Abstract
In this review, we discuss the definition, prevalence, and etiology of sporadic multiglandular disease (MGD), with an emphasis on its preoperative and intraoperative predictors. Primary hyperparathyroidism (PHPT) is the third-most common endocrine disorder, and multiglandular parathyroid disease (MGD) is a cause of PHPT. Hereditary MGD can be definitively diagnosed with detailed family history and genetic testing, whereas sporadic MGD presents a greater challenge in clinical practice, and parathyroidectomy for MGD is associated with a higher risk of surgical failure than single gland disease (SGD). Therefore, it is crucial to be able to predict the presence of sporadic MGD in a timely manner, either preoperatively or intraoperatively. Various predictive methods cannot accurately identify all cases of sporadic MGD, but they can greatly optimize the management of MGD diagnosis and treatment and optimize the cure rate. Future research will urge us to investigate more integrative predictive models as well as increase our understanding of MGD pathogenesis.
Introduction
Primary hyperparathyroidism (PHPT) was originally identified approximately 90 years ago (1). It is the third-most prevalent endocrine illness and the most common cause of hypercalcemia in patients. The vast majority of cases are single gland disease (SGD); the other instances are exceedingly uncommon cases of parathyroid cancer and rare cases of multiglandular parathyroid disease (MGD). MGD is more likely when PHPT is strongly associated with genetic disorders, such as multiple endocrine neoplasms (MEN1, MEN2A, and MEN4), hyperparathyroidism-jaw tumor syndrome (HPT-JT), or familial hyperparathyroidism (2, 3). In genetic disorders, multiglandular involvement is common in MEN (4, 5). In these genetic disorders, detailed family history is the most significant diagnostic tool, followed by genetic screening, when applicable, to identify vulnerable individuals with the proper clinical, laboratory, and pathological results (6). MEN1 and MEN2 are autosomal dominant disorders; germline-inactivating mutations in the MEN1 oncogene can be found in MEN1, and inactivating mutations in the RET gene are present in MEN2A (7, 8). MEN4 syndrome is the result of mutations in the cell cycle-dependent kinase inhibitor 1B (CDKN1B) gene, which encodes the p27 protein (8). In addition, in any instance of sporadic PHPT, MGD should be investigated. Recognizing sporadic MGD is a great challenge based on the clinical practice context. PHPT due to SGD can be cured by minimally invasive parathyroid adenomectomy, but PHPT due to MGD requires bilateral cervical explorations, with an increased risk of postoperative complications and an increased risk of postoperative disease persistence or recurrence (9, 10). To maximize and optimize cure rates, precise prediction of MGD would be helpful in planning for the least invasive operation and guiding patients through the risks and advantages of PHPT surgery. The definition, pathogenesis, etiology, and epidemiology of MGD are the main topics of this review, with a focus on the preoperative and intraoperative predictors of sporadic MGD.
Definition and epidemiology of sporadic MGD
Sporadic primary hyperparathyroidism (SPHPT) is a very frequent condition with an increasing frequency among elderly and female individuals (11). The vast majority of cases are attributable to disseminated uniglandular parathyroid adenomas. Rarely, multiple glands are involved, presenting as multiple adenomas or parathyroid hyperplasia (12, 13). The definitions of parathyroid adenoma, parathyroid hyperplasia, and multiple adenomas have been debated for decades (14), and there is still no consensus on the pathological differential features of adenomatous and hyperplastic parathyroid glands. Traditionally, PHPT with the involvement of multiple parathyroid glands has been referred to as parathyroid hyperplasia (15). However, based on a recent understanding of the underlying pathogenesis of polyclonal tumor proliferation in MGD, the affected parathyroid glands are now also referred to as multi-glandular multiple parathyroid adenomas. The term ‘parathyroid hyperplasia’ is reserved for secondary hyperparathyroidism in the 2022 WHO classification (6, 16). The standard definition of MGD is the presence of histological cellular hyperplasia in more than one gland after surgical and pathological evaluation of any enlarged gland (17). Sporadic MGD, on the other hand, is described on the basis of the exclusion of congenital and familial PHPT. Regarding the definition of MGD, there are different opinions from scholars who believe that the classification criteria for abnormal parathyroid glands should include not only size, histology, and morphology but also function, and that function should be superior to morphology (18, 19, 20). Controversy exists as to which definition is the most reliable, and scholars who do not favor a predominantly functional approach are mainly concerned that an enlarged gland that is temporarily non-secretory may begin to secrete PTH autonomously weeks, months, or years later, ultimately leading to a high rate of recurrence after surgery (21).
