Abstract
Background
Primary hyperparathyroidism (PHPT) is increasingly diagnosed as asymptomatic due to routine biochemical screening. While parathyroidectomy (PTX) is the definitive treatment, age-specific management strategies for asymptomatic patients remain contentious, particularly in patients >50 years. Current evidence lacks detailed comparisons of disease characteristics and surgical outcomes across age-stratified asymptomatic cohorts. This study aims to bridge this information gap.
Methods
This retrospective cohort study analyzed 199 asymptomatic PHPT patients who underwent PTX at Shanghai Sixth People’s Hospital between 2017 and 2024. Data regarding demographics, biochemical parameters, imaging data, surgical details, complications and outcomes were collected and compared by age at diagnosis (≤50 or >50 years).
Results
Among 199 patients who underwent PTX, 128 (64.3%) were >50 years old and 71 (35.7%) were ≤50. Patients in the younger cohort (≤50 years) exhibited significantly lower preoperative 25-hydroxyvitamin D levels (P<0.001), larger parathyroid adenomas (P=0.049), stronger correlations between adenoma volume and preoperative serum parathyroid hormone (PTH) and calcium levels (P<0.001), longer operative durations (P=0.01), and higher rates of endoscopic parathyroidectomy (EPTX) (P<0.001). Quadrant-level localization accuracy via ultrasonography was significantly higher in younger patients (85.5% vs. 71.9%; P=0.03; V=0.15). Transient hypocalcemia occurred more frequently in patients ≤50 years (18.3% vs. 13.3%), although this difference was not statistically significant (P=0.34). No significant intergroup differences were observed in other postoperative complications or cure rates.
Conclusions
Patients ≤50 years demonstrated superior preoperative localization accuracy, which was associated with larger tumor size. Patients >50 years exhibited a non-significantly lower trend in transient hypocalcemia. Both age cohorts achieved comparably high surgical cure rates, supporting the efficacy of PTX across age groups for asymptomatic PHPT.
Keywords: Asymptomatic primary hyperparathyroidism (asymptomatic PHPT), age, parathyroidectomy (PTX), endocrine surgery, preoperative imaging examination
Highlight box.
Key findings
• Younger asymptomatic primary hyperparathyroidism (PHPT) patients (≤50 years) presented with significantly lower preoperative vitamin D levels, larger parathyroid adenomas, and stronger correlations between adenoma volume and serum parathyroid hormone (PTH)/calcium.
• Preoperative ultrasonography provided superior quadrant-level localization accuracy in patients ≤50 years (85.5% vs. 71.9%).
• Surgical cure rates were equally high in both age cohorts.
What is known and what is new?
• Parathyroidectomy (PTX) is the definitive treatment for PHPT. Management of asymptomatic patients, particularly those >50 years, remains debated, and evidence directly comparing age-stratified cohorts is limited.
• This study provides a detailed comparison of disease characteristics and surgical outcomes between asymptomatic patients ≤50 and >50 years. It identifies distinct clinical and surgical profiles, including better preoperative localization in younger patients, likely due to larger adenoma size, while confirming high cure rates across all ages.
What is the implication, and what should change now?
• PTX is highly effective for asymptomatic PHPT regardless of age. Age-specific differences in adenoma size and localization accuracy suggest tailored preoperative planning could be optimized. Age should not be a barrier to surgical referral for asymptomatic PHPT. Clinicians should be aware of the potential for more challenging localization in older patients.
Introduction
Primary hyperparathyroidism (PHPT) is an endocrine disorder caused by the overproduction of parathyroid hormone (PTH), leading to hypercalcemia and hypophosphatemia (1). Clinical manifestations typically include bone pain, osteoporosis, and nephrolithiasis (2,3). Following the introduction of multichannel autoanalyzer in the 1970s, routine serum calcium screening became widely implemented (4), leading to the incidental diagnosis of over 80% of PHPT cases in developed countries as asymptomatic. Asymptomatic PHPT is characterized by the absence of overt symptoms or signs referable to the skeletal, renal, gastrointestinal, or neuromuscular systems. The condition is most often detected incidentally during the clinical evaluation of incidentally discovered hypercalcemia, elevated PTH levels, osteoporosis, or parathyroid tumors (5). However, even incidentally diagnosed asymptomatic patients exhibit measurable objective signs, such as reduced cortical bone density, hypercalciuria, nephrocalcinosis, or diminished creatinine clearance (3,6). In developing countries, routine biochemical screening has also become increasingly prevalent. As highlighted in our prior research, the incidence of asymptomatic PHPT is rising steadily (7). However, the conventional definition of “asymptomatic” PHPT is increasingly debated, as evidence suggests associations between PHPT and poorly characterized subjective symptoms—including neurocognitive dysfunction such as insomnia, depression, and anxiety—many of which demonstrate postoperative improvement following parathyroidectomy (PTX) (8,9).
