Modern approaches to intraoperative parathyroid localization

Sergey V. Zinchenko; Зинченко Сергей Викторович; Ilfat Z. Galiev; Галиев Ильфат Зульфатович; Egor K. Kulbida; Кульбида Егор Константинович; Kirill A. Petukhov; Петухов Кирилл Алексеевич; Niyaz F. Muratov; Муратов Нияз Фанусович

doi:10.17816/KMJ643228

Modern approaches to intraoperative parathyroid localization

Authors: Zinchenko S.V.¹, Galiev I.Z.¹, Kulbida E.K.¹, Petukhov K.A.¹, Muratov N.F.¹
Affiliations:
1. Kazan (Volga Region) Federal University
Issue: Vol 106, No 6 (2025)
Pages: 992-1000
Section: Reviews
Submitted: 19.12.2024
Accepted: 04.07.2025
Published: 22.10.2025
URL: https://kazanmedjournal.ru/kazanmedj/article/view/643228
DOI: https://doi.org/10.17816/KMJ643228
EDN: https://elibrary.ru/JXFFPY
ID: 643228

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Abstract

Hyperparathyroidism is a prevalent endocrine disorder that frequently manifests with severe symptoms. Primary hyperparathyroidism is caused by parathyroid adenoma, whereas secondary and tertiary hyperparathyroidism are typically reported in patients with renal failure on maintenance hemodialysis. Modern cinacalcet-based therapy for secondary hyperparathyroidism has long-term positive effects. However, surgical resection of affected parathyroid glands remains the only curative therapy option in tertiary hyperparathyroidism. In polyglandular primary and (especially) tertiary hyperparathyroidism, parathyroidectomy requires the most accurate examination of the parathyroid glands, thyroid gland, and surrounding structures. Despite advancements in preoperative topical and functional diagnostic approaches, the specific location of the affected parathyroid glands remains unknown until surgery in half of patients. Existing parathyroid imaging techniques, such as intraoperative ultrasound, gamma detection, and methylene blue staining, have demonstrated limited efficacy. Fluorescence imaging using indocyanine green, aminolevulinic acid, and various autofluorescence modes is highly effective. However, its use is limited by high equipment costs, reproducibility issues, and difficulties in achieving the claimed results. This necessitates improvements of intraoperative parathyroid imaging algorithms, which is the focus of this review.

Keywords

hyperparathyroidism, parathyroid gland, imaging, surgery, ICG, NIRAF, 5ALA

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Introduction

Currently, primary hyperparathyroidism (pHPT) is one of the most common endocrine disorders following diabetes mellitus and thyroid diseases [1]. Secondary (sHPT) and tertiary (tHPT) hyperparathyroidism are the most frequent complications in patients with end-stage chronic kidney disease. Their development is associated with impaired calcium–phosphorus homeostasis and altered calcitriol (vitamin D) metabolism, leading to parathyroid hormone (PTH) secretion becoming independent of serum calcium and phosphorus concentrations [1, 2]. As a result, sHPT develops, with diffuse parathyroid gland (PTG) hyperplasia as its morphological substrate. Further disease progression leads to tHPT, which is morphologically characterized by the development of autonomously functioning parathyroid adenomas [1, 2]. Pharmacotherapy aimed at suppressing PTH synthesis is effective at early stages of sHPT; however, it is not applicable in pHPT, tHPT, and long-standing persistent sHPT [1, 3]. Thus, surgical treatment remains the only effective therapeutic option for these patient groups [1].

Although parathyroid surgery has been developing since the mid-20th century, a unified standardized surgical approach, extent of resection, or timing of intervention for sHPT and tHPT has not yet been established. The most widely used approaches are subtotal parathyroidectomy and total parathyroidectomy with autotransplantation [2]. An analysis conducted by Triponez et al. showed a more pronounced postoperative decrease in PTH levels in patients who underwent total parathyroidectomy than in those who underwent subtotal resection [2]. Moreover, Rothmund et al. reported a lower recurrence rate of hyperparathyroidism in patients who underwent total parathyroidectomy with autotransplantation [3]. Notably, autotransplanted parathyroid tissue will not adequately function until neovascularization occurs; therefore, transient hypoparathyroidism is more common and more pronounced after such radical procedures than after subtotal parathyroidectomy [4]. Furthermore, parathyroid autotransplantation may fail and result in long-term hypoparathyroidism [4].

Precise understanding of PTG localization is crucial for adequate parathyroidectomy [5]. Preoperative imaging modalities such as ultrasound and parathyroid scintigraphy remain relevant. However, their accuracy is markedly decreased in cases of multigland parathyroid disease in pHPT, sHPT, and tHPT [5, 6]. The present review provides a detailed assessment of current intraoperative topical diagnostic approaches for PTG localization.

