Preoperative phosphorus levels may serve as a predictor of recurrent/persistent lesions after surgery for primary hyperparathyroidism: a cross-sectional study

Introduction

Primary hyperparathyroidism (PHPT) is a disease caused by excessive secretion of parathyroid hormone (PTH) due to primary parathyroid disease, which may lead to hypercalcemia, damage to the skeletal or urinary system. Surgery remains the preferred treatment and the only potential cure for PHPT (1,2). Historically, bilateral neck exploration (BNE) was the primary surgical approach for PHPT (3,4); however, in recent years, there has been a gradual shift toward minimally invasive parathyroidectomy (MIP) as the predominant method, as most cases of PHPT (80–90%) are caused by a single parathyroid adenoma (5-10).

The success rate of the surgery is affected by numerous factors. The advent of intraoperative parathyroid hormone (IOPTH) monitoring has further enhanced surgical success rates (11-15). However, not every center is equipped for IOPTH monitoring, just as the First Affiliated Hospital of Zhejiang University is not. The use of IOPTH monitoring can increase both the financial costs and surgical time (16,17). In cases in which preoperative ultrasound and ^99mTc-methoxyisobutylisonitrile parathyroid scintigraphy with single-photon emission computed tomography/computed tomography (^99mTc-MIBI SPECT/CT or MIBI) accurately localize the lesion, some centers that do not use IOPTH monitoring intraoperatively have reported similar success rates to those that routinely employ IOPTH monitoring (18-20).

In addition to IOPTH monitoring, numerous other factors affect the success rate of surgery. We collected data at the Department of Thyroid Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University and conducted several relevant retrospective analysis studies. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-156/rc).

Methods

This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University (No. 20230053) and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. As this was a retrospective study, informed consent was not required.

Patients who underwent surgery for PHPT at the First Affiliated Hospital of Zhejiang University, a tertiary hospital, between August 2017 and June 2022, were initially identified. To be included in the study, the patients had to have complete data, have benign parathyroid disease, and have only undergone parathyroid surgery; otherwise, they were excluded from the study. Due to the retrospective nature of this single-center study and limitations in the sample size, there might be some inherent biases in the results.

All patients in this study underwent routine blood vitamin D level testing, and none exhibited vitamin D deficiency. Since IOPTH monitoring was unavailable at the First Affiliated Hospital of Zhejiang University, all surgeries were performed without it. Rapid intraoperative frozen section pathology was used to confirm the removal of diseased parathyroid. Postoperative success was defined as a ≥50% reduction in PTH levels on the first postoperative day, followed by the normalization of PTH levels. Patients were considered cured if during a follow-up period exceeding 6 months, there was no abnormal increase in the calcium or PTH levels. Recurrence refers to the normalization of PTH and blood calcium levels within 6 months post-surgery, followed by an elevation thereafter. Persistence, on the other hand, denotes an increase in PTH and blood calcium levels within the first 6 months after surgery. And if creatinine levels exceed the normal range, it is considered renal dysfunction.

The following data were collected for all patients: age, gender, surgical method, number of pathological parathyroid glands and their maximum diameter, preoperative image examination data, osteoporosis or fracture (yes/no) (together, they are defined as a new variable: skeletal damage), and postoperative pathology type, as well as urolithiasis, alkaline phosphatase (ALP), creatinine, PTH, calcium, albumin, and phosphorus levels on the first postoperative day and 6 months postoperatively. Additionally, osteoporosis, fracture, and urolithiasis together were defined as a new variable: target organ damage.

Statistical analysis

We analyzed and compared the surgical success rates, cure rates, recurrence rates, and the incidence of persistent lesions. Univariate and multivariate analyses were conducted to identify the risk factors for surgical success, recurrence rates, and the incidence of persistent lesions. The statistical methods used included chi-square tests, t-tests, one-way analysis of variance, multivariate binary logistic regression analysis, and receiver operating characteristic (ROC) curve analysis. All the statistical analyses were performed using International Business Machines Corp (IBM) Statistical Package for the Social Sciences (SPSS) version 24.0. A P value <0.05 was considered statistically significant.