Despite evolving clinical presentations, PTX remains the only definitive cure for all patients with PHPT, particularly those with symptomatic disease (10-12). For asymptomatic individuals, this intervention has also been shown to halt or even reverse end-organ damage caused by PHPT, including reducing the risk of nephrolithiasis and improving bone mineral density (BMD) (4,12-14). The latest guidelines from the American Association of Endocrine Surgeons (AAES) recommend that all symptomatic patients and those with overt disease manifestations have clear indications for surgical intervention (15). However, the role of age in treatment decisions for asymptomatic patients remains contentious. The 4th International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism advocates PTX for younger patients (≤50 years), a threshold primarily justified by the higher lifetime risk of disease progression in younger patients, and those with specific biochemical abnormalities (16).
Age ≤50 years has consistently been an indication for PTX. However, few studies have compared disease characteristics and therapeutic outcomes among patients near this age threshold, particularly within the growing asymptomatic cohort. Existing research predominantly emphasizes population-level commonalities in PHPT, with limited investigation into age-specific pathophysiological or prognostic variations (17). This retrospective cohort study synthesized demographic, biochemical, and postoperative follow-up data to elucidate age-related variations in clinical and biochemical profiles among asymptomatic PHPT patients. We further evaluated the therapeutic efficacy of PTX across age-stratified subgroups, establishing evidence-based foundations for individualized clinical management. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-592/rc).
Methods
A retrospective cohort study was conducted on asymptomatic PHPT patients who underwent PTX (n=199) at the Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China) between January 2017 and December 2024. All enrolled patients met the updated surgical criteria outlined by the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism (Table S1). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Shanghai Sixth People’s Hospital (No. 2025-KY-004). Informed consent was taken from all the patients. Clinical data were retrospectively collected from institutional electronic medical records.
The diagnosis of asymptomatic PHPT was established according to the diagnostic framework recommended by the Fourth International Workshop on Asymptomatic PHPT (16), the key guideline contemporaneous with our study period (2017–2024). Symptomatic PHPT was defined by the presence of classic, objective complications, specifically nephrolithiasis or overt bone disease. Patients were classified as having asymptomatic PHPT if their condition came to clinical attention incidentally during investigation of unrelated issues or routine laboratory testing. Although some patients subsequently underwent evaluation that revealed low BMD on dual-energy X-ray absorptiometry (DXA) or imaging evidence of nephrolithiasis, these findings did not reclassify them as symptomatic; instead, the terminology was adjusted to indicate the presence of target organ involvement. Nonspecific, subjective symptoms (e.g., fatigue, depression, anxiety, difficulty concentrating) were not considered definitive for symptomatic classification, and patients presenting solely with such symptoms were consistently categorized as asymptomatic. Inclusion criteria comprised asymptomatic PHPT patients with complete clinical data who underwent PTX and had postoperative histopathological confirmation of parathyroid hyperplasia, adenoma, or carcinoma. Exclusion criteria comprised: (I) postoperative histopathological confirmation of normal parathyroid tissue; (II) severe renal dysfunction (estimated glomerular filtration rate <45 mL/min/1.73 m2); (III) incomplete clinical documentation; (IV) patients with known or suspected hereditary forms of hyperparathyroidism; (V) preoperative administration of calcium, calcimimetic, vitamin D, or vitamin D analogs. The final study cohort comprised 199 eligible patients stratified by age into two groups: ≤50 years (n=71) and >50 years (n=128) (Figure S1).
