Abstract
Background:
Surgery for irreversible hyperparathyroidism is the preferred management for kidney transplant patients. The authors analyzed the factors associated with persistent hypercalcemia after parathyroidectomy in kidney transplant patients and evaluated the appropriate extent of surgery.
Materials and methods:
The authors retrospectively analyzed 100 patients who underwent parathyroidectomy because of persistent hyperparathyroidism after kidney transplantation at a tertiary medical center between June 2011 and February 2022. Patients were divided into two groups: 22 with persistent hypercalcemia after parathyroidectomy and 78 who achieved normocalcemia after parathyroidectomy. Persistent hypercalcemia was defined as having sustained hypercalcemia (≥10.3 mg/dl) 6 months after kidney transplantation. The authors compared the biochemical and clinicopathological features between the two groups. Multivariate logistic regression analysis was used to identify potential risk factors associated with persistent hypercalcemia following parathyroidectomy.
Results:
The proportion of patients with serum intact parathyroid hormone (PTH) level is greater than 65 pg/ml was significantly high in the hypercalcemia group (40.9 vs. 7.7%). The proportion of patients who underwent less than subtotal parathyroidectomy was significantly high in the persistent hypercalcemia group (17.9 vs. 54.5%). Patients with a large remaining size of the preserved parathyroid gland (≥0.8 cm) had a high incidence of persistent hypercalcemia (29.7 vs. 52.6%). In the multivariate logistic regression analysis, the drop rate of intact PTH is less than 88% on postoperative day 1 (odds ratio 10.3, 95% CI: 2.7–39.1, P=0.001) and the removal of less than or equal to 2 parathyroid glands (odds ratio 6.8, 95% CI: 1.8–26.7, P=0.001) were identified as risk factors for persistent hypercalcemia.
Conclusion:
The drop rate of intact PTH is less than 88% on postoperative day 1 and appropriate extent of surgery for controlling the autonomic function were independently associated with persistent hypercalcemia. Confirmation of parathyroid lesions through frozen section biopsy or intraoperative PTH monitoring can be helpful in preventing the inadvertent removal of a parathyroid gland and achieving normocalcemia after parathyroidectomy.
Keywords: hypercalcemia, hyperparathyroidism, kidney transplantation, parathyroid hormone, parathyroidectomy
Introduction
Highlights
We analyzed factors associated with persistent hypercalcemia after parathyroidectomy.
Kidney transplantation patients with tertiary hyperparathyroidism were selected.
Drop rate of parathyroid hormone levels is less than 88% postsurgery was a risk factor.
Resection of less than or equal to 2 parathyroid glands was also an independent risk factor.
Frozen biopsy and intraoperative parathyroid hormone monitoring can confirm parathyroid lesions.
Secondary hyperparathyroidism occurs as a result of another underlying disease that initially leads to low levels of calcium in the body, such as chronic kidney disease. After a prolonged period of secondary hyperparathyroidism, tertiary hyperparathyroidism (THPT) may develop, which is characterized by autonomous and excessive secretion of parathyroid hormone (PTH) due to intrinsic dysfunction of the parathyroid gland1,2. Secondary hyperparathyroidism usually improves after successful kidney transplantation (KT); however, 20–25% of patients may experience persistently high levels of serum PTH for up to 1 year after KT, and this is more common in patients who have undergone dialysis for extended periods before transplantation3,4.
Clinical manifestations of patients with THPT are similar to those of patients with primary hyperparathyroidism. Increased levels of serum PTH and calcium can lead to adverse events such as renal bone disease, fractures, renal allograft dysfunction, and graft failure5,6. Moreover, THPT increases the long-term risk of cardiovascular disease and mortality7,8. Persistent hypercalcemia following parathyroidectomy can have harmful effects on the renal graft, resulting in tubulointerstitial calcification. However, no specific evidence exists regarding the effect of normocalcemic THPT on renal function following parathyroidectomy9.