Results

Between August 2017 and June 2022, the data of 255 patients who underwent surgery for PHPT at the First Affiliated Hospital of Zhejiang University were reviewed. After excluding five patients with parathyroid carcinoma, 11 patients with concurrent papillary thyroid carcinoma, and six patients with incomplete data, 233 patients were included in the study. The cohort comprised 76 males (32.6%) and 157 females (67.4%), with a male-to-female ratio of approximately 1:2. The mean age of the patients was 55.08±12.46 years. The mean follow-up duration was 11.30±5.20 months (Table 1).

In this study, IOPTH monitoring was not used in any case. Intraoperative frozen section pathology confirmed that all cases were either parathyroid adenomas or parathyroid hyperplasia. The overall surgical success rate was 97.8%, the cure rate was 89.6%, the recurrence rate was 8.2%, and the persistent lesion incidence was 2.2%. Of the total cases, 208 (89.3%) underwent MIP for a single adenoma, 9 (3.9%) underwent unilateral neck exploration (UNE), and 16 (6.9%) underwent BNE (Table 1). There were no significant differences in the surgical success rate, cure rate, recurrence rate, or persistent lesion incidence among the different surgical approaches (P>0.05).

All patients underwent ultrasound (Figure 1) and ^99mTc-MIBI SPECT/CT (Figure 2) examinations. Compared with postoperative pathology, the accuracy rates for MIBI and ultrasound were 97% and 69.5%, respectively, and the difference between the rates was significant (P<0.05). Postoperative pathology revealed 180 cases of parathyroid adenoma (77.3%) and 53 cases of parathyroid hyperplasia (22.7%); no significant differences were observed in the recurrence or persistent lesion rates (P>0.05).

Figure 1 Ultrasound image of a parathyroid adenoma. The marked area indicates a parathyroid adenoma located on the dorsal side of the lower pole of the thyroid gland.

Figure 2 This is an image of dual-phase ^99mTc-MIBI SPECT/CT or MIBI. The marked area indicates the parathyroid adenoma (arrows). Upper left: plain CT image. Upper right: cross-sectional image of ^99mTc-MIBI SPECT. Lower right: coronal image of ^99mTc-MIBI SPECT. Lower left: fused image of the upper left and upper right images. ^99mTc-MIBI SPECT/CT or MIBI, ^99mTc-methoxyisobutylisonitrile parathyroid scintigraphy with single-photon emission computed tomography/computed tomography.

The univariate analysis of the risk factors for surgical success indicated that preoperative PTH and serum calcium were significantly negatively correlated with surgical success (P<0.05) (Table 2). However, multivariate analysis did not show any significance. The univariate analysis identified preoperative target organ damage, urolithiasis, and preoperative PTH, ALP, and phosphorus levels as risk factors for postoperative recurrence/persistent lesions (P<0.05) (Table 3). The multivariate analysis revealed that only the preoperative phosphorus level was a significant risk factor for recurrence/persistent lesions (P<0.05) (Table 4). In addition, ROC curve analysis showed that blood phosphorus levels below 0.865 mmol/L were associated with a higher incidence of recurrence/persistent lesions, with a sensitivity of 0.718, specificity of 0.67 and youden index of 0.388 (Figure 3).

Figure 3 This is a receiver operating characteristic curve, showed that blood phosphorus levels below 0.865 mmol/L were associated with a higher incidence of recurrence/persistent lesions, with a sensitivity of 0.718, specificity of 0.67 and youden index of 0.388. AUC, area under the curve; CI, confidence interval.

Discussion

Surgery remains the primary treatment for PHPT. With the continuous advancement of imaging technology, the preoperative localization of diseased parathyroid glands has become highly accurate in the vast majority of cases (21-24). Consequently, MIP has emerged as the mainstream approach, replacing BNE (25-29). At the First Affiliated Hospital of Zhejiang University, all the patients underwent preoperative ultrasound and MIBI examinations, 89.3% of the patients suffered from a single parathyroid adenoma, and all of the patients underwent MIP, which is consistent with the literature (5). Our study found no significant differences in the surgical success rate, cure rate, recurrence rate, or incidence of persistent lesions between MIP, UNE, and BNE.