The true prevalence of MGD in SPHPT is difficult to determine. Previous studies have reported a wide variation in the prevalence of sporadic MGD, ranging from 2.4% to 34.3% (22, 23, 24). This discrepancy may be due to several reasons, including factors such as population, sample size, different definitions of MGD, sensitivity of parathyroid imaging, experience of surgeons and pathologists, extent of parathyroid surgery, criteria for surgical success, and duration of follow-up (25, 26).
Etiology and pathogenesis of sporadic MGD
Sporadic MGD occurs seemingly in the context of unknown genetic, epigenetic, physiological, or environmental factors leading to increased tumor susceptibility (27), and its etiology is unknown. However, factors such as smaller glands, a history of previous lithium treatment or radiation therapy, and low serum calcium and parathyroid hormone (PTH) levels are more common in patients with MGD (13, 28, 29).
In the case of SPHPT, it is not clear whether MGD represents a neoplastic process or simply that the parathyroid glands are differentially affected and result in asynchronous hyperplasia. Some studies have reported that MGD is a heterogeneous disease, most likely a polyclonal disease (30, 31). At the gene level, Morrison et al. (32) and Velazquez et al. (33) reported most of the genes predicting MGD (FOXG1B, SORBS1, NRXN3, ENC1, HNT, NRP1, MANBA, PHF16, ZMAT4, CDH1, HOOK1, and EGFR). These genes are involved in the pathogenesis of MGD.
Preoperative predictors of sporadic MGD
Age, gender, and weight
Over the past few decades, a large number of scholars have actively studied the preoperative predictors of sporadic MGD (34). PHPT is thought to be most common in older women, but little is known about PHPT in children and adolescents. The few studies that have addressed ‘pediatric PHPT’ have consistently concluded that it manifests itself as a different entity, with more severe symptoms, mostly familial PHPT, and therefore a higher incidence of MGD (35, 36, 37). It is unknown how common sporadic MGD is in this age range. After excluding familial PHPT, which is more prevalent in younger patients, the majority of the research that is now available, however, more or less concurs that age or gender has no bearing on the occurrence of sporadic MGD (22, 38, 39). In exploring the relationship between body weight and sporadic MGD, Glenn et al. (29) were the first to find that obese patients had a higher risk of developing MGD in multivariate analysis. Previous research has postulated an inherent mechanism linking parathyroid dysfunction, obesity, and serum calcium metabolism. It has also been indicated that catecholamine-induced lipolysis may be inhibited by the PTH-dependent rise of intracellular calcium (40, 41).
Neurocognitive disorders
After a thorough evaluation of the literature, we concluded that there is insufficient data at this time to draw any conclusions about a relationship between MGD and clinical symptoms in SPHPT. Notably, a study established a strong correlation between parathyroid hyperplasia and neurocognitive problems (42). In the modern picture, attention has begun to focus on the more ambiguous neurocognitive symptoms such as depression, anxiety, memory loss, poor concentration, sleep disturbances, and cognitive dysfunction that are often present in patients with PHPT, both classical PHPT and mild PHPT (2, 43, 44). Repplinger et al. (42) collected data by means of a preoperative questionnaire from 111 patients, of whom none were diagnosed with MEN. A statistical analysis of the data concluded that the presence of neurocognitive dysfunction in patients with PHPT could be a predictor of parathyroid hyperplasia. Moreover, there was a linear relationship between the number of neurocognitive symptoms and the risk of parathyroid hyperplasia.
Manifestations of SPHPT
The adoption of the routine chemical suite of tests in the 1970s transformed PHPT from a typical, symptomatic disease to a mild, insidious disease. The diagnosis of PHPT is based on biochemical assessment and is typically characterized by elevated serum calcium (calcium >10.5 mg/dL on repeat testing and corrected for albumin) with a corresponding increase in PTH levels (PTH >65 pg/mL) (45). However, there is tremendous variability in the biochemical profile of the disease, with normal hormonal PHPT characterized by elevated serum calcium levels and inappropriately normal PTH levels, a variant first reported by Hollenberg & Arnold in 1991 (46). Normocaloric PHPT, on the other hand, is characterized by normal serum calcium levels and elevated serum PTH levels and may represent an early disease entity, with some patients developing hypercalcemia over time (47). According to a retrospective review of 121 patients at Nantes University Hospital who had mild SPHPT (serum calcium ≤2.85 mmol/L), there is a higher incidence of MGD in patients with mild SPHPT (which includes normohormonal SPHPT and normocaloric SPHPT), particularly in the normocalcemic (normal range 2.20–2.55 mmol/L or 8.80–10.2 mg/dL) SPHPT group (48). Parikh et al. (47) reached similar conclusions in their study.