Two main options available for THPT treatment: surgical (parathyroidectomy) and medical, with the calcimimetic drug, cinacalcet. Although conflicting studies exist, most research on the two treatments confirms that surgery is more effective than medical treatment in terms of reducing levels of serum PTH and calcium, as well as preserving graft function10–13. Most current recommendations state that prior to surgery, imaging methods including 99mTechnetium methoxy isobutyl isonitrile (99mTc MIBI) and single-photon emission computed tomography/computed tomography (SPECT/CT) should be used to identify ectopic or supernumerary parathyroid glands14. Furthermore, most current recommendations for surgery support total parathyroidectomy with autotransplantation or subtotal parathyroidectomy and relocation of the gland remnants, with an emphasis on the use of intraoperative PTH or autofluorescence15–18.
However, some patients may experience persistent hypercalcemia despite having normal PTH levels, or persistent high PTH levels with normocalcemia, even after undergoing parathyroidectomy. To date, few studies have analyzed the causes of increased serum calcium levels among postoperative laboratory values of patients with THPT.
Therefore, we aimed to investigate the factors that contribute to the development of persistent hypercalcemia in patients with THPT even after parathyroidectomy and evaluate the extent of surgery in THPT after KT.
Materials and methods
Study design and population
We conducted a retrospective analysis of 100 kidney transplant patients who underwent parathyroidectomy for THPT between June 2011 and February 2022 at a single tertiary medical center. Patients were divided into two groups according to their levels of serum calcium: the normocalcemia group, whose serum calcium levels were within the normal range (8.6–10.2 mg/dl) 6 months after parathyroidectomy, and the persistent hypercalcemia group, whose serum calcium levels were greater than or equal to 10.3 mg/dl 6 months after parathyroidectomy. Data regarding KT [dialysis type and duration before KT; type of KT; serum calcium, serum PTH, and serum phosphorus level; and estimated glomerular filtration rate (eGFR) after KT] and parathyroidectomy (type of parathyroidectomy, size of the largest gland, serum calcium level, serum PTH level, eGFR after parathyroidectomy, size and weight of the remnant gland, and missing glands) were collected from electronic medical records. Patients with insufficient or missing data, as well as patients who remained on dialysis after KT were excluded (Fig. 1).
Figure 1.
Flow chart of study patients. KT, kidney transplantation; PTX, parathyroidectomy; THPT, tertiary hyperparathyroidism.
Prior to parathyroidectomy, we conducted ultrasonography and SPECT/CT to confirm the potential ectopic or supernumerary parathyroid glands. This retrospective study received approval from the Institutional Review Board at our institution, and the requirement for obtaining informed consent from patients was waived due to the retrospective nature of the study. The study was registered with the Research Registry, in accordance with the 2013 Declaration of Helsinki by the World Medical Association. The work has been reported in line with the strengthening the reporting of cohort, cross-sectional, and case–control studies in surgery (STROCSS) criteria19.
Definitions
THPT was defined as persistent PTH elevation with hypercalcemia following KT. Persistent hypercalcemia was defined as a serum calcium level of greater than or equal to 10.3 mg/dl 6 months after KT. The duration of dialysis was defined as the total time spent on dialysis before receiving a renal transplant. Subtotal parathyroidectomy was defined as the removal of all parathyroid glands except for a vascularized remnant of the smallest gland. Total parathyroidectomy with autotransplantation was defined as the removal of all parathyroid glands and autotransplantation of a fragment of one gland to either the sternocleidomastoid or brachioradial muscle. GFR was calculated using the Modification of Diet in Renal Disease Study equation (MDRD Study equation). The drop rate of PTH was calculated by comparing the preoperative PTH level just before surgery with the PTH level on postoperative day (POD) 1. Missing parathyroid gland refers to cases where only a portion of the patient’s total parathyroid gland was discovered during the operation.
Statistical analysis
All statistical analyses were performed using IBM SPSS Statistics version 26 for Windows (IBM Corp.). Continuous variables are reported as mean±SD along with their ranges-> deletion and were compared using Student’s t-test. Fisher’s exact test and the χ2 test were used to analyze categorical variables. Receiver operating characteristic (ROC) curves were plotted to analyze the predictive value of a drop in intact PTH level for persistent hypercalcemia. Potential risk factors for persistent hypercalcemia that had a P-value of ≤0.2 in the univariate analysis were included in the multivariate logistic regression model. P-values <0.05 were considered statistically significant.
