Correlation between preoperative biochemical indices and intraoperative findings in primary hyperparathyroidism

Introduction

Primary hyperparathyroidism (PHPT) is a common endocrine disorder caused by pathological hypersecretion of parathyroid hormone (PTH) from one or more parathyroid glands. Surgical excision of the abnormal parathyroid tissue is the only definitive curative treatment. Precise preoperative imaging localization of parathyroid tumors is critical for choosing proper surgical methods and ensuring successful surgery (1-4), but may be challenging due to the variable size, number, and location of parathyroid tumors (5-7).

Several studies have investigated the association between biochemical indices and parathyroid tumor size, number, location, and imaging results. In these studies, the strength of the correlation of serum PTH and serum calcium (Ca) levels with parathyroid tumor size varies from none [correlation coefficient (r) <0.30], weak (0.30≤r<0.50), to moderate (0.50≤r<0.70) (8-14). Studies investigating the association of biochemical indices with parathyroid tumor number, location, and imaging results are limited and inconsistent. These mixed and fragmented results highlight the need for further investigation into the value of biochemical indices in the preoperative localization of PHPT.

This study aimed to investigate the association between biochemical indices and intraoperative parathyroid tumor size, number, location, and imaging results in a cohort of PHPT patients, and to explore whether these indices can assist in preoperative localization of PHPT. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-465/rc).

Methods

Patients

This retrospective study was conducted at Peking Union Medical College Hospital. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Peking Union Medical College Hospital (No. I-25PJ0848), and individual consent for this retrospective analysis was waived. From June 2020 to August 2022, 511 consecutive patients with surgically confirmed hyperparathyroidism hospitalized in Peking Union Medical College Hospital were included in this study. The inclusion criteria were as follows: (I) diagnosed as PHPT according to Diagnosis and Management of Primary Hyperparathyroidism by the American Medical Association (4); (II) surgically and pathologically confirmed PHPT; (III) older than 18 years old; and (IV) complete clinical, biochemical, and imaging data. The exclusion criteria were as follows: (I) diagnosed as secondary or tertiary hyperparathyroidism; (II) younger than 18 years old; (III) postoperative serum PTH or serum Ca levels did not return to normal, or the postoperative serum Ca level exceeded the upper limit of normal within 6 months; and (IV) patients with multiple endocrine neoplasia (MEN). Finally, 462 PHPT patients were enrolled in this study, and the flowchart is shown in Figure 1.

Figure 1 Flowchart of patients included in the study. Ca, calcium; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone.

Biochemical indices

The Department of Clinical Laboratory measured all biochemical indices. Serum PTH, plasma ionized Ca (iCa), and serum Ca levels were obtained within 1 week (7 days) before surgery. Serum PTH level was measured by an electrochemiluminescence immunoassay (E170; Roche Diagnostics, Basel, Switzerland). Plasma iCa level was measured using a blood-gas analyzer radiometer (ABL800; FLEX, Broenshoej, Denmark) and corrected to pH 7.4. Serum Ca level was determined with a Beckman automatic biochemical analyzer (AU5800; Beckman Coulter, Brea, CA, USA).

Ultrasonography (US)

All US examinations were conducted using a Philips IU22 or EPIQ7 system equipped with a linear-array transducer (L12–5 or L18–4 MHz; Philips, Amsterdam, Holland) and the “thyroid” preset. Examinations were performed with the patient supine and the neck gently extended. Both sides of the neck were scanned from the mandible to the supraclavicular fossa. The location, size, echo pattern, and vascular characteristics of any suspicious lesion were recorded. All US images were reviewed by an experienced sonographer.

^99mTc-sestamibi (^99mTc-MIBI) imaging

Dual-phase parathyroid scintigraphy was performed after the intravenous injection of 740±20 MBq ^99mTc-MIBI (Atom Hitech Co., Ltd., Beijing, China). Early (20 min) and delayed (120 min) planar images were acquired on a conventional γ-camera fitted with a pinhole collimator (E.CAM; Siemens Medical Solutions, Erlangen, Germany). Single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging was subsequently performed on a 64-slice Philips Precedence scanner. An experienced nuclear medicine physician assessed the planar images and SPECT/CT data.