Imaging
The surgical goal of PHPT is to obtain a safe surgical cure, with the basic prerequisite being the ability to identify all abnormal parathyroid glands, which depends on the accurate recognition and treatment of sporadic MGD. The location of multiple parathyroid adenomas varies; they can occur in the upper and lower parathyroid glands on either the left or right side (49). The ability to identify MGD varies widely depending on the imaging protocol, and preoperative localization imaging of the initial procedure is important to reduce the risk of surgical failure. Diagnostic imaging included ultrasound (US), computed tomography (CT), 99mTc-sestamibi single-photon emission computed tomography (SPECT), 4D-CT, and positron emission tomography/computed tomography (PET/CT).
Ultrasound has been used since the 1970s to localize abnormal parathyroid glands (50), and by the 1990s, its use became more widespread. Previous research on the utility of US to localize MGD has indicated that its sensitivity and specificity are limited and that the technique that gives the optimum benefit ratio is to combine it with other functional imaging tools (51, 52, 53).
SPECT was first described as an imaging modality for detecting parathyroid lesions by Coakley et al. (54) in 1989. Over the years, conflicting conclusions have been reported regarding the sensitivity of SPECT imaging in MGD, which may be attributed to different study design protocols, disease characteristics, and MIBI imaging modalities (55). Overall, for the detection of MGD, SPECT imaging showed low to moderate sensitivity. One study reported that negative preoperative imaging (negative imaging was characterized as no uptake of 99mTc-sestamibi tissue pictures in locations where parathyroid glands could be present) is a strong predictor of sporadic MGD (34). With the use of SPECT/CT and the improved quality of functional and anatomically well-fused imaging, the determination of sporadic MGD remains a major challenge (56). According to Tay et al. (57), the sensitivity of 99mTc-sestamibi SPECT/CT was 78% for SGD and only 31% for MGD.
PET/CT is a more advanced method of imaging the parathyroid glands, with higher spatial resolution and lower radiation exposure than 99mTc-sestamibi SPECT/CT (58). PET/CT has been reported to have some advantages in identifying small glands (less than 1 cm) (53, 59). Because the parathyroid glands in MGD are often tiny (29), individuals with MGD are ideal clinical candidates for PET/CT imaging and may benefit from it. Several PET radiotracers for the localization of parathyroid disease were evaluated, the most commonly used being 11C-methionine (11C-Met) and 18F-fluorocholine (18F-FCH). The use of 11C-Met PET for parathyroid disease first began in 1994 and then gradually evolved into 11C-Met PET/CT (60). There are fewer studies on the use of 11C-Met PET/CT in MGD. Weber et al. (61) analyzed the preoperative Met-PET/CT results of 50 patients with PHPT who had negative MIBI imaging and showed that Met-PET/CT correctly localized five of the six parathyroid glands in three patients with double adenomas. In addition, in a case reported by Hillenbrand et al. (62), both adenomas were detected on preoperative Met-PET/CT examination. The longer half-life of 18F-FCH compared to 11C-Met makes 18F-FCH PET/CT more widely available. In retrospective research encompassing 64 (just one patient with hereditary PHPT) patients with PHPT who had positive 99mTc-sestamibi imaging, 18F-FCH PET/CT offered more data on the number of pathologic parathyroid glands and their localization than 99mTc-sestamibi (63). Another study investigated 17 individuals with SPHPT whose condition was ambiguous or persistent on conventional imaging. The authors discovered MGD in 24% of these patients and correctly isolated six abnormal parathyroid glands in three patients with sporadic MGD (31). The preceding studies have confirmed the value of PET/CT in MGD to some extent, but it is primarily used for diagnostic studies of localization and characterization, and there is still a void in the research on its use as a predictor of MGD, which may certainly be explored in the future.