This study collected demographic parameters, laboratory assessments, imaging data, and operative information. Laboratory assessments included PTH, 25-hydroxyvitamin D [25(OH)D], electrolytes and alkaline phosphatase (ALP) levels. All patients underwent at least one preoperative localization imaging (neck ultrasound or 99mTc-sestamibi scan). Operative information encompassed surgical duration, operative approach, and characteristics of resected pathological parathyroid glands including number, location, size, and histopathological findings. The histological diagnosis of parathyroid carcinoma and atypical parathyroid tumors was established according to the 2022 World Health Organization (WHO) classification (18). Carcinoma was defined by the presence of unequivocal invasive features (angioinvasion, lymphatic invasion, perineural invasion, local tissue invasion, or metastasis). Atypical tumors were defined as exhibiting worrisome histological features (band-like fibrosis, cytologic atypia, increased mitotic activity) but lacking definitive invasion. All diagnoses were confirmed by consensus of two experienced endocrine pathologists. Postoperative outcomes comprised cure rates and complication incidence. Serum calcium and PTH levels were quantified at 06:00 on postoperative day 1. Postoperative monitoring at regular intervals assessed PTH levels through the 6-month postoperative period.
Statistical analysis
Statistical analyses were conducted using IBM SPSS Statistics 25.0 (IBM Corp., Armonk, NY, USA). Categorical variables are reported as frequencies (percentages). Continuous variables with normal distribution are expressed as mean ± standard deviation (SD), while non-normally distributed continuous or ordinal variables are presented as median [interquartile range (IQR)]. Intergroup comparisons employed Student’s t-test or Mann-Whitney U test for continuous variables, and chi-square or Fisher’s exact test for categorical variables. Correlation analysis utilized Pearson correlation coefficients for normally distributed continuous variables and Spearman correlation coefficients for non-normally distributed continuous or ordinal variables. Cramér’s V coefficient is a measure of association strength based on the chi-square statistic, providing an effect size interpretation for the chi-square test. All tests were bilateral, and statistical significance was defined as P<0.05.
Results
Increased number of asymptomatic PHPT patients
Between January 2017 and December 2024, a total of 199 asymptomatic patients underwent PTX for PHPT. The cohort comprised 144 females (72.4%) and 55 males (27.6%), with a median age of 55 years (Table 1). Over the eight-year study period, both the absolute number of asymptomatic PHPT patients and their proportional representation among all PHPT cases demonstrated a progressive increase (Figure 1). By 2024, the annual caseload had nearly doubled compared to 2017, reflecting heightened diagnostic awareness and expanded biochemical screening practices.
Table 1. Pre-operative characteristics of asymptomatic PHPT patients, whole cohort and stratified by age.
| Characteristics | Whole cohort (n=199) | Age ≤50 years (n=71) | Age >50 years (n=128) | P value |
|---|---|---|---|---|
| Age (years) | 55 (45, 66) | 40 (32, 46) | 62 (56, 70) | <0.001* |
| Gender | 0.26 | |||
| Male | 55 (27.6) | 23 (32.4) | 32 (25) | |
| Female | 144 (72.4) | 48 (67.6) | 96 (75) | |
| BMI (kg/m2) | 22.84 (20.98, 24.89) | 22.58 (20.83, 24.46) | 22.98 (21.09, 25.31) | 0.35 |
| Comorbidity | <0.001* | |||
| No | 144 (72.4) | 65 (91.5) | 79 (61.7) | |
| Hypertension | 43 (14.0) | 4 (5.6) | 39 (30.5) | |
| Diabetes | 4 (1.3) | 0 (0.0) | 4 (3.1) | |
| Both | 8 (2.6) | 2 (2.8) | 6 (4.7) | |
| Preoperative serum PTH (pg/mL) | 128.00 (92.81, 198.60) | 131.80 (97.04, 202.2) | 123.95 (87.57, 198.53) | 0.48 |
| Preoperative serum 25-hydroxyvitamin D (nmol/L) | 16.56 (11.94, 28.18) | 13.36 (9.83, 17.51) | 17.67 (14.13, 22.75) | <0.001* |
| Preoperative serum Ca (mmol/L) | 2.68 (2.56, 2.81) | 2.70 (2.55, 2.80) | 2.67 (2.56, 2.81) | 0.65 |
| Preoperative serum Mg (mmol/L) | 0.90 (0.84, 0.96) | 0.88 (0.80, 0.94) | 0.92 (0.86, 0.98) | 0.009* |
| Preoperative serum P (mmol/L) | 0.89 (0.78, 0.97) | 0.88 (0.78, 0.94) | 0.91 (0.78, 1.00) | 0.10 |
| Preoperative serum ALP (U/L) | 92.0 (72.0, 125.0) | 84.0 (65.0, 129.0) | 95.0 (74.0, 121.9) | 0.28 |
Data are presented as median (Q1, Q3) or n (%). P values were derived from Student’s t-test (for normally distributed continuous variables), Mann-Whitney U test (for non-normally distributed continuous variables), or Chi-square test (for categorical variables). *, P<0.05. ALP, alkaline phosphatase; BMI, body mass index; Ca, calcium; Mg, magnesium; P, phosphate; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone.