Four-dimensional CT (4D-CT) imaging

4D-CT was obtained on a 128-slice dual-source CT system (Siemens Somotom Definition Flash, Erlangen, Germany) with intravenous contrast (Ultravist, 90 mL, 370 mgI/mL). Patients breathed spontaneously and were scanned from the skull base to the carina in a supine position. Arterial, venous, and delayed phases were acquired at 30, 65, and 115 s postcontrast injection, respectively. Image reconstruction was performed on a Siemens Syngo.Via Workstation (version VA11B_HF03), and assessed by an experienced head and neck radiologist.

¹¹C-choline positron emission tomography (PET)/CT imaging

¹¹C-choline PET/CT was performed on a Siemens Biograph classic scanner equipped with an ECAT HR + PET camera (Siemens, Erlangen, Germany) and a 2-channel helical CT component. Each patient received 385±175 MBq of ¹¹C-choline intravenously. After a 20-minute uptake period, a low-dose CT scan was followed by PET imaging of the neck and upper thorax (three bed positions, 6–9 min per bed). PET data were reconstructed using an iterative algorithm with point-spread-function correction (two iterations, eight subsets, 168×168 matrix, zoom 1.0). An experienced nuclear medicine physician evaluated all images.

Surgical and pathological analysis

Surgery was performed after completing the necessary clinical and imaging examinations. The intraoperative location (left upper, left lower, right upper, right lower, and ectopic), number, maximum diameter, and volume (volume = π/6 × length × width × height) of the parathyroid tumor were recorded during the surgery for subsequent analysis. For patients with multi-gland disease (MGD), the sum of the maximum diameter and volume of all tumors was calculated for analysis. Ectopic hyperparathyroidism was diagnosed when one or more ectopic parathyroid tumors were found during the surgery in a patient. The definition of ectopic tumor included the following locations: mediastinum (the bifurcation of the innominate and carotid arteries, the preaortic region, or the posterior mediastinum below the manubrium level); retroesophageal space; within the carotid sheath; within the thymus; within the thyroid gland (including subcapsular glands); and undescended glands (situated 1 cm superior to the upper pole of the thyroid) (15).

An experienced parathyroid pathologist performed the pathological diagnosis according to the World Health Organization classification criteria (16). Pathological results were considered as the gold standard. The pathological type of parathyroid tumor was classified as parathyroid adenoma, atypical parathyroid tumor, and parathyroid carcinoma.

Statistical analysis

Statistical analysis was done by SPSS Statistics 27.0 (IBM Corp, Armonk, NY, USA) and GraphPad Prism 10 (GraphPad Software, San Diego, CA, USA). The normality of the distribution of quantitative variables was tested using the Shapiro-Wilk test. Nonparametric data were shown as median and interquartile range (IQR). Spearman’s rank correlation coefficient (r_s) was calculated to assess the correlation between biochemical indices and intraoperative parathyroid tumor size (maximum diameter and volume). The r_s was interpreted as follows: no correlation, r_s<0.30; weak correlation, 0.30≤r_s<0.50; moderate correlation, 0.50≤r_s<0.70; strong correlation, r_s≥0.70. The 95% confidence interval (CI) of r_s was also calculated. Based on surgical and pathological findings, imaging results were grouped into true positive (TP) and false negative (FN). In patients with MGD, if tumors were unilateral, the imaging result (US, ^99mTc-MIBI, 4D-CT, and ¹¹C-choline PET/CT) was classified as TP when it detected at least one tumor on the correct side; otherwise, it was classified as FN. For bilateral tumors, the imaging result was classified as TP when at least one tumor was detected on each side; otherwise, it was classified as FN. The comparison of biochemical indices between single-gland disease (SGD) and MGD, orthotopic and ectopic hyperparathyroidism, as well as imaging TP and FN groups, was performed using the Mann-Whitney U test. A P value less than 0.05 was considered statistically significant.