A literature search was performed in PubMed, Google Scholar, ClinicalTrial.gov, the Cochrane Library, NICE, eLibrary.ru, and CyberLeninka using the following keywords: гиперпаратиреоз/hyperparathyroidism, parathyroid gland, визуализация/imaging, хирургическое лечение/surgical treatment, ICG, NIRAF, 5-ALA, ПЩЖ (diffuse parathyroid gland), and интраоперационная визуализация (intraoperative imaging). The following article types were selected in English and Russian: systematic reviews, meta-analyses, narrative reviews, guidelines, randomized controlled trials, and clinical studies. The search depth was 11 years (from January 1, 2014, to January 31, 2025).

Intraoperative imaging

Intraoperative navigation methods are actively evolving and improving, including intraoperative ultrasound, fluorescence angiography, other optical imaging modalities, radiometry with a gamma probe and 99mTc, and single- or multi-channel scintillation/semiconductor detectors [5–7]. In the operating room, fast and intuitive imaging techniques are preferred, which help reduce surgical trauma, shorten operative time, and decrease the risks of recurrence and persistent disease [5–7].

A handheld gamma probe and portable gamma camera are used in minimally invasive radio-guided parathyroidectomy in highly selected patients (e.g., those with solitary adenoma and reliable preoperative imaging, such as high-resolution ultrasound and scintigraphy and/or SPECT/CT) [8–11]. Radioactivity is measured in the excised parathyroid specimen, its surgical bed, the removed PTG, and the thyroid gland. The radicality of resection is assessed by a decrease in counts in the operative field with retained activity in the excised specimen (a ≥20% decrease is considered adequate) [12]. Additionally, intraoperative rapid PTH testing is used to confirm completeness of resection.

In hereditary forms of hyperparathyroidism, other PTGs that appear macroscopically and scintigraphically normal but are less affected may later manifest as recurrent disease [13]. During surgery, particular attention should be paid to radiation dose selection [13].

In intraoperative gamma probe detection for patients with pHPT, low-dose radiotracer protocols demonstrate lower sensitivity and higher specificity in assessing postoperative outcomes compared with high-dose approaches [14]. Excess body weight, recurrent hyperparathyroidism, multiglandular involvement, and ectopic PTG location can decrease the accuracy of this method [15, 16]. These limitations also apply to intraoperative ultrasound and gamma detection [15, 16].

Fluorescence imaging using 5-aminolevulinic acid (5-ALA)

Following oral administration, 5-ALA accumulates in hyperplastic and adenomatously altered PTG, enabling its intraoperative visualization under blue-light illumination [17]. The use of 5-ALA provides clear discrimination between PTG and adjacent tissues [18]. In a study, Kalashnikov et al. compared 5-ALA-based visualization in patients with parathyroid adenomas and those with thyroid condition. Visualization was achieved in 95% of cases in the parathyroid lesion group. No phonation disturbances or recurrent laryngeal nerve damage were reported, leading Kalashnikov et al. to conclude that photodynamic visualization techniques should be considered in surgical management of parathyroid disease [19]. In a study of intraoperative parathyroid gland visualization using 5-ALA, Vshivtsev et al. demonstrated that the fluorescence intensity of altered and hyperfunctioning PTG was subjectively higher than that of non-altered glands. PTH levels rapidly normalized postoperatively in the entire cohort. No laryngeal paresis or recurrences were reported. However, Vshivtsev et al. noted significant disadvantages of this method; phototoxic reactions were detected in two patients [20]. Notably, this method is associated with practical inconveniences. Depending on the protocol, the drug should be administered several times preoperatively based on patient body weight, and postoperative light protection is required. Additionally, full darkening of the operating room is required, and fluorescence assessment remains qualitative and subjective (by eye) [21]. Dolidze et al. evaluated the use of 5-ALA in postoperative hypoparathyroidism diagnostics. Among 226 patients, transient hypoparathyroidism occurred in 4 (1.8%) cases; no persistent hypocalcemia was recorded. Autotransplantation of parathyroid tissue was required in one (0.44%) case. Deficiency in or low levels of vitamin D were determined in 35% of patients, mostly associated with sHPT. In all cases, the deficiency was corrected with vitamin D supplementation. In 23 patients (10.17%), no prominent fluorescence effect was observed following 5-ALA administration, requiring transition to the second step of the protocol (i.e., helium–neon laser use and fluorescence registration with a laser spectroanalyzer). According to Dolidze et al., this approach prevents permanent hypoparathyroidism and decreases the incidence of transient hypoparathyroidism [21].