In 2006, Rodgers et al. (64) first used 4D-CT of the parathyroid glands as a localization tool. 4D-CT utilizes dynamic changes in iodine contrast to identify abnormal parathyroid glands and can accurately identify the anatomical details and functional status of the parathyroid glands (65). Previous studies using 4D-CT have described a range of sensitivities and specificities for sporadic MGD that are generally superior to scintigraphy and US examination but still exhibit low to moderate sensitivity overall (66). More exceptionally, Starker et al. (67) reported a sensitivity of 85.7% (six of seven cases) for localizing MGD lesions with 4D-CT. A report of a 2016 study suggested that the largest candidate lesion found on 4D-CT less than 7 mm had a specificity of up to 79% for MGD, even when only one lesion was found (68).
Preoperative scoring system
Researchers have been working to identify preoperative scoring systems that are predictive of the presence of MGD in order to select the most appropriate surgical procedure. The scoring system can be a biomarker alone or a combination of markers and imaging tests. Examples of this are the CaPTHUS score, the Wisconsin index (WIN score), the 4D-CT MGD score, and the composite MGD score (Table 1). These MGD clinical models emphasize the value of high specificity.
Preoperative scoring models.
| Model | Predictive factors | Points/categories |
|---|---|---|
| CaPTHUS | Total serum calcium level (≥3 mmol/L (≥12 mg/dL)) | 1 |
| Intact PTH level ≥2 times the upper limit of normal intact PTH levels | 1 | |
| Neck ultrasound results are positive for one enlarged parathyroid gland | 1 | |
| Sestamibi scan results positive for one enlarged parathyroid gland | 1 | |
| Concordant sestamibi scan and neck ultrasound results for one enlarged gland on the same side of the neck | 1 | |
| Wisconsin index (WIN) | Multiplication of preoperative serum calcium by preoperative PTH levels | Low (<800) |
| Medium (801–1600) | ||
| High (>1600) | ||
| 4D-CT MGD score | No. of candidate lesions identified on 4D-CT | |
| Single lesion | 0 | |
| ≥2 or no lesion on 4D-CT | 2 | |
| Maximum diameter of largest lesion on 4D-CT | ||
| >13 mm | 0 | |
| 7–13 mm | 1 | |
| <7 mm or no lesions | 2 | |
| Composite MGD score | No. of candidate lesions identified on 4D-CT | |
| Single lesion | 0 | |
| ≥2 or no lesion on 4D-CT | 2 | |
| Maximum diameter of largest lesion on 4D-CT | ||
| >13 mm | 0 | |
| 7–13 mm | 1 | |
| <7 mm or no lesions | 2 | |
| WIN | ||
| >1600 | 0 | |
| 801–1600 | 1 | |
| <800 | 2 |
MGD, multiglandular disease; PTH, parathyroid hormone.
The most commonly used are the CaPTHUS score proposed by Kebebew et al. (69) in 2006 and the WIN score first described by Mazeh et al. (70) in 2013. The dichotomous scoring model CaPTHUS combines preoperative biochemical and diagnostic imaging data, including blood calcium levels (≥3 mmol/L (12 mg/dL)), intact serum PTH levels (≥2 times the upper limit of normal PTH levels), positive neck US and sestamibi scans of one enlarged parathyroid gland, and concordance between the results of the sestamibi and the neck ultrasound (identification of an enlarged parathyroid gland ipsilateral to the neck). CaPTHUS uses a score of 3 as a threshold, and a total score of 3 and above has a 100% positive predictive value for PHPT due to SGD. Therefore, the presence of MGD should be suspected when the total score is below 3. A 2015 study retrospectively analyzed 1421 patients with PHPT who underwent parathyroidectomy at the University of Wisconsin Hospital between 2003 and 2012 and showed that the PPV of a CaPTHUS score of ≥3 predicting SGD decreased to 91%, which may be due to the fact that the CaPTHUS score was applied to a milder PHPT population in that study (71). The following year, a study by Mogollón-González et al. (13) attempted to validate the CaPTHUS model in a southern European population and found that 98%, 97.7%, and 100% of patients with scores of 3, 4, and 5, respectively, had SGD.
The WIN score is based on the product of preoperative serum calcium levels and preoperative PTH levels as a means of predicting the likelihood of the presence of additional hyperfunctioning parathyroid glands. The study by Mazeh et al. (70) categorized patients into three groups: low (<800), intermediate (801–1600), and high (>1600), and developed a nomogram combining WIN scores and parathyroid weights. The results of the study confirmed that the nomogram was accurate in predicting the odds of MGD. Subsequently, the utility of the WIN score was validated by Serradilla-Martín et al. (19) and De et al. (72). Serradilla-Martín et al. (19) found a PPV of 92.5% for SGD when the WIN score was greater than 2000 and the weight of the resected gland exceeded 1 g. De et al. (72) performed the WIN test on 236 patients and showed that the WIN score predicted SGD with a sensitivity of 75.0%, a PPV of 88.8%, and an accuracy of 69.1%. All of the above studies suggest good performance on the CaPTHUS and WIN rating scales, but the identified thresholds do not definitively rule out MGD.