Results

Patients’ characteristics

A total of 462 patients were included in this study. Of the 462 patients, 100 (21.6%) were males, and 362 (78.4%) were females, with a median age of 55 (IQR, 45–63) years. Of the 325 (70.3%) patients with clinical symptoms, 234 (50.6%) had skeletal symptoms, 168 (36.4%) had urinary symptoms, 66 (14.3%) had gastrointestinal symptoms, and 45 (9.7%) had neuromuscular symptoms. Sixteen (3.5%) patients had a previous parathyroid surgery history, 24 (5.2%) patients had a previous thyroid surgery history, and 203 (43.9%) patients had concurrent thyroid disease. The minimum, maximum, and median intervals between the last preoperative blood sample and surgery were 1, 7, and 2 (IQR, 1–4) days, respectively. The median levels of serum PTH, plasma iCa, and serum Ca were 142.5 (IQR, 107.0–212.3) pg/mL, 1.36 (IQR, 1.31–1.43) mmol/L, and 2.72 (IQR, 2.60–2.83) mmol/L, respectively.

A total of 490 parathyroid tumors were found in 462 patients, including 452 parathyroid adenomas and 38 atypical parathyroid tumors. The median parathyroid tumor maximum diameter was 1.70 (IQR, 1.20–2.30) cm, and the median parathyroid tumor volume was 0.53 (IQR, 0.27–1.30) cm³. Among these patients, 435 (94.2%) were SGD and 27 (5.8%) were MDG. Four hundred and twenty-nine (92.9%) patients were orthotopic hyperparathyroidism, and 33 (7.1%) patients were ectopic hyperparathyroidism. For patients with orthotopic hyperparathyroidism, 294 (68.5%) had clinical symptoms, with a median interval of 24 (IQR, 8–60) months between the onset of clinical symptoms and surgery. For patients with ectopic hyperparathyroidism, 31 (93.4%) had clinical symptoms, with a median interval of 44 (IQR, 21–62) months between the onset of clinical symptoms and surgery. Thirty-three ectopic parathyroid tumors were found in 33 patients with ectopic hyperparathyroidism. The locations of these ectopic parathyroid tumors were as follows: 14 in the thymus, 9 in the mediastinum, 5 within the thyroid gland, 3 in the carotid sheath, and 2 in the retroesophageal space. Patients’ characteristics are summarized in Table 1.

Correlation between biochemical indices and parathyroid tumor size

The r_s of serum PTH, plasma iCa, and serum Ca with intraoperative parathyroid tumor maximum diameter were 0.352 (95% CI: 0.269–0.433), 0.342 (95% CI: 0.259–0.422), and 0.224 (95% CI: 0.136–0.309), respectively. The r_s of serum PTH, plasma iCa, and serum Ca with intraoperative parathyroid tumor volume were 0.394 (95% CI: 0.309–0.466), 0.355 (95% CI: 0.272–0.436), and 0.256 (95% CI: 0.169–0.341), respectively. Serum PTH and plasma iCa levels were weakly correlated with intraoperative parathyroid tumor size, while no correlation was found between serum Ca levels and parathyroid tumor size (Spearman’s rank correlation test, P<0.001, respectively) (Figure 2).

Figure 2 Correlation between biochemical indices and intraoperative parathyroid tumor size. (A) Correlation analyses of serum PTH (a), plasma iCa (b), and serum Ca (c) levels with parathyroid tumor maximum diameter. (B) Correlation analyses of serum PTH (a), plasma iCa (b), and serum Ca (c) levels with parathyroid tumor volume. Ca, calcium; iCa, ionized calcium; PTH, parathyroid hormone; r_s, Spearman’s rank correlation coefficient.

Comparison of biochemical indices between SGD and MGD

In SGD, the median serum PTH, plasma iCa, and serum Ca levels were 142.0 (IQR, 107.0–206.3) pg/mL, 1.36 (IQR, 1.31–01.43) mmol/L, and 2.71 (IQR, 2.60–2.82) mmol/L, respectively. In MGD, the median serum PTH, plasma iCa, and serum Ca levels were 171.0 (IQR, 108.0–449.0) pg/mL, 1.36 (IQR, 1.30–1.43) mmol/L, and 2.77 (IQR, 2.56–2.91) mmol/L, respectively. No significant difference was found in serum PTH, plasma iCa, and serum Ca levels between SGD and MGD groups (Mann-Whitney U test, P=0.10, 0.84, and 0.26, respectively) (Table 2).

