Hyperparathyroidism (HPT) is a generalized disturbance of calcium (Ca) and phosphate metabolism that occurs as a result of the oversecretion of parathyroid hormone (PTH), and it can involve many of the organs and systems within the human body. The underlying cause of the hypersecretion allows HPT to be subdivided into primary hyperparathyroidism (PHPT), secondary hyperparathyroidism (SHPT), and tertiary hyperthyroidism (THPT) (1). The majority of PHPT cases (95%) occur sporadically, approximately 85% of PHPT patients is caused by a solitary adenoma, and about 15-20% are caused by multiple gland disease (2, 3). Hyperfunctional parathyroid glands overproduce PTH and leads to hypercalcemia. SHPT is one of the most common serious complications in patients with chronic renal failure on long-term hemodialysis. Parathyroid cell proliferation and PTH secretion increased is due to persistent hyperphosphatemia, hypocalcemia and a lack of VD. Most SHPT patients have multiple enlarged parathyroid glands and frequent parathyroid anatomical variations in location (4).The clinical manifestations of HPT are diverse and include urinary calculi, osteopenia, pathological fractures, and skeletal deformity.

The main treatment for PHPT is parathyroidectomy. In the treatment of SHPT, vitamin D receptor (VDRA) and calcium supplement are first used to regulate the treatment. If the drug treatment is not effective, surgical resection of the parathyroid gland can be chosen (5). Due to less operative time and fewer complications than traditional bilateral exploration, minimally invasive parathyroidectomy (MIP) is recommended in HPT (6). The anatomical location of parathyroid glands has a higher probability of variation (7). Therefore, accurate localization before surgery can improve the success rate of surgery. There are three different options, subtotal parathyroidectomy, total parathyroidectomy with or without auto-transplantation in SHPT patients. If the surgeon does not remove all hyperfunctioning parathyroid tissue, the recurrent SHPT would happen. It has also been reported that relapsing hyperparathyroidism by autografted parathyroid tissue may require extensive demolition of surrounding muscle tissue in addition to excision of hyperactive parathyroid tissue (8). Therefore, identification of hyperactive parathyroid tissue preoperatively is important.

Numerous examination medthods were used preoperatively or intraoperatively in localizing the hyperfunctional parathyroid lesions or predicting the presence of multiglandular disease (3, 9–11). There is widespread used of Technetium 99m methoxyisobutylisonitrile (^99mTc-MIBI) dual-phase planar imaging and single-photon emission computed tomography (SPECT) combined with computed tomography (CT)-SPECT/CT fusion imaging in PHPT and SHPT (12–14). It is used for the localization of hyeperfunction parathyroid glands in PHPT and significantly improved the outcomes of patients undergoing minimally invasive parathyroidectomy in PHPT and can also assist surgeons in selecting the lowest degree of PTG hyperplasia which is appropriate to autotransplantation in SHPT (15). However, there are few articles discussed about the differences between the ^99mTc-MIBI uptake in PHPT and SHPT. This study aims to evaluate the features of PHPT and SHPT, and the differences between them, by examining several biomarkers (PTH, alkaline phosphatase [ALP], phosphorus [P] and Ca), the volume of the tumors, and ^99mTc-MIBI uptake in dual-phase planar and SPECT/CT fusion images.

The radiopharmaceutical ^99mTc-MIBI is liposoluble, intracellular, and cationic, and it accumulates in the mitochondria of viable cells by means of an electrochemical gradient due to the activity of respiratory chain (16). It is a radiopharmaceutical commonly used to perform parathyroid scintigraphy, and it can accumulate in abnormal PTG tissues, especially those that are rich in oxyphil cells (17). The sensitivity of ^99mTc-MIBI scan was 100% in oxyphil cell dominant PHPT patients and was 71.2% in chief cell and mixed cell-dominant PHPT patients (18). The study conducted by Cordes et al. (19) demonstrated that in 82% of ^99mTc-MIBI negative cases oxyphil cells were absent. The absence of oxyphil cells, with their large numbers of mitochondria, in PTGs probably lead to a decrease in the number of radiotracer binding sites resulting in negative ^99mTc-MIBI imaging (19). The PTG in true positive ^99mTc-MIBI imaging consisted predominantly of oxyphil cells and opposite in false negative ^99mTc-MIBI imaging (20). SHPT, a common complication of CRF, is characterized by parathyroid hyperplasia consisting mainly of chief cells (21). A meta-analysis showed the sensitivity of ^99mTc-MIBI plannar imaging in SHPT patients was 58% (16). In our study, the ^99mTc-MIBI dual-phase planar imaging in SHPT patients was positive in 13 out of 14 patients. The T/NT ratios of the ^99mTc-MIBI dual-phase planar images were lower in the SHPT patients than in the PHPT patients, but not to a statistically significant degree. The T/NT ratios in the SPECT/CT fusion images, eliminating overlapping effects, were significantly lower of the SHPT patients compared to PHPT. Adenomas were primarily present in the PHPT patients, while hyperplasia was primarily present in the SHPT patients. Parathyroid adenomas and parathyroid carcinomas are mainly composed of a mixture of chief and transitional oxyphil cells (22). Chief cells were found in all parathyroid hyperplasia lesions, and oxyphil cells were found in 67.9% of parathyroid hyperplasia lesions (23).