Figure 1.
Annual asymptomatic PHPT number and proportion. PHPT, primary hyperparathyroidism; PTX, parathyroidectomy.
Clinical and biochemical characteristics
A total of 199 patients diagnosed with asymptomatic PHPT were included in this study. Patients were stratified by age into two groups: ≤50 years (n=71; median age: 40 years, IQR: 32–46 years) and >50 years (n=128; median age: 62 years, IQR: 56–70 years). No statistically significant differences were observed between the two age groups regarding baseline demographic characteristics, including gender distribution (P=0.26) and body mass index (P=0.35). However, a significant difference was noted in the prevalence of comorbidities. Patients in the >50 years group exhibited a significantly higher rate of having at least one comorbidity compared to the ≤50 years group (38.3% vs. 8.5%, P<0.001). Analysis of preoperative serum biochemical parameters revealed no significant differences between the age groups in levels of PTH (P=0.48), calcium (P=0.65), phosphate (P=0.10) or ALP (P=0.28). Conversely, preoperative 25(OH)D levels were significantly higher in the >50 years group than in the ≤50 years group (P<0.001). Furthermore, preoperative serum magnesium levels were also significantly elevated in the older group compared to the younger group (P=0.009).
Operative information by age
The operative information stratified by age groups are summarized (Table 2). Compared to patients aged >50 years, those ≤50 years demonstrated significantly longer operative duration (P=0.01) and a higher rate of endoscopic parathyroidectomy (EPTX) (P<0.001). Significant volumetric differences were observed, with patients aged >50 years exhibiting smaller parathyroid adenomas (P=0.049). The mean volume of resected parathyroid glands was 0.98 cm3 (range: 0.02–6.83 cm3). A statistically significant positive correlation existed between adenoma volume and both preoperative PTH and serum calcium level (Figure 2A-2D). This association was markedly stronger in patients aged ≤50 years compared to older counterparts. No significant intergroup differences existed in gland multiplicity, anatomical location or pathological subtypes.
Table 2. Operative information of asymptomatic PHPT patients, whole cohort and stratified by age.
| Characteristics | Whole cohort (n=199) | Age ≤50 years (n=71) | Age >50 years (n=128) | P value |
|---|---|---|---|---|
| Surgery type | <0.001* | |||
| Open surgery | 185 (93.0) | 59 (83.1) | 126 (98.4) | |
| EPTX | 14 (7.0) | 12 (16.9) | 2 (1.6) | |
| Operative duration (min) | 45 (35, 60) | 50 (40, 60) | 45 (35, 50) | 0.005* |
| Number of diseased parathyroid glands | 0.62 | |||
| Single | 195 (98.0) | 69 (97.2) | 126 (98.4) | |
| Multiple | 4 (2.0) | 2 (2.8) | 2 (1.6) | |
| Location of diseased parathyroid glands | 0.50 | |||
| Superior | 54 (27.1) | 21 (29.6) | 33 (25.8) | |
| Inferior | 143 (71.9) | 50 (70.4) | 93 (72.7) | |
| Both | 2 (1.0) | 0 (0.0) | 2 (1.6) | |
| Parathyroid volume | 0.04* | |||
| ≤2 cm3 | 144 (72.4) | 45 (63.4) | 99 (77.3) | |
| >2 cm3 | 55 (27.6) | 26 (36.6) | 29 (22.7) | |
| Pathology | 0.81 | |||
| Adenoma | 129 (64.8) | 48 (67.6) | 81 (63.3) | |
| Atypical adenoma | 20 (10.1) | 6 (8.5) | 14 (10.9) | |
| Hyperplasia | 46 (23.1) | 15 (21.1) | 31 (24.2) | |
| Carcinoma | 4 (2.0) | 2 (2.8) | 2 (1.6) | |
Data are presented as median (Q1, Q3), n (%). P values were derived from Chi-square test (for categorical variables). *, P<0.05. EPTX, endoscopic parathyroidectomy; PHPT, primary hyperparathyroidism.