Comparison of biochemical indices between orthotopic and ectopic hyperparathyroidism

In orthotopic hyperparathyroidism, the median serum PTH, plasma iCa, and serum Ca levels were 139.7 (IQR, 105.6–203.9) pg/mL, 1.36 (IQR, 1.31–1.43) mmol/L, and 2.71 (IQR, 2.60–2.83) mmol/L, respectively. In ectopic hyperparathyroidism, the median serum PTH, plasma iCa, and serum Ca levels were 204.8 (IQR, 142.5–275.3) pg/mL, 1.38 (IQR, 1.29–1.47) mmol/L, and 2.74 (IQR, 2.55–2.93) mmol/L, respectively. Serum PTH levels in ectopic hyperparathyroidism were significantly higher than those in orthotopic hyperparathyroidism (Mann-Whitney U test, P<0.001). However, plasma iCa and serum Ca levels were not significantly different between these two groups (Mann-Whitney U test, P=0.76 and 0.82) (Table 3).

Comparison of biochemical indices between imaging TP and FN groups

US was performed in all 462 patients, ^99mTc-MIBI in 457 patients, 4D-CT in 66 patients, and ¹¹C-choline PET/CT in 47 patients. Among patients who underwent US, 303 were TP and 159 were FN. Among patients who underwent ^99mTc-MIBI, 395 were TP and 62 were FN. Among patients who underwent 4D-CT, 57 were TP and 9 were FN. Among patients who underwent ¹¹C-choline PET/CT, 42 were TP and 5 were FN. Serum PTH, plasma iCa, and serum Ca levels were not significantly different between the imaging (US, ^99mTc-MIBI, 4D-CT, and ¹¹C-choline PET/CT) TP and FN groups (Mann-Whitney U test, P=0.10–0.88) (Table 4). Based on the median serum PTH level (142.5 pg/mL), PHPT patients were divided into the low-PTH group and the high-PTH group. For the low-PTH group, the sensitivities of US, ^99mTc-MIBI, 4D-CT, and ¹¹C-choline PET/CT were 66.1%, 85.0%, 90.0%, and 93.8%, respectively. For the high-PTH group, the sensitivities of US, ^99mTc-MIBI, 4D-CT, and ¹¹C-choline PET/CT were 65.2%, 87.4%, 78.3%, and 87.1%, respectively.

Discussion

This study investigated the association between biochemical indices and intraoperative parathyroid tumor size, number, location, and imaging results in a cohort of PHPT patients. Our results indicated that serum PTH and plasma iCa levels were weakly correlated with intraoperative parathyroid tumor size, and serum PTH levels tend to be associated with ectopic hyperparathyroidism.

Most studies reported that serum PTH levels were weakly correlated with parathyroid tumor volume (0.30≤r<0.50), whereas serum Ca levels were not (r<0.30) (8-14). In a cohort study involving 1,086 PHPT patients, the r of serum PTH and serum Ca levels with parathyroid tumor volume were 0.50 and 0.338, respectively (13). A retrospective study of 2,000 PHPT patients reported that serum PTH levels were weakly correlated with parathyroid tumor volume (r=0.37), whereas serum Ca levels were not (r=0.28) (8). Our results were consistent with these findings. In addition, we introduced plasma iCa into our analysis. Plasma iCa is the biologically active form of Ca and is not influenced by serum albumin. It is commonly used in clinical practice and can provide the most clinically relevant assessment of Ca status (17-20). Our results indicated that plasma iCa levels were weakly correlated with intraoperative parathyroid tumor volume. It is not readily clear why the present results show only a weak correlation of serum PTH and plasma iCa levels with parathyroid tumor volume. One possible reason could be that the varying proportions of chief, transitional, oncocytic, and water-clear cells occupying parathyroid tumors impact the biochemical indices, with chief cells thought to be the primary secretory cells in the parathyroid glands (16,21). In addition to tumor volume, we investigated the association between biochemical indices and intraoperative parathyroid tumor maximum diameter, and found that serum PTH and plasma iCa levels were weakly correlated with intraoperative parathyroid tumor maximum diameter. This suggests that, as simple and convenient parameters, serum PTH and plasma iCa levels can roughly indicate intraoperative parathyroid tumor size in clinical practice.

