SHPT is a common complication of CKD and is followed by disorders of calcium and phosphorus metabolism, abnormal PTH secretion, and parathyroid hyperplasia. Serum PTH plays a critical role in the maintenance of calcium and phosphate levels. Unlike PHPT, which is independent of PTH secretion by the parathyroid tissue, in SHPT, compensatory PTH secretion occurs due to hypocalcaemia. Therefore, in patients with SHPT, the serum calcium level can be increased or remain normal. In our study, all patients had increased serum PTH, but only 23.33% of patients showed increased serum calcium. We found that 23 patients showed punctate and annular calcification in the hyperplastic parathyroid glands, and annular calcification might be a special sign of SHPT[28-30]. Soft tissue and vascular calcification is commonly present in end-stage renal disease, secondary to disturbances in the calcium and phosphate balance and HPT, which may explain why the parathyroid glands were more prone to calcification in patients with SHPT[31, 32]. A previous study showed an association between serum ALP and vascular calcification via modulation of the pyrophosphate pathway[33, 34]. Serum PTH can increase bone metabolic conversion to elevate the serum ALP level. Therefore, as we reported, calcification of the parathyroid glands might be correlated with serum PTH and ALP.
For severe SHPT, parathyroidectomy remains the best treatment option when drug treatment fails. However, surgical results among SHPT patients are less satisfactory compared with PHPT due to the incomplete intraoperative identification of all parathyroid glands. Therefore, preoperative imaging and localization are critical to a successful operation. US is the most commonly used imaging modality due to its advantages of low cost and simple manipulation, but it is limited in the detection of ectopic parathyroid glands and is dependent on the examiner’s experience. CT may be necessary to locate parathyroid glands precisely, especially for the ectopic glands in the mediastinum . MRI has the advantage of no radiation and a slightly greater sensitivity than CT, and it is especially useful in detecting mediastinal parathyroid glands. Different from the above anatomical imaging modalities, 99mTc-MIBI imaging is a functional exploration with the advantage of detecting ectopic glands and is based on the different washout rates between the thyroid tissue and hyperplastic parathyroid tissue. Dual-phase 99mTc-MIBI scintigraphy has high sensitivity and specificity but also has multiple limitations, such as the lack of a precise anatomical location of the lesion, which increased the difficulty of distinguishing hyperplastic parathyroid lesions from thyroid lesions. 99mTc-MIBI SPECT/CT is significantly superior to planar imaging in the detection of parathyroid abnormalities because it provides more precise anatomical localization, particularly for ectopic lesions, as well as the identification of supernumerary glands and parathyroid glands with the lowest 99mTc-MIBI uptake[11, 37].
In our study, we directly compared US, dual-phase 99mTc-MIBI scintigraphy, and early and delayed 99mTc-MIBI SPECT/CT in SHPT patients. The overall sensitivity and accuracy of early SPECT/CT were higher than those of the other techniques and slightly higher than those in previous studies[23, 24]. For detecting ectopic parathyroid glands, the sensitivity of early 99mTc-MIBI SPECT/CT was significantly higher than that of US and dual-phase 99mTc-MIBI scintigraphy, and the percentage was similar to that reported in a previous study (90.5%). Our results show that early 99mTc-MIBI SPECT/CT was superior to the other modalities in detecting parathyroid lesions in SHPT patients. Hybrid SPECT/CT can provide not only functional information acquired through SPECT but also an accurate anatomical depiction of the parathyroid gland location and size and adjacent structures through CT, especially in cases of ectopic and supernumerary parathyroid glands. With delayed 99mTc-MIBI SPECT/CT, two investigational groups reported a high sensitivity of 59.3% and 85%, and in our study, the sensitivity was 73.4%. In our investigation, we found that the 99mTc-MIBI uptake of some hyperplastic parathyroid glands on early 99mTc-MIBI SPECT/CT was slightly higher than the background uptake but lower than the thyroid uptake and that further clearance in delayed SPECT/CT caused false-negative results on delayed SPECT/CT. Schachter et al. reported that delayed 99mTc-MIBI SPECT/CT may be nondiagnostic when similar washout rates are found in thyroid and parathyroid tissue. Therefore, we suggest early 99mTc-MIBI SPECT/CT in combination with dual-phase 99mTc-MIBI scintigraphy as the routine preoperative evaluation, while delayed 99mTc-MIBI SPECT/CT may not be necessary due to the involvement of more radiation than early 99mTc-MIBI SPECT/CT alone. Meanwhile, dual-phase 99mTc-MIBI scintigraphy cannot be replaced by early 99mTc-MIBI SPECT/CT because the former provides a rough indication of the presence of an ectopic parathyroid gland and assists in determining the SPECT/CT scan range.