Results
Clinical characteristics of patients
The patients who underwent parathyroidectomy had the following characteristics after transplantation: persistent elevation of PTH, severe hypercalcemia, persistent hypercalcemia 6 months after KT, and low bone mineral density (Fig. 2). The characteristics of patients after parathyroidectomy in THPT according to the presence of persistent hypercalcemia are enlisted in Table 1. The mean age of patients in the normocalcemia group was lower than that of patients in the persistent hypercalcemia group (48.7±10.9 vs. 54.9±7.5 years, P=0.014). Regarding differences based on the extent of surgery, the proportion of patients who underwent subtotal parathyroidectomy was higher in the normocalcemia group than in the persistent hypercalcemia group (75.6 vs. 45.5%, P=0.002). In terms of the serum intact PTH level before parathyroidectomy, the normocalcemia group had a higher mean PTH level compared to the persistent hypercalcemia group (461±425 vs. 256±143 pg/ml, P=0.029). Although the eGFR did not significantly differ between the two groups before KT, patients in the persistent hypercalcemia group had a higher eGFR at 1 year after KT (67.3±19.8 vs. 74.9±15.4ml/min/1.73 m2, P=0.001) and before parathyroidectomy (65.6±18.9 vs. 76.9±16.7 ml/min/1.73 m2, P=0.017).
Figure 2.
Biochemical characteristics and BMD of patients prior to parathyroidectomy. The numbers of patients with severe hypercalcemia and persistent hypercalcemia may overlap. BMD, bone mineral density; PTH, parathyroid hormone.
Table 1.
Characteristics of patients after parathyroidectomy in tertiary hyperparathyroidism according to the presence of persistent hypercalcemia.
| Mean±SD; Frequency (%) | ||||
|---|---|---|---|---|
| Variables | Normocalcemia (N=78) | Persistent hypercalcemia (N=22) | P | |
| Age (years) | 48.7±10.9 | 54.9±7.5 | 0.014 | |
| Sex | ||||
| Male | 45 (57.7%) | 7 (31.8%) | 0.032 | |
| Female | 33 (42.3%) | 15 (68.2%) | ||
| Serum albumin (g/dl) | ||||
| Before PTx | 3.9±0.2 | 3.8±0.2 | 0.254 | |
| After PTx | 3.9±0.2 | 3.9±0.2 | 0.669 | |
| Serum total protein (g/dl) | ||||
| Before PTx | 6.9±0.4 | 6.8±0.3 | 0.418 | |
| After PTx | 6.9±0.4 | 6.9±0.4 | 0.625 | |
| Dialysis type | 0.184 | |||
| Hemodialysis | 63 (80.8%) | 21 (95.5%) | ||
| Peritoneal dialysis | 15 (19.2%) | 1 (4.5%) | ||
| Type of KT | 0.587 | |||
| Living donor | 27 (34.6%) | 9 (40.9%) | ||
| Deceased donor | 51 (65.4%) | 13 (59.1%) | ||
| Dialysis duration (months) | 118.8±62.8 | 130.0±78.8 | 0.478 | |
| Time interval between KT and parathyroidectomy (months) | 26.0±23.6 | 36.2±33.9 | 0.108 | |
| Type of operation | 0.002 | |||
| Less than subtotal PTx | 14 (17.9%) | 12 (54.50%) | ||
| Subtotal PTx | 59 (75.6%) | 10 (45.5%) | ||
| Total PTx with AT | 5 (6.4%) | 0 | ||
| Size of the largest parathyroid (cm) | 1.6±0.7 | 1.4±0.5 | 0.149 | |
| Serum calcium (mg/dl) | ||||
| Before KT | 10.3±0.9 | 10.5±0.9 | 0.399 | |
| 3 months after KT | 11.3±0.9 | 11.5±0.8 | 0.343 | |
| Before PTx | 11.4±0.8 | 11.4±0.7 | 0.868 | |
| Serum intact PTH (pg/ml) | ||||
| Before KT | 820±585 | 600±468 | 0.116 | |
| 3 months after KT | 366±286 | 295±154 | 0.274 | |
| Before PTx | 461±425 | 256±143 | 0.029 | |
| Serum phosphorus (mg/dl) | ||||
| Before KT | 6.5±1.4 | 6.2±1.3 | 0.076 | |
| 3 months after KT | 2.0±0.4 | 1.9±0.3 | 0.323 | |
| Before PTx | 2.2±0.6 | 2.4±0.6 | 0.380 | |
| eGFR (ml/min/1.73 m2) | ||||
| Before KT | 4.7±1.0 | 4.7±0.8 | 0.001 | |
| 1 year after KT | 67.3±19.8 | 74.9±15.4 | 0.001 | |
| Before PTx | 65.6±18.9 | 76.9±16.7 | 0.017 | |
AT, autotransplantation; eGFR, estimated glomerular filtration rate; KT, kidney transplantation; PTx, parathyroidectomy; PTH, parathyroid hormone.