Near-infrared fluorescence imaging

With methylene blue: This technique was historically considered for parathyroid visualization and initially demonstrated efficacy [22, 23]. However, subsequent studies showed no significant differences compared with the control group, possibly due to insufficient dosing [24]. At higher doses, adverse effects, including neurotoxicity and dermatologic complications, were reported, which led to discontinuation of the practical use of methylene blue [24, 25].

With indocyanine green (ICG): This agent has long been used in ophthalmology for retinal angiography and, in recent years, has demonstrated efficacy in cholangiography, assessment of gastrointestinal anastomotic perfusion and skin flaps in plastic surgery, adrenalectomy, real-time lymph node mapping, tissue perfusion evaluation in diabetic foot, and PTG visualization [26–29]. ICG is a nontoxic, inert organic compound administered intravenously; it binds to plasma proteins and reflects light from a low-energy laser with a wavelength of approximately 806 nm, which is captured by the camera [30]. Although ICG is not a selective agent and allows for visualization of perfusion in all tissues, the more pronounced vascularization of the PTGs enables their differentiation from adjacent structures [31]. The technique involves the intravenous administration of 3–4 mL of ICG solution (diluted with water for injection) following surgical exposure. After 30–60 seconds, perfusion can be visualized in real time using a camera detecting the corresponding emission wavelength; repeated administration is possible if needed [32]. In 2015, Chakedis et al. described the first successful intraoperative localization of a parathyroid adenoma using ICG [32]. In a similar study by DeLong et al., this method enabled the intraoperative detection of parathyroid lesions in all 18 of 54 patients where routine preoperative imaging had failed to detect them [26]. The advantages of ICG include the absence of false-positive results in published studies [33] and safety and ease of use for the surgeon [33, 34]. Studies by Richard et al. demonstrated that ICG significantly improves the accuracy of PTG identification compared with conventional methods [35], which is particularly crucial given the variability of gland anatomy [36, 37]. The limitations of the method include iodine content (with risk of allergy) and the need for expensive equipment (i.e., a light source and a camera with dedicated filters) [27, 38, 39].

In 2019, Henegan et al. reported a case of an intrathyroidal parathyroid adenoma detected using near-infrared (NIR) imaging (750–1000 nm) [40]. NIR does not provide information on PTG viability, as fluorescence persists even after devascularization; therefore, Alesina et al. proposed combining autofluorescence with ICG to assess PTG vascularization intraoperatively [41]. Rossi et al. evaluated 11 patients with pHPT who underwent parathyroidectomy. Histopathological examination of 15 resected specimens confirmed 14 parathyroid adenomas and one schwannoma. All adenomas showed a heterogeneous NIRAF pattern, which was distinct from the homogeneous pattern observed in the schwannoma. A bright cap was identified in 9 of 14 (64.3%) parathyroid adenomas, indicating the method’s high effectiveness [42]. Recent experience with NIR autofluorescence reported by Frey et al. demonstrated no significant difference between standard parathyroidectomy and surgery supplemented by additional visualization. The use of NIR autofluorescence did not substantially influence the number of glands identified or resected, nor did it affect complication rates [43]. A large single-center prospective series by Akgun et al., which analyzed 1506 normal and 597 abnormal PTG NIRAF images, demonstrated significantly higher fluorescence intensity in hyperplastic glands [44]. The same group compared outcomes in solitary adenomas and multigland disease. Heterogeneity of autofluorescence was found to be more frequent in multigland disease. However, Akgun and Berber emphasized that these differences should be considered in intraoperative practice [45].

Furthermore, Takeuchi et al. investigated the correlation of NIRAF in pHPT and sHPT. In all quantitative comparisons (in situ/ex vivo and mean and maximum intensity), autofluorescence was more pronounced in pHPT than in sHPT. Visual subjective in situ scoring demonstrated 100% autofluorescence positivity in pHPT versus 33% in sHPT. Subjective visual classifications correlated with autofluorescence intensity. The ratio of maximum to mean fluorescence signal was higher in both pHPT and sHPT than in normal PTG [46].

A critical aspect of intraoperative PTH assessment was highlighted in a study by Indelicato et al., where NIRAF was used as an alternative to intraoperative PTH (ioPTH) measurement in patients with pHPT due to parathyroid adenoma, in cases with concordant findings from two preoperative imaging modalities regarding the location of the affected PTG. The results demonstrated successful minimally invasive parathyroidectomy in all patients. The mean waiting time for ioPTH results was 37 minutes. Indelicato et al. identified three fluorescence patterns: cap (46%), heterogeneous (30%), and homogeneous (24%). They concluded that when preoperative imaging reliably confirms PTG location, NIRAF may replace ioPTH, decreasing operative time without compromising patient outcomes and laboratory endpoints [47].