We found significantly higher serum PTH levels in ectopic hyperparathyroidism than in orthotopic hyperparathyroidism, which was consistent with Durmuş et al.’s results (22). For instance, a 67-year-old female PHPT patient had a serum PTH level of 449 pg/mL, whose preoperative US and ^99mTc-MIBI results were negative. Subsequent 4D-CT identified a suspicious parathyroid tumor measuring 1.2 cm × 1.6 cm × 0.7 cm in the retroesophageal space, which was confirmed by surgical pathology. The reason for higher serum PTH levels in ectopic hyperparathyroidism remains unclear in existing studies. Previous studies have found that ectopic parathyroid tumors may be more aggressive compared to parathyroid tumors in classical localizations, which may be a potential reason (16,22). Our results indicated that clinical symptoms were more pronounced in patients with ectopic hyperparathyroidism, and the interval between the onset of clinical symptoms and surgery was significantly longer for patients with ectopic hyperparathyroidism than for those with orthotopic hyperparathyroidism. These factors may account for the higher serum PTH levels in ectopic hyperparathyroidism. Previous studies also reported significantly higher serum Ca levels in ectopic hyperparathyroidism than in orthotopic hyperparathyroidism (22,23), which was not observed in our research. Further studies are needed to explore whether serum PTH and Ca levels are different between the ectopic and orthotopic hyperparathyroidism.

A few studies focused on the differences in biochemical indices between SGD and MGD and presented inconsistent results (24-26). A multicenter study involving 517 PHPT patients (491 with SGD and 126 with MGD) reported that serum PTH and serum Ca levels were not significantly different between SGD and MGD (24). Another study observed 191 patients (155 with SGD and 36 with MGD) and found significantly higher serum PTH and serum Ca levels in patients with SGD (25). Our study involved 462 PHPT patients (435 with SGD and 27 with MGD) and found no significant difference in serum PTH, plasma iCa, and serum Ca levels between SGD and MGD. These inconsistent results may be related to the differences in patient selection and MGD proportion.

In the current study, we investigated the association of biochemical indices with US, ^99mTc-MIBI, 4D-CT, or ¹¹C-choline PET/CT results. Previous studies reported significantly higher serum PTH levels in ^99mTc-MIBI TP patients than in ^99mTc-MIBI FN patients (27-31). In contrast to previous studies, we found no association between serum PTH levels and ^99mTc-MIBI results. Our findings and those of previous studies suggest that serum PTH levels had no association with US or 4D-CT results, nor did serum Ca levels with US or ^99mTc-MIBI results (27-32). None of the previous studies provided any information on the association of serum PTH or serum Ca levels with ¹¹C-choline PET/CT results. The studies about the usefulness of serum PTH and Ca for imaging localization are relatively few and preliminary; therefore, more studies are needed.

The major strength of our study is that we comprehensively investigated the value of serum PTH, plasma iCa, and serum Ca levels in preoperative localization of PHPT from the aspects of parathyroid tumor size, number, location, and imaging results in a cohort of PHPT patients. However, some limitations of our study should also be mentioned. First, it was a single-center retrospective study, which was subject to the limitations inherent in this type of study design. Multicenter prospective studies are needed to validate our findings. Second, biochemical indices in our study were obtained relying on a single preoperative measurement, without accounting for potential influencing factors such as disease chronicity, medications, vitamin D status, hydration, preoperative endocrinologic management, serum albumin, sample handling and storage conditions, and the time between sample collection and processing. These factors can substantially affect biochemical indices and may partly explain the weak correlations we observed. We did not establish the multivariate model because the data on these potential influencing factors were not systematically collected. Third, this study was limited by its relatively small sample size, especially the number of patients with ectopic hyperparathyroidism and those who underwent 4D-CT or ¹¹C-choline PET/CT. Fourth, previous studies pointed out that invasive intraoperative localization tools, such as rapid PTH gradients from the internal jugular veins, can help lateralize disease or detect mediastinal or multiglandular involvement (33,34). This contrasts with the limitations of conventional preoperative biochemical indices.

Conclusions

Serum PTH and plasma iCa levels were weakly correlated with intraoperative parathyroid tumor size. Higher serum PTH levels tend to be associated with ectopic hyperparathyroidism. The ability of biochemical indices to reliably predict parathyroid tumor anatomical features (size, number, or location of glands) appears to be limited.

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-aw-465/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-465/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-465/prf

Funding: This work was supported by the National High Level Hospital Clinical Research Funding (Nos. 2022-PUMCH-B-065 and 2022-PUMCH-B-064).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-465/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Peking Union Medical College Hospital (No. I-25PJ0848), and individual consent for this retrospective analysis was waived.

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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