Clinical outcomes and complications
Postsurgical laboratory values are presented in Table 2. The serum calcium levels were consistently high in the persistent hypercalcemia group during the follow-up period, which included 1 day, 3 months, 6 months, and 1 year after parathyroidectomy (P=0.001). The serum intact PTH level was also higher in the persistent hypercalcemia group on POD1 (P=0.001) and 1 year after parathyroidectomy (P=0.039); however, no significant difference in serum intact PTH levels was observed between the two groups 6 months after the parathyroidectomy. The proportion of patients with a drop in PTH levels of greater than 88% on POD 1 was higher in the normocalcemia group compared to the persistent hypercalcemia group (74.4 vs. 18.2%, P=0.001); additionally, the mean value of the drop rate was higher in the normocalcemia group (90.8±8.5% vs. 70.9±22.2%, P=0.001). Conversely, the proportion of patients with PTH levels greater than 65 pg/ml on POD 1 was higher in the persistent hypercalcemia group than in the other group (40.9 vs. 7.7%, P=0.001).
Table 2.
Postoperative laboratory values.
| Mean±SD; Frequency (%) | ||||
|---|---|---|---|---|
| Variables | Normocalcemia (N=78) | Persistent hypercalcemia (N=22) | P | |
| Serum calcium (mg/dl) | ||||
| 1 day after PTx | 9.1±0.8 | 9.9±0.7 | 0.001 | |
| 3 months after PTx | 9.5±0.5 | 10.5±0.4 | 0.001 | |
| 6 months after PTx | 9.4±0.4 | 10.4±0.7 | 0.001 | |
| 1 year after PTx | 9.4±0.5 | 10.5±0.4 | 0.001 | |
| Serum intact PTH (pg/ml) | ||||
| 1 day after PTx | 30±27 | 68±59 | 0.001 | |
| 6 months after PTx | 119±68 | 137±73 | 0.388 | |
| 1 year after PTx | 108±69 | 159±110 | 0.039 | |
| PTH drop rate of more than 88% on POD1 | 58 (74.4%) | 4 (18.2%) | 0.001 | |
| Mean of drop rate of PTH on POD1 (%) | 90.8±8.5 | 70.9±22.2 | 0.001 | |
| PTH on POD1 (pg/ml) | 0.001 | |||
| <65 | 72 (92.3%) | 13(59.1%) | ||
| >65 | 6 (7.7%) | 9 (40.9%) | ||
| Persistent hyperparathyroidism | 0.041 | |||
| <65 | 24 (30.8%) | 2 (9.1%) | ||
| >65 | 54 (69.2%) | 20 (90.9%) | ||
| eGFR (ml/min/1.73 m2) | ||||
| 6 months after PTx | 60.4±19.4 | 71.9±17.1 | 0.020 | |
| 1 year after PTx | 61.3±21.1 | 71.1±17.0 | 0.117 | |
eGFR, estimated glomerular filtration rate; POD, postoperative day; PTH, parathyroid hormone; PTx, parathyroidectomy.
