Topical Diagnostics of Parathyroid Glands: A Literature Review Volume 62- Issue 3

Galiev Ilfat Zulfatovich¹*, Zinchenko Sergey Viktorovich², Vakhitova Renata Shamilevna³, Petukhov Kirill Alekseevich⁴ and Kulbida Egor Konstantinovich⁴

• ¹Department of Surgery of Kazan (Volga Region) Federal University, Russia
• ²Head of the Department of Surgery of Kazan (Volga Region) Federal University, Russia
• ³Head of the Department of Nephrology of the Medical and Sanitary Unit of Kazan (Volga Region) Federal University, Russia
• ⁴Department of Postgraduate Education of Kazan (Volga Region) Federal University, Russia

Received: July 01, 2025; Published: July 08, 2025

*Corresponding author: Galiev Ilfat Zulfatovich, Department of Surgery of Kazan (Volga Region) Federal University, Kazan, Russia

DOI: 10.26717/BJSTR.2025.62.009759

Abstract PDF

Secondary and tertiary hyperparathyroidism (sHPT, tHPT) are common endocrine diseases, often occurring with severe symptoms, in most cases caused by chronic renal failure in patients on programmed hemodialysis. Today, when conservative therapy is ineffective and threshold PTH values are reached 600 pg/ml for more than 6 months, surgical removal of pathologically altered parathyroid glands is the only method of treating vHPT and tHPT. The main objective of the review is to study current trends and techniques of intraoperative visualization of the parathyroid glands, compare these methods and evaluate their effectiveness. The use of qualitatively new technologies for the diagnosis of parathyroid glands, such as identification by autofluorescence in the near infrared spectrum (NIRAF), the technique of using indocyanine green (ICG) and the method of visualization using 5-aminolevulinic acid under UV radiation, which allow, according to the authors, intraoperatively visualize the localization of parathyroid glands with more than 90% accuracy glands are subject to detailed consideration and study, which is what this study is devoted to.

Keywords: Secondary and Tertiary Hyperparathyroidism; Parathyroid Gland; Imaging; Surgical Treatment; Icg; Niraf; 5-Ala

Currently, secondary and tertiary hyperparathyroidism are among the most common complications in patients with end-stage chronic kidney disease (CKD), which is associated with impaired phosphorus-calcium metabolism, altered metabolism of calcitriol (vitamin D), when the secretion of parathyroid hormone (PTH) becomes independent of the concentration of calcium and phosphorus. In the early stages of chronic hemodialysis in patients with CKD, the associated disorders of phosphorus-calcium metabolism and vitamin D metabolism lead to secondary hyperparathyroidism (sHPT), the morphological substrate of which is hyperplasia of the parathyroid glands (PS). This condition is reversible and completely regresses in most patients after transplantation of a donor kidney. Further persistence of vHPT in patients with CKD on programmed hemodialysis leads to tHPT, which is expressed morphologically in the formation of autonomous hyperfunctioning adenomas of the parathyroid gland. In connection with the improvement of hemodialysis and the development of transplantology, the life expectancy of patients with CKD continues to increase. There is an accumulation of intercurrent diseases, including oncological ones, the treatment of which in case of uncorrected vHPT and tHPT is extremely difficult, and sometimes simply impossible.

Drug therapy of hyperparathyroidism aimed at:

1) Prevention and correction of hyperphosphatemia;

2) Achievement of target values of serum calcium;

3) Achievement of individual target values of iPTH [1], is quite effective in the early stages of vHPT, but has a number of significant disadvantages:

1) It still remains quite expensive;

2) Its effectiveness does not extend to tHPT and long-term persistent vHPT.

Thus, surgical treatment remains the only effective treatment option for this category of patients [2-4]. Despite the fact that parathyroid surgery has been developing since the mid-20th century, a single and standardized surgical method, volume, and timing of the intervention for vHPT and tHPT have not yet been developed. The most commonly used approaches are subtotal parathyroidectomy and total parathyroidectomy with autotransplantation. Thus, the analysis conducted by Triponez, et al. [5] proves a confident decrease in PTH in the postoperative period in patients with total parathyroidectomy than in patients who underwent subtotal resection [5]. Rothmund, et al. [6] also found a low rate of hyperparathyroidism recurrence in patients who underwent total parathyroidectomy with auto transplantation [6]. It is worth noting that auto transplanted parathyroid tissue will not function fully until it undergoes neovascularization, so transient hypoparathyroidism is more common and pronounced after such radical operations than after subtotal parathyroidectomy. Auto transplantation of parathyroid glands can also be unsuccessful and lead to long-term hypoparathyroidism [7,8]. For adequate parathyroidectomy, a clear understanding of the localization of the parathyroid glands is necessary. Preoperative visualization techniques of the parathyroid glands, such as ultrasound and parathyroid scintigraphy, have not lost their importance to this day.

