both the false positive and false negative rate of sestamibi scanning [34]. Falsely negative scans can also be caused by calcium channel blockers that interfere with the uptake of the isotope by parathyroid cells [35]. Other gland characteristics that can increase the likelihood of a negative scan include small size, superior position, and a paucity of oxyphil cells [36-38].
In patients without prior parathyroid surgery, sestamibi scintigraphy alone has a sensitivity of 41 to 96 percent [39] but provides limited anatomic detail. Planar sestamibi scintigraphy can be enhanced by combination with three-dimensional imaging (SPECT), a subtraction thyroid scan, or fusion with CT images (MIBI-SPECT-CT). There is a growing consensus that MIBI-SPECT or MIBI-SPECT-CT is superior to MIBI alone in localizing parathyroid adenomas [40-42].
SPECT and SPECT/CT — Sestamibi-single photon emission computed tomography (SPECT or MIBI-SPECT) is a three-dimensional sestamibi scan that provides higher-resolution imaging and improves the performance of sestamibi scanning (image 1). The multidimensional images illustrate the depth of the parathyroid gland or glands in relation to the thyroid and improve the detection of ectopic glands compared with planar sestamibi scintigraphy [43-45].
SPECT imaging substantially reduces the likelihood of missing multiglandular disease compared with planar imaging [46,47]. However, even with imaging showing a clear, bright focus of increased uptake, multiglandular disease is still a possibility [29,46,47]. Because SPECT imaging has a high rate (7 to 16 percent) [46,48,49] of missed multiglandular disease, a validated adjunct to exclude multiglandular disease such as intraoperative parathyroid hormone (PTH) monitoring or four-gland parathyroid exploration should be routinely utilized.
SPECT-CT fusion adds the ability to discriminate parathyroid adenomas from other anatomic landmarks, which may facilitate the surgical procedure [50-52]. In a single-institution retrospective and observational study of 1388 patients who underwent parathyroid exploration for primary hyperparathyroidism, SPECT-CT had greater accuracy for both single-gland disease (83 versus 77 percent) and multigland disease (36 versus 22 percent) than SPECT alone. The negative imaging rates were similar between the two imaging cohorts (about 10 percent) [53].
In patients without prior parathyroid surgery, reported sensitivities of sestamibi dual-phase scan with SPECT or SPECT/CT ranged from 67 to 86 percent [41,42,54,55], and PPV ranged from 91 to 96 percent [54,55]. In reoperative patients, the sensitivity and PPV were 33 to 74 percent, and 86 percent, respectively [56,57].
Ultrasound — Neck ultrasonography (US) is also often utilized for parathyroid localization (image 2). Sonographic characteristics of parathyroid adenomas include homogeneous hypoechogenicity and an extrathyroidal feeding vessel with peripheral vascularity seen on color Doppler imaging (image 3).
US is highly sensitive in experienced hands and is inexpensive, noninvasive, and reproducible in the operating room. However, the accuracy of ultrasound is operator dependent. According to two meta-analyses of observational studies, the sensitivity of ultrasound for detecting enlarged parathyroid glands ranged from 76 to 80 percent, and the PPV was 93 percent [55,58].
In reoperative cases, intraoperative US can be used to localize the adenoma and facilitate surgery in a previously dissected and scarred field. It is therefore advantageous for endocrine surgeons to learn to perform neck US [48], and studies have shown comparable sensitivity for localizing parathyroid adenomas compared to radiologist-performed US (77 to 87 percent) [48,59]. The sensitivity and PPV of US in reoperative patients were 46 to 69 percent, and 71 percent, respectively [56,60,61].
As with sestamibi-based techniques, the sensitivity of US for parathyroid adenoma localization is reduced in patients with thyroid nodules [62]. However, US is very helpful for the characterization and evaluation of any thyroid pathology, facilitating operative planning. Since concurrent thyroid pathology is present in 20 to 30 percent of patients with primary hyperparathyroidism [63], this common problem should be addressed preoperatively (eg, with fine needle aspiration) and/or intraoperatively (eg, with concurrent thyroidectomy). In addition, US-directed fine needle aspiration with analysis of PTH levels can be helpful for confirming suspected parathyroid lesions such as intrathyroidal adenomas or cysts or in the reoperative setting when the diagnosis is unclear [64,65]. However, and importantly, fine needle aspiration should not be performed if the diagnosis of parathyroid cancer is considered likely, as seeding of the cancer is a potential complication [2]. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Parathyroid carcinoma'.)
Disadvantages to the use of US alone include decreased accuracy in patients with smaller parathyroid gland size, obesity, or mediastinal glands located behind the clavicles [32,66]. Most experts in parathyroid surgery rely on both US and SPECT for preoperative localization, although this varies by geography and institutional expertise [67-69]. Combining 99mTc-sestamibi scintigraphy with neck US also provides high sensitivity for predicting the location of parathyroid adenomas in patients who have hyperthyroidism or other thyroid diseases [39]. Sonography provides additional anatomic information about the thyroid gland that could alter surgical management [70,71].