The status of the resected parathyroid and remnant parathyroid is presented in Table 3. The proportion of patients with more than two resected parathyroid glands was higher in the normocalcemia group (82.1 vs. 45.5%, P=0.001); however, no significant difference in the total weight of the resected parathyroid glands were noted between the two groups. In terms of the number of resected parathyroid glands, in the normocalcemia group, the proportion of patients with 3, 3.5, 4 resected parathyroid glands was 44.9, 26.9, and 6.4%, respectively. Patients with successful resection of three or more parathyroid glands constituted the majority. Conversely, in the persistent hypercalcemia group, this proportion was lower (P=0.02). The proportion of patients with missing parathyroid glands was high in the persistent hypercalcemia group, although this difference was not statistically significant (P=0.051). The perioperative and postoperative complications are presented in Table 4. While there were some complications in the normocalcemia group, no significant difference between the two groups was observed.
Table 3.
Status of resected and remnant parathyroid.
| Mean±SD; Frequency (%) | ||||
|---|---|---|---|---|
| Variables | Normocalcemia (N=78) | Persistent hypercalcemia (N=22) | P | |
| Size of remnant parathyroid (mm) | 6.5±2.3 | 7.2±2.7 | 0.280 | |
| <8 | 45 (70.3%) | 9 (47.4%) | 0.065 | |
| ≥8 | 19 (29.7%) | 10 (52.6%) | ||
| Number of the resected parathyroid gland | 0.001 | |||
| ≤2 | 14 (17.9%) | 12 (54.5%) | ||
| >2 | 64 (82.1%) | 10 (45.5%) | ||
| Weight of the sum of resected parathyroid (mg) | 2341±3490 | 1565±1361 | 0.322 | |
| Mean number of resected parathyroid glands | 3.0±0.7 | 2.6±0.7 | 0.020 | |
| 1.0 | 3 (3.8%) | 0 | ||
| 1.5 | 0 | 1 (4.6%) | ||
| 2.0 | 11(14.2%) | 11 (50%) | ||
| 2.5 | 3 (3.8%) | 0 | ||
| 3.0 | 35 (44.9%) | 5 (22.7%) | ||
| 3.5 | 21 (26.9%) | 5 (22.7%) | ||
| 4.0 | 5 (6.4%) | 0 | ||
| Missing parathyroid glands | 16 (20.5%) | 9 (40.9%) | 0.051 | |
Table 4.
Perioperative and postoperative complications.
| Frequency (%) | ||||
|---|---|---|---|---|
| Variables | Normocalcemia (N=78) | Persistent hypercalcemia (N=22) | P | |
| 0.547 | ||||
| Bleeding | 2 (3.8%) | 0 | ||
| Hypocalcemia | 4 (7.5%) | 0 | ||
| Recurrent laryngeal nerve injury | 1 (1.9%) | 0 | ||
Risk factors for persistent hypercalcemia
The results of the Cox proportional hazard regression analysis are presented in Table 5. The multivariate analysis revealed that a drop in intact PTH levels below 88% at POD 1 (OR 10.28, 95% CI: 2.70–39.13, P=0.001) and the removal of two or less parathyroid glands were independent predictors of persistent hypercalcemia after parathyroidectomy (odds ratio 6.84, 95% CI: 1.75–26.70, P=0.006). ROC curve analysis was performed to evaluate the predictive value of a drop in intact PTH level below 88% on POD 1 for persistent hypercalcemia (Fig. 3). The area under the ROC curve was 0.836 (95% CI: 3.90–43.20, P<0.001), and the optimal cutoff value for the drop rate of PTH at POD 1 was 88%.
Table 5.