Overweight patients, recurrent hyperparathyroidism, multiple lesions, atypical location of the parathyroid gland can reduce the accuracy of these methods. All these disadvantages are inherent in intraoperative ultrasound and gamma detection [9-14]. In this review, we discuss in detail the issues of intraoperative fluorescence navigation of the parathyroid gland, when all available methods of preoperative diagnostics did not provide complete information on the number, location and size of all pathologically altered parathyroid glands. It should be noted that the choice of one or another method of intraoperative visualization is complicated by the lack of representative systemic reviews and meta-analyses. Visual navigation of the parathyroid gland using intravenous infusion of methylene blue solution in the preoperative period with the development of blue staining of the parathyroid gland is quite effective [15]. However, methylene blue stains only 46.0% of the parathyroid gland [16], and its use can lead to the development of acute neurological disorders after surgery [17,18]. To date, this technique is not used due to the above disadvantages. The use of indocyanine green (ICG) as a fluorescent dye in surgery has attracted the attention of surgeons due to its ability to improve visualization of anatomical structures. ICG was first synthesized in 1955 and was initially used in ophthalmology to assess vascular perfusion.

The first attempts to use ICG in surgery began in the early 2000s, when surgeons began to explore its use in various fields such as cardiac surgery, oncology, and later endocrine surgery. One of the first significant studies to examine the use of ICG in parathyroid surgery was a 2016 study by Fortuny, et al. [19] which demonstrated its potential to reduce complications following parathyroid surgery [11]. Since then, studies have continued to confirm the efficacy and safety of ICG, leading to its widespread adoption in clinical practice. Studies such as those by Richard, et al. [20] have shown that the use of ICG significantly improves the accuracy of parathyroid gland identification compared to traditional imaging techniques. This is especially important in cases where the anatomical position of the glands may vary [12]. Several studies, such as those by Raffaelli, et al. [8] have found that the use of ICG in parathyroidectomy is associated with lower rates of hypoparathyroidism and other complications [8]. The use of ICG may reduce the invasiveness of surgeries, allowing for more gentle interventions, as supported by multiple studies. However, this method also has its drawbacks in use, such as:

1) The need for appropriate fluorescent imaging systems that are unavailable in most medical institutions;

2) The possibility of developing allergic reactions to the introduction of ICG;

3) A decrease in the effectiveness of ICG imaging when the anatomical relationships of organs change due to cicatricial and / or tumor processes;

4) Additional time and financial costs for training medical personnel when introducing ICG technology.

The most important advantage of indocyanine green over other methods is the ability to verify vascularization of the gland with almost 100% sensitivity. High susceptibility of ICG to blood vessels allows surgeons to avoid damaging important structures. Visualization of blood flow allows assessing the state of the parathyroid glands during surgery. These data help to determine which of the glands are functioning normally, which is important for improving calcium control after surgery [21-26]. Fortuny, et al. [19] demonstrated that ICG angiography can reliably predict parathyroid vascularity and obviate the need for calcium supplementation if at least one well-perfused parathyroid gland is identified intraoperatively. Using this technique in 13 patients with HPT, all 4 parathyroid glands were visualized in all cases. A correlation was obtained between parathyroid remnant perfusion and its function in the postoperative period. Thus, it is possible to draw conclusions about the function of the parathyroid glands and predict the occurrence of postoperative hypocalcemia [8,27]. Protoporphyrin IX, which is formed from free 5-aminolevulinic acid (5- ALA, Alasens) and accumulates in the mitochondria of both normal and pathologically altered parathyroid glands, has high fluorophore accumulation properties [43]. Methods for intraoperative identification of parathyroid glands have been proposed (Patent of the Russian Federation No. 2458689 Chissov V.I. et al., 2012).

The procedure is as follows: 5-ALA is administered orally in the preoperative period, the operation is performed with irradiation of the surgical field with polarized blue light [28]. According to the results of the study by Dolidze et al., conducted as part of the study of the pre-, intra- and postoperative period of surgical treatment with intraoperative visualization in patients with parathyroid adenomas, it was proven that the parathyroid gland was visualized in 94% of patients. Also, normalization of the ionized calcium level was noted within 6 months in 100% of patients, a decrease in PTH by more than 50%, and due to clear visualization of the parathyroid gland, no recurrent nerve injury was recorded in any of the cases. This approach, according to the authors, significantly improves the results of surgical treatment of solitary parathyroid adenoma in patients with primary hyperthyroidism [29]. In 2020, Zinchenko SV, et al. described a technique similar to the technique described by Chissov, VI et al. The Russian Federation patent No. 2019142608 “Method for intraoperative identification of hyperplasia and tumors of the parathyroid glands in patients with primary, secondary and tertiary hyperparathyroidism” states that adequate parathyroidectomy in patients with vHPT and tHPT does not require high doses of the drug (in the above-stated 30 mg of Alasens per kg of body weight versus 10-20 mg/kg of body weight).