Sepahdari et al. (73) developed a scoring model based on the dimensions of the 4D-CT images (including the size of the largest lesion and the number of suspicious lesions) and a combined score combined with biochemical information (e.g., preoperative calcium and PTH levels and WIN) (Table 1). The two scores were derived from a retrospective analysis of 155 patients from two academic institutions, and the thresholds used to assign score points were based on the size of the lesions and the range of biochemical markers in the previous literature (70). A study by Sepahdari et al. (73) found that higher scores on the 4D-CT MGD score (between 0 and 4) and the composite MGD score (between 0 and 6) tended to favor MGD. In particular, the composite MGD score, with scores of ≥4, ≥5, and 6, had a specificity of 81%, 93%, and 98%, respectively. The following year, Sho et al. (68) prospectively validated these two scoring systems and suggested that the specificity of 4D-CT MGD scores ≥3 and 4 was 74% and 88%, respectively, whereas the specificity of composite MGD scores ≥4, ≥5, and 6 was 72%, 86%, and 100%, respectively. The above studies have shown that both scoring systems can help determine the overall likelihood of MGD even if only one lesion is detected and can identify subsets of patients with a higher likelihood of MGD.
Machine learning
Machine learning (ML) is a growing and emerging field that can be applied to different clinical settings. Broadly speaking, ML is a collection of methods that allow computers to learn rules from existing datasets and synthesize complex combinations of numerous variables in a short period of time to predict disease. Imbus et al. (74) reported two promising approaches to ML and used only biochemical and clinical data to predict MGD. First, to obtain maximum accuracy, RandomTree was used: accuracy 94.1%, sensitivity 94.1%, specificity 83.8%, positive predictive value 94.1%, and area under the subject operating characteristic curve 0.984. Secondly, JRip was used to optimize the PPV of MGD to 100%. A more recent study, on the other hand, utilized a machine learning classifier (MLC) to help identify patients with MGD in whom 99mTc-sestamibi SPECT/CT could not show all parathyroid adenomas (PTAs) (16). It was found that MLC achieved a true PPV of 72% for patients with MGD and that the PTA weights derived from the MLC model trained by preoperative biochemical indices combined with preoperative localized CT images can be applied in the clinical setting.
Intraoperative predictors of sporadic MGD
Weight of first removed gland
Many studies have reported gland weight or size as a predictor of MGD, with a higher likelihood of MGD occurring in smaller abnormal parathyroid glands removed for the first time intraoperatively. A study from the University of Pittsburgh included 1150 patients with sporadic PHPT who underwent parathyroidectomy. They concluded that the risk of developing MGD was significantly higher (from 11.3% to 39.7%) when the first removal of the gland weighed <200 mg compared to the removal of a larger gland (gland weight ≥200 mg) (75). In another 2016 retrospective study, smaller, first-removed abnormal parathyroid glands were an independent predictor of sporadic MGD (29).
Intraoperative parathyroid hormone
Intraoperative parathyroid hormone (IOPTH) monitoring was introduced in 1991 by Irvin et al. (76). Since then, IOPTH has become an essential prerequisite for minimally invasive parathyroid surgery and has progressively become the only clinically accepted direct indicator of successful removal of all PTA. Current research indicates that the IOPTH is a more reliable predictor of MGD, but there is controversy about which IOPTH interpretation criteria are most reliable. A summary analysis of the relevant literature to date shows the following main IOPTH criteria (Table 2).
IOPTH interpretation criteria.
| Criteria | Definition |
|---|---|
| Miami | A drop in PTH level of ≥50% from the highest known PTH level (whether pre-incision or pre-excision of gland) at 10 min after excision of the abnormal gland had been completed |
| Double standard | Based on the Miami criterion, which combines a decrease in PTH of ≥50% with a final PTH level within the normal reference range |
| Vienna | ≥50% decay from a defined ‘baseline’ level (right after induction of anesthesia before skin incision) 10 min after excision |
| Rome | ≥50% IOPTH drop into the normal range at 20 min |
| Halle | IOPTH drop into the low-normal range at 15 min (<35 pg/mL) |
| 75% criteria | ≥75% IOPTH drop into the normal range |
| 72% criteria | An IOPTH drop of 72% was found to have optimal discriminating ability |
IOPTH, intraoperative parathyroid hormone; MGD, multiglandular disease.