Despite high sensitivity and accuracy, selective application in certain patient groups remains possible. Small adenomas may be mistakenly regarded as normally functioning PTGs by the surgeon [46]. In a study conducted by Lee et al. in 2017–2021, including 131 patients (151 PTG), autofluorescence intensity negatively correlated with gland weight (lighter glands demonstrated stronger fluorescence) and positively with age (higher intensity was observed in older patients). No correlation was found with preoperative serum calcium, PTH, body mass index, or sex [48].

The limitations of NIRAF include the need for complete operating room darkening to register fluorescence, which increases operative time [49], and its limited ability to localize deeply situated PTGs covered by other tissues, as light penetrates only a few millimeters [49]. In a comparative study by Kahramangil et al., both ICG fluorescence and parathyroid autofluorescence showed comparable sensitivity (95% [60/63 PTGs] and 98% [61/62 PTGs], respectively) [50].

In a study by Palermo et al., Raman spectroscopy differentiated normal and adenomatous PTGs with 100% accuracy in a cohort of 18 patients [51]. This method appears promising for intraoperative differential diagnosis between normal and pathologically altered PTGs [52].

Table 1 presents a summary of comparative evaluation of available intraoperative parathyroid imaging techniques.

Table 1. Comparison of intraoperative parathyroid imaging techniques

Advantages	Limitations	Performance
Intraoperative ultrasound [24]
Wide availability (equipment commonly accessible) Low cost Ability to evaluate concomitant thyroid condition No radiation exposure	High operator dependency Blind zones (tracheoesophageal groove and mediastinum) Limited effectiveness in multigland disease or with multinodular goiter Anatomical factors (short and/or thick neck; small parathyroid gland size)	Sensitivity: 51%–91% Specificity: 61%–91% Overall accuracy: 56%–98%
Intraoperative gamma probe [10]
Provides additional information on approximate anatomic localization of parathyroid glands	Requires expensive equipment and is associated with significant radiation exposure	Fails to visualize parathyroid glands in 29% of cases of primary operations and 56% of reoperative cases
Fluorescence imaging with 5-aminolevulinic acid [18]
Provides clear differentiation between parathyroid glands and adjacent tissues	Requires several preoperative administrations depending on the protocol and patient body weight Postprocedural light isolation is required Complete operation room darkening is required Only qualitative and subjective (by eye) assessment possible	Sensitivity: 85%–95% Specificity: 90%–98% Accuracy: 88%–95%
Methylene blue parathyroid gland visualization [24]
Provides sufficiently clear visualization	May lead to acute postoperative neurological disturbances	Sensitivity: 46%
Fluorescence imaging with indocyanine green [35]
Provides sufficiently clear visualization	Requires laser excitation at 802 nm	Sensitivity: 85%–100% Specificity: 90%–100% Accuracy: 93%–98%
Near-infrared autofluorescence imaging [44, 45]
Limited ability to localize deeply located parathyroid glands (covered by other tissues)	Requires complete operating room darkening Inability to assess parathyroid gland viability	Sensitivity: 98% Specificity: 80%–90% Accuracy: 90%–95%
Raman spectroscopy [52]
Enables differentiation between normal and adenomatous parathyroid glands	Requires expensive equipment Still in the research phase	Sensitivity: 100%

Conclusion

Surgery remains the primary treatment option for pHPT and for drug-resistant sHPT and tHPT.

Intraoperative visualization of the PTG and their complete removal may be challenging even for experienced surgeons. Despite the large number of studies on intraoperative parathyroid navigation, the most inexpensive and effective method of fluorescent visualization is 5-ALA-based imaging. It does not require costly equipment or additional fluorescent agents and is associated with low rates of side effects and complications.

Further research is required to optimize surgical treatment for multiglandular pHPT, sHPT, and tHPT.

Additional Information

Author contributions: Z.S.V.: supervision, writing—review & editing; G.I.Z.: supervision, writing—review & editing; K.E.K.: writing—original draft; P.K.A.: writing—review & editing; M.N.F.: supervision. All authors approved the version of the manuscript to be published and agree to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Acknowledgments: The authors express their gratitude to the faculty members of Kazan Federal University (Russia).

Funding sources: No funding.

Disclosure of interests: The authors have no relationships, activities, or interests for the last three years related to for-profit or not-for-profit third parties whose interests may be affected by the content of the article.

Statement of originality: No previously published material (text, images, or data) was used in this work.

Data availability statement: The editorial policy regarding data sharing does not apply to this work, as no new data was collected or created.

Generative AI: No generative artificial intelligence technologies were used to prepare this article.

Provenance and peer review: This paper was submitted unsolicited and reviewed following the standard procedure. The peer review process involved two external reviewers, a member of the editorial board, and the in-house science editor.