Univariate and multivariate logistic regression analysis of risk factors related to persistent hypercalcemia after parathyroidectomy.
| Risk factors | Univariate adjusted OR (95% CI) | P | Multivariate adjusted OR (95% CI) | P |
|---|---|---|---|---|
| Age | 1.07 (1.01–1.13) | 0.017 | 1.05 (0.97–1.14) | 0.255 |
| Male sex | 2.92 (1.07–7.97) | 0.036 | 1.04 (0.24–4.54) | 0.956 |
| Drop rate of intact PTH (<88%) on POD1 | 13.05 (3.94–43.19) | 0.001 | 10.28 (2.70–39.13) | 0.001 |
| PTH level (>65 pg/ml) on POD1 | 8.31 (2.53–27.31) | 0.001 | 4.13 (0.67–25.43) | 0.127 |
| Number of resected parathyroid glands (≤2) | 5.49 (1.98–15.20) | 0.001 | 6.84 (1.75–26.70) | 0.006 |
| Size of remnant parathyroid (≥0.8 cm) | 2.63 (0.92–7.51) | 0.070 | 2.87 (0.64–12.88) | 0.168 |
| Missing parathyroid glands | 2.68 (0.98–7.38) | 0.056 | 0.57 (0.06–5.42) | 0.624 |
OR, odds ratio; POD, postoperative day; PTH, parathyroid hormone; PTH, parathyroid hormone.
Figure 3.
ROC curve of drop rate of parathyroid hormone on POD1 (AUC =0.836, P < 0.001, drop rate of PTH <88% → OR 13.1 [95% CI 3.90–43.20]). AUC, area under the ROC curve; OR, odds ratio; PTH, parathyroid hormone; POD, postoperative day; ROC, receiver operating characteristic.
Management for persistent hypercalcemia after initial parathyroidectomy
We considered both surgical and medical treatments that can modify postoperative persistent hypercalcemia due to failed therapy (Table 6).
Table 6.
Management of persistent hypercalcemia after initial parathyroidectomy at last follow-up.
| Variables | Normocalcemia (N=78) | Persistent hypercalcemia (N=22) |
|---|---|---|
| Persistent hypercalcemia at last follow-up | 17 (observation due to mild hypercalcemia) 1 (reoperation for a missing parathyroid gland) |
|
| Transition from hypercalcemia to normocalcemia at last follow-up | 2 (cinacalcet) 1 (reoperation for a missing parathyroid gland) 1 (reoperation for an ectopic parathyroid at right level 3) |
|
| Recurrent hypercalcemia at last follow-up | 1 (observation due to mild hypercalcemia) |
There were 22 patients with persistent hypercalcemia after the initial parathyroidectomy. Among these 22 patients, 17 were under observation due to mild hypercalcemia. One was under observation because of mild hypercalcemia after reoperation for a missing parathyroid gland.
Two patients transitioned to normocalcemia by taking medication (cinacalcet), while two patients transitioned to normocalcemia by reoperation: one for a missing parathyroid gland and the other for an ectopic location at right level 3.
The median follow-up duration was 23.8 months.
Discussion
In end-stage renal disease, the kidneys fail to excrete phosphorus and produce calcitriol (1,25-dihydroxy vitamin D). This leads to a decrease in serum calcium levels and stimulation of the parathyroid glands, resulting in secondary hyperparathyroidism. In this process, if the parathyroid glands exhibit autonomous function and continuously secrete PTH, it is classified as THPT. In general, secondary hyperparathyroidism resolves after KT, whereas THPT can be distinguished from secondary hyperparathyroidism by the persistence or recurrence of hyperparathyroidism after KT. Accordingly, THPT is characterized by elevated levels of serum PTH and calcium even following KT20,21. High serum levels of PTH are associated with vascular calcification, mineral bone disease, and cardiovascular disease, and can contribute to an increased mortality rate in patients5,6.
Coronary artery occlusive disease is a leading cause of death among dialysis patients and is known to persist after KT, even if the underlying cause is corrected by the transplantation. If predicting the progression to THPT before KT is possible, preventing calcific aortic disease during dialysis might also be possible. Coronary artery calcification progresses when parathyroidectomy is not performed, and appropriate parathyroidectomy can prevent cardiovascular calcification22.