Most patients in our study had four proven lesions, which reminds us to identify as many as four parathyroid lesions as possible when diagnosing SHPT. As we found that all of the calcified parathyroid glands (45 lesions) were confirmed to be parathyroid hyperplasia by pathology, if calcified nodules are observed in the parathyroid region, parathyroid hyperplasia should be suspected. However, large-sample, multicentre studies are still needed to confirm these findings.
The main reason for the low sensitivity of US is believed to be the frequent misdiagnosis of inferior parathyroid lesions, especially mediastinal ectopic parathyroid glands. The examiner’s experience in the accurate determination of lesions is also a critical factor that cannot be ignored. It was reported that the sensitivity of US for diagnosing SHPT ranged from 46.24% to 91.5%[17, 21, 22], which is similar to our result (75.65%).
Our observations show that the sensitivity of dual-phase 99mTc-MIBI scintigraphy was the lowest of the four modalities. The reasons are as follows. First, although dual-phase 99mTc-MIBI scintigraphy can effectively detect ectopic parathyroid glands, only a general increase in radioactivity can be observed, and the number of lesions cannot be clearly distinguished when multiple parathyroid gland lesions are adjacent to each other. Second, some hyperplastic parathyroid glands were positive for p-glycoprotein, and 99mTc-MIBI was quickly eliminated from the parathyroid glands, leading to negative uptake images on scintigraphy. Third, the findings on dual-phase 99mTc-MIBI scintigraphy are related to the size and weight of the parathyroid glands, and smaller parathyroid gland lesions can be easily missed[24, 40]. Fourth, lesions located behind the thyroid gland and with similar 99mTc-MIBI uptake are difficult to detect on scintigraphy but can be identified on SPECT/CT. In a meta-analysis, the pooled sensitivity of dual-phase 99mTc-MIBI scintigraphy in SHPT was 58%, which is slightly higher than our result.
David Taieb et al. reported that the most common causes of false-positive results on parathyroid scintigraphy were the presence of thyroid nodules, thymoma, metastatic and inflammatory lymph nodes, while skeletal brown tumours may also be a rare cause of false-positive lesions. However, in our study, multiple false-positive lesions found on US and early and delayed 99mTc-MIBI SPECT/CT were mostly confirmed to be lymph nodes, followed by thyroid nodules. The most likely explanation for this difference is that we identified fewer false-positive lesions, and all our patients were SHPT patients and not PHPT patients. One false-positive lesion found on dual-phase 99mTc-MIBI scintigraphy was attributed to the focal 99mTc-MIBI uptake of the manubrium sterni. A previous study suggested that the 99mTc-MIBI uptake of bone might reflect the presence of active metabolic bone disease but did not reflect changes that occurred in the microstructure of bone. However, this remains to be evaluated further. In addition, the specificity of early 99mTc-MIBI SPECT/CT in our study is lower than that in a previous study (75%), probably due to the small number of true-negative cases.
Our study is limited by its retrospective design and relatively small cohort of patients. Therefore, future prospective randomized studies of preoperative imaging modalities are needed for more accurate and objective investigations.