Reducing the doses of the administered photosensitizer based on 5-ALA made it possible to completely level out the development of photodermatoses. In addition, strict adherence to the time interval of 120 minutes after the administration of 5-aminolevulinic acid in order to create a brighter “glow” of tissues with increased metabolism and a short interval of maintaining visual optical concentration is not required, since the elimination of 5-ALA is significantly extended in patients on programmed hemodialysis [30]. It should also be noted that the only 5-ALA drug produced and used in Russia is Alasens, these names are synonyms in the context of the article [30]. The prospects of this visualization method are undeniable and many studies confirm this thesis. Kalashnikov, et al. conducted a study in which they compared the technique of using 5-ALA in patients with parathyroid adenomas and thyroid pathology. In the group with parathyroid pathology, it was possible to visualize the parathyroid gland in 95% of patients. No phonation disorders or damage to the recurrent nerve were detected, which allows the authors to express an opinion on the need to use photodynamic visualization techniques in the surgical treatment of parathyroid gland diseases [30]. Vshivtsev, et al. in their study of intraoperative visualization of the parathyroid gland using 5-ALA proved that the fluorescence intensity of altered and hyperfunctioning glands was subjectively higher than that of unchanged ones. In all patients in the sample, PTH decreased to normal values in a short time.

No laryngeal paresis was detected, and relapses were not noted in any of the cases. However, the research team rightly noted a significant drawback of the technique: a phototoxic reaction was detected in 2 patients [31]. The “youngest” method of visualizing the parathyroid gland is near infrared autofluorescence (NIRAF). In 2011, Paras et al. presented a new technique for detecting intraoperative parathyroid glands in the near infrared range. The study proved that the fluorescence intensity of the parathyroid gland is higher than that of the thyroid tissue [32]. This was followed by a similar method by MacWade et al. in 2013. In 2014, MacWade, et al. presented the feasibility of near-infrared imaging for intraoperative identification of parathyroid glands using a modified Karl Storz camera [33]. Subsequently, several studies have supported these findings that near-infrared fluorescence can aid in the detection of parathyroid tissue during thyroid surgery. Early studies using near-infrared fluorescence imaging allowed surgeons to scan the surgical field for parathyroid tissue using a camera with a 25 cm field of view, but this requires turning off the operating room lights due to interference between ambient light and the light emitted by the parathyroid glands’ internal fluorophores in the near-infrared optical window [34,35]. Despite the interest of surgeons in the development of the technique, scientific research is limited to single reviews representative of the sample.

A large monocentric prospective study by Akgun, et al. [36] which examined NIRAF images in 1506 normal and 597 altered parathyroid glands, indicates that there are differences between the luminescence intensity of normal and hyperplastic parathyroid glands, where the altered gland is illuminated significantly brighter [37]. Despite the high sensitivity and accuracy stated by the authors, cases of selective approach for a particular patient cannot be excluded. Sometimes small adenomas can be verified by a surgeon as a normally functioning parathyroid gland. Lee, et al. in their study examined NIRAF data in patients who had undergone parathyroidectomy in their anamnesis. From 2017 to 2021, 131 patients with primary hyperparathyroidism underwent parathyroidectomy of 151 parathyroid glands. The mean near-infrared autofluorescence intensity of parathyroid glands was negatively correlated with weight, with lighter glands fluorescing more strongly, and positively correlated with age, with glands in older patients fluorescing more strongly. At the same time, no correlations were found with preoperative blood calcium levels, PTH, BMI, and gender [8,38,39].

The main method of treating secondary and tertiary hyperparathyroidism when conservative therapy is ineffective for 6 months and the threshold PTH value is over 600 pg/ml is surgical intervention. Even for an experienced surgeon, visualization of the parathyroid glands and their complete removal is often an impossible task. Preoperative topical diagnostic techniques for parathyroid glands in vHPT and tHPT have their limitations and cannot fully provide information on the exact number, location and size of the affected parathyroid glands. Therefore, in surgical treatment of vHPT and tHPT, the main emphasis is placed on intraoperative navigation.

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