In our study, all the lesions in PHPT which were pathologically confirmed as adenomas and carcinomas were positive both on the dual-phase ^99mTc-MIBI planar imaging and the SPECT/CT fusion imaging. Among the 14 SHPT patients, 12 had multiple lesions, but not all of the lesions in SHPT were positive on the ^99mTc-MIBI dual-phase planar imaging. The SPECT/CT fusion imaging T/NT ratios were lowest in the NHA subgroups, and highest in the PC subgroup. These findings suggest that ^99mTc-MIBI may uptake less in SHPT than PHPT lesions. There are some studies about the oxyphil cells proportion of parathyroid lesions in the PHPT or SHPT (24, 25), but there is little studies directly compared the oxyphil cells proportion between PHPT and SHPT. The predominant cell type found in PHPT and SHPT lesions may account for the differences in the degree of visualization of different lesions on ^99mTc-MIBI dual-phase planar imaging.

Another factor that influences ^99mTc-MIBI accumulation in the parathyroid glands is the parathyroid lesion size (20). Histopathological examination of the resected glands after surgery revealed that the mean volume of the parathyroid lesions was significantly larger in the PHPT group than in the SHPT group in our study. Other studies have also reported the weight and volume of parathyroid lesions. In PHPT, the median weight of an adenoma was found to be 3.0 g-4.1g (26, 27). While the mean mass of lesions in SHPT was found to be 0.91g (28) and the mean volume of a PTG was 838 ± 939 mm³ in a study with CKD), which is consistent with the present study (29). Elsewhere, in a study of 17 patients, the median weight of parathyroid adenomas gland was larger than of hyperplastic glands with difference (30). The smallest volume in our study was evident in the PH subgroup. Oxyphil cells are larger than chief cells histologically (12–20 and 6–8 μm, respectively) (31). It had a trend towards larger size and weight when the percentage of oxyphil cells >75% in PHPT lesions (25). The volume of lesions decreased as the number of lesions increased (32). Multiple parathyroid lesions are often involved in patients with SHPT. The growth of PTG was stopped by the active form of vitamin D (calcitriol) in chronic renal failure (CRF) patients with comorbid SHPT (33). Most SHPT patients in CKD and SHPT receive vitamin D treatment. Considering the above factors, the difference of volume between PHPT and SHPT is related to oxyphil cells components and disease characteristics.

^99mTc-MIBI SPECT/CT sensitivity is significantly lower in multiple gland disease (MGD) than single-gland disease (SGD) may due to the reason that MGD usually is due to hyperplasia and SGD usually is due to adenoma (32). All the PHPT patients had a single parathyroid lesion identified upon ^99mTc-MIBI dual-phase planar imaging were confirmed by surgery and pathology. Among the 13 SHPT patients with positive ^99mTc-MIBI dual-phase planar imaging result, 11 patients had multiple lesions. In addition, the SPECT/CT fusion imaging found a further eight lesions in these 13 SHPT patients that had no increased ^99mTc-MIBI uptake. Parjeet Kaur et al. (26) suggested that the misdiagnosis of MGD as a single adenoma(SA) on ^99mTc-MIBI scans may be the result of an increased focus on a single enlarged gland, which leads to other small lesions being missed in the context of MGD. The higher rate of negative ^99mTc-MIBI dual-phase planar imaging results in SHPT compared with PHPT may be related to multi-gland hyperplasia.

The study by Min Zhang et al. (34) showed the retention rate of ^99mTc-MIBI in PC lesions was significantly higher than that in benign lesions, and the diameter of PC was larger than adenoma (3). In consist with them, the highest T/NT ratio and the largest volume is both in PC subgroup in our study. Among the pathologic lesions responsible for primary hyperparathyroidism, include adenoma, atypicaladenoma, double adenoma, multigland hyperplasia, and rarely carcinoma, 0.5-2% is parathyroid carcinoma (21). In this study, all 5 cases of parathyroid adenocarcinoma received treatment due to PHPT-related symptoms and were pathologically confirmed as cancer after surgery. We selected ^99mTc-MIBI positive patients with post-operative pathology from suspected HPT patients, so the total number of patients selected was small, leading to selection bias.

There was a significant difference between the mean age of PHPT and SHPT patients in our study. The median age of PHPT patients was 63 year and the median age of SHPT patients was 34 years with significant difference in our study. This result is consistent with the reported mean age of PHPT patients and the group age of SHPT mentioned in the study (2, 35, 36). The age of SHPT patients become younger with the degree of disease (37). With the growth of age or pathological state, the number of eosinophils from the degeneration of the master cells in parathyroid tissues gradually increases (38, 39). In a study of SHPT, the number of focal eosinophilic cells increased with age and the mean age in higher oxyphil cell proportion group was older than in lower group (24). We speculated the difference age between PHPT and SHPT patients may be related to the oxyphil cells.

Our study is limited by its relatively small number of patients and retrospective design which had not analyzed the chief cell and oxphil cell components in the resected lesions. Therefore, future prospective large cohort study needed for analyzing the difference that the uptake of ^99mTc-MIBI and the oxphil content in parathyroid lesions between PHPT and SHPT patients.

In conclusion, the proportion of patients who had a positive result on the ^99mTc-MIBI dual-phase planar imaging was higher in the PHPT group than in the SHPT group, the T/NT ratios on the ^99mTc-MIBI dual-phase planar and SPECT/CT fusion imaging were higher in the former group and the volume of parathyroid lesions involved in SHPT was also smaller than in PHPT. Therefore, it is recommended to combine other technology when ^99mTc-MIBI imaging is negative in patients with SHPT and it should be aware the possibility of cancer when abnormal concentration and large lesions observed in PHPT patients.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethics committee of Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University.

Conception and design of the research: YW and WZ. Acquisition of data: YL and NL. Analysis and interpretation of the data: YW and NL. Statistical analysis: YL. Writing of the manuscript: YW. Critical revision of the manuscript for intellectual content: WZ. All authors contributed to the article and approved the submitted version.