The most common is the Miami criterion, which is a decrease in PTH of greater than or equal to 50% within 10 min after removal of the hyperfunctional gland compared with the highest value (before incision or removal). The clinical value of this criterion was fully recognized in the study by Lew et al. (20). Similarly, another study, after evaluating the validity of the Miami criterion and other criteria in the field, concluded that the Miami criterion was the most accurate (77). In addition, some scholars advocate the use of a ‘double standard’, based on the Miami criterion, which combines a decrease in PTH of ≥50% with a final PTH level within the normal reference range, in order to obtain a higher degree of accuracy (78).
In addition, the more studied ones include: (i) Vienna criteria: the first sample (before skin removal and before any neck manipulation) was defined as baseline (BL) PTH, with a ≥50% decrease in IOPTH compared to baseline values within 10 min after removal of the gland; (ii) Rome criteria: ≥50% decrease in PTH from the highest pre-excision value 20 min after removal of the abnormal gland and into the normal range; (iii) Halle's criterion: PTH falls to the lower end of the normal range (PTH <35 pg/mL) within 15 min of removal of hyperfunctional parathyroid tissue (17, 79, 80, 81, 82). Regarding the use of IOPTH interpretive criteria in MGD, different researchers have different recommended protocols. Several studies have concluded that the Rome and Halle criteria are the most effective in detecting MGD (15, 83, 84). In contrast, a study by Riss et al. (79) found that when analyzing patients with SGD and MGD, the accuracy and specificity of applying the Vienna criterion were 92% and 89%, the Miami criterion was 93% and 54%, and the Halle criterion was 72% and 89%, respectively. Therefore, they concluded that it is necessary to recommend the Vienna criterion as a standard for interpreting PTH curves.
Some research groups have argued that the ‘50% drop rule’ tends to miss patients with MGD, resulting in a high rate of surgical failure. They have developed other methods of IOPTH interpretation to help identify patients with MGD. Hughes et al. (85) studied 1855 patients who underwent centralized parathyroidectomy and showed that a ≥75% decrease in IOPTH from baseline and into the normal reference range (‘75% criterion’) increased PPV in MGD from 93.2% to 96.6% compared to the 50% criterion. Another study used ROC analysis for the first time in a large patient cohort, excluding patients with normohormonal or normocaloric PHPT. Their results found that a 72% decrease in IOPTH had optimal discriminatory power for MGD (the ‘72% criterion’). However, this optimal threshold has poor sensitivity and specificity (17).
Overall, intraoperative real-time assessment of PTH is more sensitive than localization tests, but more research is still needed to explore the behavioral differences (or kinetic differences) in IOPTH between the two groups of patients with SGD and MGD and perhaps to develop better criteria for identifying patients with MGD. In addition, it has been shown that IOPTH combined with preoperative imaging is the best predictor of MGD (86).
Conclusion and future directions
Hereditary MGD can be definitively diagnosed in patients with primary hyperparathyroidism using a detailed family history and genetic testing, whereas sporadic MGD is less common in patients with PHPT, where diagnosis and management are more difficult and require multidisciplinary support. It is hypothesized that SGD and MGD are distinct disease entities, but little is known about the etiology and pathogenesis of MGD. Over the past few decades, researchers have worked to explore effective predictors of sporadic MGD, and although there is no single method that can accurately identify all cases of MGD, it is undeniable that these predictors contribute to the diagnosis of sporadic MGD to some extent. Evaluating patients in an integrated manner is becoming increasingly important in the clinical setting. The IOPTH is the most sensitive and widely used clinical predictor, and combining the IOPTH with other adjuncts (clinical, biochemical, and imaging localization) may provide the best results in MGD prediction.
Looking forward, more integrated predictive models need to be explored to help clinicians develop optimal MGD treatment plans and reduce the incidence of postoperative PHPT persistence or recurrence. Meanwhile, the reasons for the occurrence of sporadic MGD are unknown, and there is a need to improve our understanding in these areas in future work.
Declaration of interest
There is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work is supported by the Chongqing Medical Scientific Research Project (2021MSXM087).
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