Medical treatment (with calcimimetics) or surgical treatment (parathyroidectomy) are both viable options for addressing THPT. In some cases, treatment with calcimimetics can effectively reduce PTH levels and parathyroid volume; however, its effectiveness is limited when the parathyroid volume is too large. In cases of hyperparathyroidism prior to transplantation, and only 20% of patients treated with calcimimetics experience a reduction in PTH levels and a decrease in parathyroid volume of ~30%23.
In our previous study, we found that parathyroidectomy was more effective than calcimimetics in reducing calcium and PTH levels, and that parathyroidectomy did not have a significant effect on the function or graft outcome of a transplanted kidney24. In addition, persistent hyperparathyroidism can increase the risk of graft failure over an extended time. Therefore, the risk factors for persistent hyperparathyroidism were studied by analyzing data collected before and after KT25,26. Persistent hyperparathyroidism can be predicted in advance during the dialysis stage prior to KT by identifying a pretransplant PTH level of greater than 450 pg/ml as the cutoff value25. Recent studies have reported that performing parathyroidectomy before KT is more effective in preventing persistent hyperparathyroidism and renal allograft failure than performing it after transplantation25,27. At present, the preferred treatment for THPT is either subtotal parathyroidectomy or total parathyroidectomy with autotransplantation28.
For patients undergoing parathyroidectomy because of THPT, the current guidelines aim to achieve and maintain normocalcemia while avoiding postoperative hypoparathyroidism29. In cases where surgical methods are used to regulate PTH levels to within a normal range, postoperative hypoparathyroidism can lead to severe hypocalcemia or complications related to bone health15. On the other hand, in cases where the primary goal of treating hypercalcemia is to restore normal calcium levels, the PTH may remain elevated above the normal range even after calcium levels have returned to normal24. Therefore, in some patients, serum calcium or serum PTH levels may remain elevated even after parathyroidectomy for THPT. For this reason, some endocrine surgeons have become interested in evaluating the success of parathyroidectomy by properly monitoring the drop in PTH levels through intraoperative PTH monitoring30,31.
According to previous studies, elevated serum levels of PTH or calcium during follow-up may indicate the presence of hypertrophic remnant parathyroid glands32,33. Specifically, Numano et al. and Pattou et al. reported that supernumerary glands can lead to persistent hyperparathyroidism even after parathyroidectomy. In our study, the proportion of patients who underwent less than subtotal parathyroidectomy was 17.9% in the normocalcemia group and 54.5% in the persistent hypercalcemia group, and the numbers of resected parathyroid glands in the majority of patients in the normocalcemia group and persistent hypercalcemia group were three and two, respectively. In univariate and multivariate logistic regression analyses, having two or fewer resected parathyroid glands was identified as a risk factor for persistent hypercalcemia following parathyroidectomy. The confirmation of a parathyroid lesion through frozen biopsy or intraoperative PTH monitoring can be helpful in preventing the failure to remove the appropriate volume of the parathyroid gland and achieving normocalcemia following parathyroidectomy.
Schneider et al.34 reported a 97% decrease in PTH levels and a 4% rate of persistent disease in patients with renal hyperparathyroidism who underwent subtotal parathyroidectomy. In our study, the mean drop rate of PTH at POD 1 was higher in the normocalcemia group (90.8%) than in the persistent hypercalcemia group (70.9%), and the proportion of patients with a PTH drop rate greater than 88% was also higher in the normocalcemia group (74.4 vs. 18.2%). Additionally, the serum intact PTH level on POD 1 was lower in the normocalcemia group than in the persistent hypercalcemia group (30 vs. 68 pg/ml), and the incidence of patients with serum intact PTH levels exceeding 65 pg/ml was significantly higher in the persistent hypercalcemia group (40.9 vs. 7.7%). In univariate and multivariate logistic regression analysis, the drop rate of intact PTH less than 88% at POD1 was a risk factor for persistent hypercalcemia following parathyroidectomy. These findings suggest that a low PTH drop rate and a high serum PTH on POD1 may be associated with persistent hyperparathyroidism, and that the 88% PTH drop rate can serve as a useful tool for predicting this condition.