Figure 2.
Correlation analysis of parathyroid volume with biochemical indicators stratified by age. (A) Correlation between parathyroid volume and preoperative serum Ca in the ≤50 years group. (B) Correlation between parathyroid volume and preoperative serum Ca in the >50 years group. (C) Correlation between parathyroid volume and preoperative serum PTH in the ≤50 years group. (D) Correlation between parathyroid volume and preoperative serum PTH in the >50 years group. (E) Correlation between parathyroid volume and percentage decrease of PTH in the ≤50 years group. (F) Correlation between parathyroid volume and percentage decrease of PTH in the >50 years group. Ca, calcium; PTH, parathyroid hormone.
Imaging accuracy by age
Preoperative imaging findings were compared with intraoperative localization of pathological parathyroid glands. Among the 199 patients, 190 underwent preoperative neck ultrasonography and 147 received parathyroid scintigraphy (99mTc-sestamibi scan). Ultrasonography demonstrated 94.7% accuracy (n=180) in lateralization prediction, while scintigraphy achieved 95.2% accuracy (n=140). Both modalities showed significantly lower true-positive rates for quadrant prediction compared to laterality prediction: 76.8% (n=146) for ultrasonography and 81.0% (n=119) for scintigraphy. Patients aged ≤50 years exhibited superior quadrant prediction rates compared to older counterparts (85.5% vs. 71.9%, P=0.03), with no significant differences observed between other comparison groups (Table 3).
Table 3. Comparison of the predictive accuracy of MIBI and US in different age groups.
| Variable | Whole cohort (n=199) | Age ≤50 years (n=71) | Age >50 years (n=128) | P value |
|---|---|---|---|---|
| MIBI | ||||
| Laterality prediction rate | 95.2% | 96.1% | 94.8% | 0.73 |
| Quadrant prediction rate | 81.0% | 82.4% | 80.2% | 0.75 |
| US | ||||
| Laterality prediction rate | 94.7% | 97.1% | 93.4% | 0.27 |
| Quadrant prediction rate | 76.8% | 85.5% | 71.9% | 0.03* |
P values were derived from Chi-square test (for categorical variables). *, P<0.05. MIBI, 99mTc-sestamibi scan; US, ultrasound.
Peri-operative PTX outcomes by age
No significant intergroup differences emerged in postoperative biochemical parameters (Table 4). A significant association was observed between the percentage decrease in PTH and resected glands volume in patients >50 years (P=0.002). However, this correlation is not significant in patients aged ≤50 (P=0.054) (Figure 2E,F). Analysis of postoperative complications revealed higher incidence of transient hypocalcemia in patients >50 years (13.3%) versus those ≤50 years (18.3%), though this difference lacked statistical significance (P=0.34). Notably, no instances of wound infection or recurrent laryngeal nerve injury occurred in either group. Postoperative bleeding was observed in a single case within the >50 years cohort. Serum PTH levels decreased significantly one day postoperatively in both groups, exhibited a modest rise by postoperative day 7, and stabilized thereafter. Changes in PTH levels across time points are illustrated in Figure 3.