Four-dimensional computed tomography — 4D-CT scans take advantage of the rapid contrast uptake and washout that is characteristic of parathyroid adenomas for precise anatomic localization (image 4). Most protocols include noncontrast images followed by additional acquisitions (up to three) after contrast injection. However, some centers utilize fewer acquisitions to limit radiation exposure. The fourth delayed phase is no longer considered necessary because the three-phase protocol (noncontrast, arterial, venous phase) can provide balance between radiation exposure and diagnostic performance [72].
The primary disadvantage of 4D-CT is the radiation exposure, which, compared with sestamibi imaging, results in a >50-fold higher dose of radiation absorbed by the thyroid. The additional radiation leads to an age-dependent higher risk of developing thyroid cancer; hence, the use of 4D-CT should be highly selective in younger patients [73].
In patients without prior parathyroid surgery, the overall sensitivity of 4D-CT ranged between 62 and 88 percent [74,75] and the PPV between 84 and 90 percent [54,76]. In reoperative patients, the sensitivity ranged from 50 to 91 percent and PPV from 69 to 100 percent [75,77-79].
4D-CT is particularly useful in the setting when initial imaging with sestamibi is negative [54]. In retrospective studies, the pathological gland was localized with 4D-CT to allow minimally invasive parathyroidectomy in approximately 75 percent of patients with otherwise negative US and/or SPECT/CT [80].
Magnetic resonance imaging — Parathyroid adenoma characteristics on MRI include intermediate to low signal intensity on T1 imaging and high intensity on T2 imaging. Cervical lymph nodes can also have similar imaging characteristics, which limits the accuracy of MRI.
The protocols and equipment of MRI performed for localizing parathyroid adenomas have not been standardized (with, without, or with and without contrast; 1.5T versus 3T machine), which may skew the reported performance data.
In patients without prior parathyroid surgery, the sensitivity of MRI neck without and with intravenous contrast performed at 1.5T has been reported to be between 64 and 79 percent [56,81]. When performed at 3T, the sensitivity ranged between 64 and 98 percent, and the PPV ranged between 67 and 95 percent [82,83].
For reoperative surgery, MRI may provide a useful noninvasive imaging modality to localize abnormal parathyroid tissue and does not require iodinated contrast or exposure to ionizing radiation. Using standard protocols, the reported sensitivity and PPV of MRI for abnormal parathyroid tissue ranged from 63 to 82 percent, and 85 to 100 percent, respectively [56,84]. The sensitivity and PPV increased to 90 to 93 percent and 90 to 100 percent, respectively, when dynamic sequences were used [56,84].
Positron emission tomography — Since the 1990s, PET, usually performed with low-dose CT or MRI, has been used to localize parathyroid adenoma (PET-CT; PET-MRI). Despite encouraging data, parathyroid PET has not been widely available in the United States.
To date, 11C-methionine and 18F-fluorocholine PET have been studied most extensively [85]. Because of its short physical half-life, the use of 11C-methionine is restricted to facilities with an on-site cyclotron. A meta-analysis and a small direct comparison study of the two modalities both reported superior sensitivity of 18F-fluorocholine (92 versus 80 percent), with similar positive predictive values (94 versus 95 percent) [86,87].
In Europe and selected centers in the United States [88], 18F-fluorocholine-PET-CT has been used successfully and accurately to localize parathyroid adenomas. In a 2019 systematic review, it had a sensitivity of 80 to 100 percent and a specificity of 95 to 100 percent [89]. Given the superior diagnostic performance and low radiation exposure, the 2021 European Association of Nuclear Medicine guidelines recommended 18-fluorocholine PET as an alternative first-line imaging modality to sestamibi and neck US [90].
However, 18F-fluorocholine-PET is not commercially available in the rest of the world and needs to be synthesized locally [5,91], and its cost-effectiveness has not been proven superior to conventional imaging algorithms [92,93].
Invasive localization — Parathyroid glands tend to drain ipsilaterally and inferiorly relative to their anatomic location. As such, sampling of PTH levels during selective transvenous catheterization of multiple neck and mediastinal veins can be used to infer the laterality and regional location of parathyroid lesions [26].
Invasive procedures, such as selective venous sampling or selective arteriography, are reserved for patients who have had prior neck surgery, require reoperative surgery, and in whom noninvasive testing has been unrevealing [24,94].
Risks associated with invasive localization procedures include groin hematoma, anaphylaxis from the iodinated contrast, contrast-induced acute renal failure, and stroke. They are also expensive and require an experienced interventional radiologist to perform. Because of improvements in noninvasive imaging technologies, the need for invasive testing has declined substantially.