Many studies have shown that IOPTH monitoring can enhance surgical success rates for PHPT (11-15). However, satisfactory surgical outcomes can also be achieved without IOPTH monitoring (18-20). In fact, not all centers have access to IOPTH monitoring. As IOPTH monitoring was unavailable, we used rapid frozen section pathology as an alternative to ensure the accurate removal of the diseased parathyroid tissue. Additionally, we determined the number and location of diseased parathyroid glands based on preoperative examinations, and selected the appropriate surgical method accordingly. For solitary lesions, MIP was performed; for multiple unilateral lesions, UE was performed; and for multiple bilateral lesions or negative ultrasound and MIBI results, BNE was performed. The overall surgical success rate of our study was 97.8%, which is comparable to that reported by other centers (14-19). Some studies suggest that IOPTH monitoring offers little benefit for patients with both positive MIBI and ultrasound results (30,31). Thus, if the number and localization of the lesions are accurately determined preoperatively by high-resolution ultrasound or MIBI, rapid frozen section pathology can achieve satisfactory surgical outcomes even without IOPTH monitoring.

Previous report has indicated that MIBI is more accurate than ultrasound, and is the only method capable of locating ectopic parathyroid glands (32). In our study, MIBI achieved an accuracy rate of 97%, while that of ultrasound was only 69.5% (P<0.05). Ultrasound is a cost-effective examination method; however, it is often limited by thyroid nodules, blood vessels, cervical lymph nodes, and the skill level of the examiner. In our study, diseased parathyroid glands failed to be detected in many ultrasound examinations because they were mistaken for thyroid nodules. Given the close proximity of the parathyroid glands to the thyroid gland, the inexperienced sonographers often misidentified enlarged lesions as thyroid nodules. Thus, MIBI was found to be more reliable than ultrasound in the preoperative localization of diseased parathyroid glands.

In PHPT, elevated PTH and calcium levels, along with decreased phosphorus levels, are correlated with disease severity. Previous studies have shown that preoperative PTH and serum calcium levels, and tumor size are related to the surgical success rates and postoperative recurrence (33-36). In our study, the univariate analysis revealed that higher preoperative PTH and serum calcium were associated with lower surgical success rates (P<0.05). But multivariate analysis failed.

Additionally, the univariate analysis showed that preoperative target organ damage, urolithiasis, and preoperative PTH, ALP, and phosphorus levels were risk factors for postoperative recurrent/persistent lesions (P<0.05) (Table 3). The multivariate analysis revealed that only the preoperative phosphorus level was a significant risk factor for postoperative recurrence/persistent lesions (P<0.05) (Table 4). The ROC curve analysis indicated that a preoperative phosphorus level below 0.865 mmol/L was associated with a higher incidence of recurrent/persistent lesions, and had a sensitivity of 0.718, a specificity of 0.67 and youden index of 0.388 (Figure 3).

Recent study has suggested that the role of phosphates in PHPT may have been underestimated and warrants renewed attention (1). Low serum phosphate levels may indicate a poorer prognosis and a less favorable clinical phenotype for PHPT patients (37). It may be that preoperative phosphorus levels could be used to predict the incidence of postoperative recurrence or persistent lesions, and offer clinically valuable insights for decision making. For example, when evaluating the indications for PHPT surgery, in addition to considering hypercalcemia, more consideration should be given to low blood phosphorus.

This was a retrospective study with a limited sample size, and thus had numerous shortcomings. A multicenter study with a larger sample size may yield more accurate and convincing results.

Conclusions

At centers where IOPTH is unavailable, rapid frozen section pathology can achieve satisfactory surgical outcomes for PHPT. The phosphorus level is a predictor of postoperative recurrence/persistent lesions. These findings may guide clinical decisions. For instance, when assessing the indications for surgery in patients with PHPT, greater attention should be paid to low blood phosphorus levels. Prospective studies with larger sample sizes, conducted across multiple centers may yield more convincing results.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-156/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-156/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-156/prf

Funding: This work was supported by the Basic Public Welfare Research Project of Zhejiang Province (No. LGF22H070004).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-156/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University (No. 20230053). As this was a retrospective study, informed consent was not required.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)