Table 4. Characteristics of the perioperative data, surgical complications and patient hospitalization time of asymptomatic PHPT patients, whole cohort and stratified by age.
| Variable | Whole cohort (n=199) | Age ≤50 years (n=71) | Age >50 years (n=128) | P value |
|---|---|---|---|---|
| First postoperative serum Ca (mmol/L) | 2.25 (2.15, 2.42) | 2.21 (2.14, 2.31) | 2.29 (2.17, 2.43) | 0.11 |
| First postoperative PTH level (pg/mL) | 12.95 (6.52, 25.30) | 12.72 (6.74, 25.64) | 13.49 (6.47, 25.25) | 0.92 |
| Percentage decrease of PTH (%) | 90.84 (79.57, 96.09) | 90.84 (77.32, 96.35) | 90.82 (80.13, 95.69) | 0.67 |
| Hospitalization time (days) | 5.10±3.00 | 4.94±2.55 | 5.19±3.23 | 0.59 |
| Postoperative hypocalcemia | 30 (15.1) | 13 (18.3) | 17 (13.3) | 0.34 |
| Wound infection | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| Postoperative bleeding | 1 (0.5) | 0 (0.0) | 1 (0.8) | – |
| Recurrent laryngeal nerve injury | 0 (0.0) | 0 (0.0) | 0 (0.0) | – |
| Cure | 194 (97.5) | 70 (98.6) | 124 (96.9) | 0.41 |
Data are presented as median (Q1, Q3), n (%) or mean ± standard deviation. P values were derived from Student’s t-test (for normally distributed continuous variables), Mann-Whitney U test (for non-normally distributed continuous variables), or Chi-square test (for categorical variables). Ca, calcium; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone.
Figure 3.
Fluctuations in PTH levels measured on the day of admission and at follow-up points in different age groups. PTH, parathyroid hormone.
Discussion
The increasing detection of asymptomatic PHPT through routine screening necessitates refined management strategies, particularly regarding age-specific outcomes of definitive treatment. Although PTX is curative, optimal approaches for asymptomatic patients >50 years remain debated. While prior studies have examined age-related differences within general PHPT cohorts, granular comparisons focused specifically on disease characteristics and surgical results between younger and older patients within the asymptomatic population are lacking. This critical knowledge gap impedes tailored clinical decision-making. Addressing this deficiency, our study is, to our knowledge, the first to provide a focused analysis through a retrospective comparison of clinical profiles and surgical outcomes between asymptomatic PHPT patients aged ≤50 years and >50 years undergoing PTX at a tertiary center.
This eight-year retrospective analysis revealed a significant increase in both the number and proportion of asymptomatic PHPT cases, consistent with findings from global multicenter studies (19-21). Notably, asymptomatic PHPT case numbers showed a temporary decline during the 2021–2022 coronavirus disease 2019 (COVID-19) pandemic period (Figure 1), suggesting that public health emergencies may impede detection.
Furthermore, beyond epidemiological characteristics, biochemical parameters, clinical manifestations, and their age-related heterogeneity in presentation and prognosis constitute critical factors for clinical decision-making. Migoń et al. demonstrated that symptomatic PHPT patients with nephrolithiasis or osteoporosis exhibit significantly elevated PTH and serum calcium levels, confirming a robust association between biochemical abnormalities and clinical manifestations (22). In contrast, our asymptomatic cohort showed no statistically significant intergroup differences in core biochemical parameters across age strata. This divergence from symptomatic populations likely reflects milder biochemical derangements with slower progression in asymptomatic PHPT, indicating that age does not predominantly drive biochemical dynamics in this subgroup (23). An important academic controversy exists regarding the natural history of asymptomatic PHPT. Rubin et al. reported stable average serum calcium levels over 15 years (24), whereas Assadipour et al. found progression to end-organ damage was most closely associated with PHPT duration rather than hypercalcemia severity (3). These divergent findings suggest the mechanism linking biochemical markers to clinical prognosis remains incompletely understood, potentially involving multiple pathways such as genetic predisposition or calcium-sensing receptor regulation (5,25). The homogeneous asymptomatic cohort established in this study provides an ideal platform for elucidating such mechanisms. Further analysis revealed significantly higher serum 25(OH)D levels in asymptomatic patients aged >50 years (P<0.001), consistent with prior studies (26,27). This observation aligns with the known strong negative correlation between 25(OH)D and PTH, wherein decreased serum 1,25-dihydroxyvitamin D levels reduce serum calcium concentration and trigger excessive PTH secretion.