Selective venous sampling — Selective venous sampling is the most common invasive modality used for parathyroid localization. A 1.5- to 2-fold increase in PTH levels obtained from representative cervical vein drainage locations (inferior, middle, superior thyroid, thymic, and/or vertebral veins) compared with a peripheral location is considered an abnormal elevation. Selective venous sampling can identify hyperfunctioning parathyroid tissue when all other imaging modalities are negative [95-97]. The reported sensitivity ranged from 40 to 93 percent [79,96,98-101].
Selective arteriography — Selective arteriography is performed by combining selective transarterial hypocalcemic stimulation with nonselective venous sampling. Baseline and timed superior vena cava samplings are taken after injection with sodium citrate to induce hypocalcemia while simultaneous arteriography is performed. A positive localization is considered an increase in the PTH level to 1.4 times the baseline or a blush seen on arteriography [95].
LIMITATIONS OF PARATHYROID IMAGING
False negative studies — Negative or nonlocalizing imaging studies should not preclude initial surgery for patients with biochemically confirmed primary hyperparathyroidism who meet operative criteria. In such patients, a single adenoma is still the most likely intraoperative finding (62 to 77 percent); however, multiglandular disease is more common (20 to 38 percent) than is typical (about 15 percent) in patients with primary hyperparathyroidism [35,36]. Scan-negative patients require bilateral exploration by an experienced parathyroid surgeon and the use of intraoperative parathyroid hormone (PTH) monitoring [30,102]. When compared with patients with localized studies, equivalent long-term biochemical cure rates can be achieved, although more extensive surgery may be needed [35,95]. (See "Parathyroid exploration for primary hyperparathyroidism".)
Bilateral parathyroid exploration should be planned when imaging studies are negative or show more than one focus of activity, in cases of secondary or tertiary hyperparathyroidism, suspected syndromic hereditary etiology, or when concurrent thyroid pathology is present and warrants surgery. In the hands of experienced surgeons, bilateral exploration has a high cure rate and low morbidity [2,4]. (See "Parathyroid exploration for primary hyperparathyroidism", section on 'Bilateral parathyroid exploration'.)
It should also be mentioned that if initial imaging is negative at a medical facility that does not commonly perform parathyroid imaging, referral to a high-volume center should be considered. The sensitivity of localization has been reported to increase to as high as 92 percent in higher-volume centers [103].
Parathyroid localization techniques are generally less successful in normocalcemic primary hyperparathyroidism than in hypercalcemic diseases [104]. This may be due to a greater incidence of multiglandular disease and small adenoma sizes in normocalcemic patients. (See "Parathyroid hormone assays and their clinical use".)
False positive studies — Conversely, a single-focus positive imaging result does not reliably exclude the presence of multiglandular parathyroid disease [46] nor does positive imaging substitute for biochemical diagnosis. This is especially true for patients undergoing reoperation.
Intraoperative PTH assay may be helpful to confirm the success of the operation by demonstrating a substantial drop in parathyroid hormone level. (See "Intraoperative parathyroid hormone assays".)
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
●Purpose of preoperative localization – The diagnosis of primary hyperparathyroidism should be made based on biochemical findings alone. Imaging studies are not used as a diagnostic tool; rather, results of localization studies, interpreted in conjunction with intraoperative parathyroid hormone (PTH) testing, can facilitate minimally invasive parathyroid surgery or reoperative surgery for recurrent or persistent hyperparathyroidism. (See 'Introduction' above.)
●Initial parathyroidectomy – Preoperative localization is required for minimally invasive parathyroid surgery. The preferred localizing imaging studies include sestamibi scintigraphy (eg, MIBI-SPECT imaging) and ultrasound. Second-line imaging modalities include four-dimensional computed tomography (4D-CT), MRI, or positron emission tomography (PET, with either low-dose CT or MRI). The type, number, and sequence of studies obtained preoperatively are influenced by institutional and geographic expertise, as well as other clinical considerations (table 1). (See 'Minimally invasive parathyroidectomy' above and 'Imaging modalities' above.)
●Reoperative parathyroidectomy – For all patients under reoperation, we obtain at least two preoperative imaging studies and ensure their concordance (table 2). If the results are discordant or inconclusive, the next step depends upon the expertise of the local institution and may include either surgery with intraoperative monitoring of PTH or additional testing. (See 'Reoperation for recurrent or persistent hyperparathyroidism' above and 'Imaging modalities' above.)
●Limitations of parathyroid imaging – Patients with biochemically confirmed primary hyperparathyroidism but negative localization studies may be cured by a bilateral exploration by an experienced parathyroid surgeon. Conversely, a single-focus positive imaging result does not reliably exclude the presence of multiglandular parathyroid disease, especially in reoperative patients. To ensure a cure, a PTH assay may be helpful to confirm the success of the operation. (See 'Limitations of parathyroid imaging' above and "Intraoperative parathyroid hormone assays".)