This study has several limitations. First, this was a retrospective study conducted at a single center, which may have led to selection bias. Second, the sample size was too small to establish a statistically significant trend. Third, when considering the etiology of THPT, the histopathological characteristics, such as diffuse hyperplasia versus nodular hyperplasia or the proportion of chief cells and clear cells, must be taken into account, which could not be considered in this study due to a lack of information. Fourth, the value of intraoperative PTH could not be identified because of a lack of intraoperative information. This study included cases where either parathyroid glands were unidentified during surgery or cases where all parathyroids were identified. Where two or more visually normal parathyroid glands were present, this resulted in two or fewer resected parathyroid glands. These cases were confirmed as independent predictors of postoperative hypercalcemia. This could be indicative of certain limitations in the visual assessment of normal parathyroid glands during surgery. Therefore, we recently began intraoperative PTH monitoring to evaluate the drop in PTH levels and confirm the appropriate extent of surgery.
In conclusion, a drop rate of intact PTH less than 88% on POD 1 was independently associated with persistent hypercalcemia, as well as the appropriate extent of surgery to control autonomic function by resecting the appropriate volume of the parathyroid. The confirmation of a parathyroid lesion through frozen biopsy or intraoperative PTH monitoring can be helpful in preventing the inadvertent removal of a parathyroid gland and achieving normocalcemia following parathyroidectomy.
Ethical approval
The present study was approved by the Institutional Review Board of Asan Medical Center (no.2023-0755).
Consent
This study was conducted retrospectively, and obtaining informed consent from patients was not possible. Appropriated procedures and security measures were implemented to ensure data protection and privacy. Identifiable details were not used in the study, and anonymized information was utilized instead.
Sources of funding
This study was supported by a grant (2020IF0006) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
Author contribution
B.-C.K.: data curation, writing – original draft, writing – review and editing; W.W.K.: conceptualization, data curation, methodology, investigation, validation, writing – review and editing; S.J.P.: data curation and resources; D.K.: data curation and resources. J.W.C.: resources and supervision; Y.L.: conceptualization and supervision. T.-Y.S.: conceptualization, resources, and supervision; K.-W.C.: conceptualization and supervision; H.K.: resources and supervision; C.H.B.: resources and supervision; Y.H.K.: resources and supervision.
Conflicts of interest disclosure
The authors declare that they have no financial conflict of interest with regard to the content of this report.
Research registration unique identifying number (UIN)
Name of the registry: The Research Registry.
Unique identifying number or registration ID: Researchregistry9181.
Hyperlink to the registration: https://www.researchregistry.com/browse-the-registry#home/.
Guarantor
Won Woong Kim, M.D. Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-Gil, Songpa-gu, Seoul, 05505, Korea. Tel.: +82 2 3010 3891, E-mail: wonwoong@amc.seoul.kr.
Data availability statement
The data used in this study includes the patient’s private body information and medical information, so it is impossible to share the information for the protection of the patient’s personal information.
Provenance and peer review
No invitation.
Footnotes
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Published online 16 November 2023
Contributor Information
Byung-Chang Kim, Email: gpiaotw@amc.seoul.kr.
Hyosang Kim, Email: mateus@amc.seoul.kr.
Chung Hee Baek, Email: bch393@amc.seoul.kr.
Young Hoon Kim, Email: gskyh@amc.seoul.kr.
Shin Jeong Pak, Email: shinjeongee@naver.com.
Douk Kwon, Email: korltsilva@amc.seoul.kr.
Jae Won Cho, Email: jayisyou@gmail.com.
Yu-mi Lee, Email: niphredil@amc.seoul.kr.
Tae-Yon Sung, Email: tysung@amc.seoul.kr.
Ki-Wook Chung, Email: surgeonckw@amc.seoul.kr.
Won Woong Kim, Email: wonwoong@amc.seoul.kr.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used in this study includes the patient’s private body information and medical information, so it is impossible to share the information for the protection of the patient’s personal information.