At the pathological level, this study demonstrated that parathyroid adenoma volume exhibited significant positive correlations with both preoperative serum PTH and calcium levels (Figure 2A-2D). These findings align with the established pathophysiology of PHPT and corroborate conclusions by Fiore et al. (28). Interestingly, this volume-function correlation was particularly pronounced in patients aged ≤50 years. We hypothesize that parathyroid cells in younger patients exhibit either heightened sensitivity to calcium-PTH feedback regulation or increased tumor proliferative activity. However, this hypothesis requires validation through subsequent molecular studies.
The primary objective of preoperative radiological localization in PHPT is to identify hyperfunctional parathyroid tissue. As most PHPT cases involve single-gland disease, accurate preoperative localization, particularly quadrant identification, reduces the necessity for routine four-gland exploration (29) and is essential for performing EPTX (30). This study demonstrated significantly superior ultrasound quadrant localization accuracy in patients aged ≤50 years compared to older patients (P=0.03), whereas no significant difference was observed with MIBI scintigraphy (P=0.75). The diagnostic efficacy of MIBI for parathyroid adenomas stems from the high uptake and delayed washout of the tracer in hyperfunctional cells, attributable to their abundant mitochondria and low P-glycoprotein expression, contrasting with rapid clearance in normal thyroid tissue. This differential washout enables clear visualization of adenomas on delayed imaging (31,32). Conversely, neck ultrasound relies primarily on detecting hypoechoic nodules formed by tumor enlargement (33). Ultrasonographic performance depends strongly on parathyroid tumor size, exhibiting reduced sensitivity for smaller lesions; consequently, diminished tumor size in older patients is associated with impaired preoperative quadrant localization. Although precise localization theoretically shortens operative duration, surgical time was paradoxically longer in the ≤50 years group (P=0.005). We propose this discrepancy likely reflects surgical selection bias: younger patients more frequently underwent EPTX. The meticulous dissection required to achieve minimally invasive outcomes in EPTX may prolong operative time compared to conventional open exploration.
Successful PTX requires serum calcium and PTH levels to normalize and remain within normal ranges for at least six months postoperatively, accompanied by significant improvement or resolution of clinical signs and symptoms (34). In this study, both patient groups exhibited significant PTH reduction within 24 hours post-PTX. Although postoperative hypocalcemia occurred more frequently in patients aged ≤50 years, intergroup differences were not statistically significant. Transient PTH elevation was observed during the first postoperative week, with levels gradually normalizing by six months (Figure 3). Among 194 patients achieving normocalcemia and normal PTH at six-month follow-up, the overall cure rate exceeded 95%. No age-dependent relationship in surgical outcomes was identified, confirming the consistent efficacy of PTX across asymptomatic PHPT patients.
Several limitations inherent to this study warrant consideration. Firstly, the single-center design introduces the potential for selection bias; our patient population may therefore not be fully representative of the broader community of asymptomatic PHPT patients. Furthermore, due to this retrospective design, we were unable to perform multivariable analyses to adjust for all potential confounding factors. Consequently, our findings should be interpreted primarily as descriptive and associative, establishing correlations rather than confirming causal relationships. Secondly, while the single-center setting ensured consistent surgical protocols, it limits the generalizability of the findings to other healthcare environments or populations with different demographic or clinical characteristics. Finally, the study focused on short-term surgical outcomes; long-term data regarding BMD changes, fracture risk, renal function, quality of life, and potential recurrence were not systematically captured in this analysis. Future prospective, multi-center studies incorporating standardized long-term follow-up are essential to further validate these findings and explore the durability of cure and broader health impacts across different age groups in asymptomatic PHPT.
Conclusions
This study confirms a rising trend in asymptomatic PHPT. Key age-related differences were observed: patients >50 years had smaller adenomas and higher comorbidity rates, while those ≤50 years exhibited stronger correlations between adenoma volume and preoperative PTH/calcium levels and superior US quadrant localization. EPTX was more frequent in younger patients. Transient hypocalcemia was slightly more common in younger patients. PTX is safe and effective for asymptomatic PHPT across age groups. These findings support considering age-specific factors in preoperative planning and management.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
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 Shanghai Sixth People’s Hospital (No. 2025-KY-004). Informed consent was taken from all the patients.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-592/rc
Funding: This work was supported by the Interdisciplinary Program of Shanghai Jiao Tong University (No. YG2023LC10).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-592/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-592/dss
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