Identifying risk factors for postoperative hypocalcemia in primary hyperparathyroidism: 12-year experience in a tertiary hospital
Original Article

Identifying risk factors for postoperative hypocalcemia in primary hyperparathyroidism: 12-year experience in a tertiary hospital

Zihan Lin1 ORCID logo, Qixian Lin1, Hangzhou Yang1, Jie Kang1, Fan Yu2, Lingzi Pan1, Bo Wu1 ORCID logo

1Department of General Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2Department of Nuclear Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

Contributions: (I) Conception and design: Z Lin; (II) Administrative support: B Wu; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: Z Lin, Q Lin, J Kang; (V) Data analysis and interpretation: Z Lin, H Yang, F Yu, L Pan; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Bo Wu, PhD. Department of General Surgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Xuhui District, Shanghai 200233, China. Email: wubo7421@sohu.com.

Background: Hypocalcemia is the most common complication following parathyroidectomy (PTX) in patients with primary hyperparathyroidism (PHPT). With asymptomatic PHPT cases increasingly comprising a larger proportion of clinical presentations, the association between preoperative symptom status and postoperative hypocalcemia risk remains poorly defined. This study aimed to identify risk factors for hypocalcemia after PTX in symptomatic vs. asymptomatic PHPT patients to enable individualized calcium management protocols.

Methods: A retrospective analysis was performed on patients with primary PHPT who underwent PTX between July 2012 and August 2024. A total of 478 patients were included and categorized into two groups based on symptomatic status at admission. Data regarding demographics, surgical details, and laboratory parameters were collected. Univariate and multivariate analyses were performed to identify factors associated with postoperative hypocalcemia in PHPT patients.

Results: Multivariate analysis revealed that the preoperative serum chloride/calcium (Cl/Ca) ratio [odds ratio (OR) =1.104; 95% confidence interval (CI): 1.025–1.190; P=0.009], alkaline phosphatase (OR =1.002; 95% CI: 1.001–1.003; P=0.001) and female gender (OR =0.257; 95% CI: 0.103–0.641; P=0.004) were statistically significant predictors of early postoperative hypocalcemia in the symptomatic group. In the asymptomatic group, age ≤60 years (OR =0.379; 95% CI: 0.161–0.894; P=0.03) and a higher preoperative serum Cl/Ca ratio (OR =1.335; 95% CI: 1.170–1.523; P<0.001) were identified as independent predictors of early postoperative hypocalcemia.

Conclusions: This first stratification analysis of PHPT patients by symptomatic status identified the serum Ca/Cl ratio as a common, independent predictor of post-PTX hypocalcemia in both symptomatic and asymptomatic groups. Additionally, in symptomatic patients, alkaline phosphatase levels and female gender were associated with early hypocalcemia. Conversely, for asymptomatic patients, age ≤60 years emerged as a significant predictor.

Keywords: Primary hyperparathyroidism (PHPT); parathyroidectomy (PTX); hypocalcemia; predictive factors; serum chloride/calcium ratio (serum Cl/Ca ratio)


Submitted Sep 18, 2025. Accepted for publication Dec 04, 2025. Published online Jan 20, 2026.

doi: 10.21037/gs-2025-426


Highlight box

Key findings

• This first stratification by symptomatic status identifies the preoperative serum chloride/calcium (Cl/Ca) ratio as a common, independent predictor of post-parathyroidectomy (PTX) hypocalcemia in both symptomatic and asymptomatic primary hyperparathyroidism (PHPT) patients.

• Symptomatic patients showed additional risk factors: high alkaline phosphatase and female gender.

• Asymptomatic patients exhibited distinct predictors: age ≤60 years.

What is known and what is new?

• Hypocalcemia is a frequent complication after PTX, but risk stratification by symptomatic status has been lacking.

• This study demonstrates that predictive factors for hypocalcemia differ significantly between symptomatic and asymptomatic PHPT patients. The Cl/Ca ratio is a novel, universally applicable predictor across both groups.

What is the implication, and what should change now?

• Preoperative risk assessment should incorporate symptomatic status and the Cl/Ca ratio to guide individualized calcium monitoring and prophylactic strategies.

• Clinical protocols should adopt stratified management: asymptomatic young patients with high Cl/Ca ratio, and symptomatic females with low phosphorus, warrant intensified postoperative calcium surveillance.


Introduction

Primary hyperparathyroidism (PHPT) is characterized by the inappropriately elevated secretion of parathyroid hormone (PTH), leading to increased serum calcium and decreased serum phosphorus levels (1). Clinically, patients may present with symptoms such as bone pain, osteoporosis, and urinary calculi (2). Parathyroidectomy (PTX) represents the definitive treatment for PHPT, aiming to achieve cure through surgical removal of the affected parathyroid glands (3). However, postoperative complications may occur, including hypocalcemia, bleeding, recurrent laryngeal nerve injury, and permanent hypoparathyroidism (4-6). Among these, hypocalcemia is the most frequent, manifesting as abnormal limb sensations or perioral numbness. Severe hypocalcemia can progress to tetany, cardiac arrhythmias, seizures, or even life-threatening manifestations (4,7). Early postoperative hypocalcemia frequently prolongs hospitalization, thus increasing associated costs (8).

Patients with PHPT typically present for medical evaluation due to two primary clinical scenarios. The first involves symptomatic manifestations, such as bone pain or recurrent urinary tract stones (2). The second stems from biochemical or imaging abnormalities detected incidentally—specifically, elevated PTH levels during routine testing or identification of a neck mass via ultrasonography (9). Advances in ultrasonographic techniques and widespread osteoporosis screening implementation have driven a progressive increase in diagnoses arising from the latter reason (10).

Significantly, emerging evidence indicates a significant difference in postoperative hypocalcemia incidence between symptomatic and asymptomatic PHPT patients (11). Asymptomatic PHPT is defined by the absence of classic symptoms or signs related to the skeletal, urinary, gastrointestinal, or neuromuscular systems. This condition is frequently identified through clinical screening in the context of incidentally discovered parathyroid tumors, osteoporosis, hypercalcemia, or elevated PTH levels (12,13). This clinical disparity implies that symptom status may reflect underlying disease severity or metabolic burden, thereby influencing postoperative calcium dynamics. However, current risk assessment and management strategies for post-PTX hypocalcemia often fail to explicitly incorporate this distinction. The specific pathophysiological factors driving calcium dysregulation in each subgroup consequently remain poorly defined. Without preoperative symptom status stratification, clinicians are hindered in optimally predicting hypocalcemia risk or implementing tailored preventative strategies for individual patients.

In this study, clinical data were collected from patients with PHPT who underwent PTX at the Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. A symptom-stratified analysis was conducted to identify factors influencing postoperative calcium levels and hypocalcemia in symptomatic vs. asymptomatic PHPT patients. By elucidating these subgroup-specific predictors, this study aims to enhance preoperative risk assessment, refine postoperative management, and ultimately reduce complications, hospital stay, and associated costs. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-426/rc).


Methods

Patients

A retrospective cohort study was conducted involving 478 patients with PHPT who underwent PTX at Shanghai Sixth People’s Hospital between July 2012 and August 2024 (Figure 1). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This 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 after comprehensive disclosure of surgical procedures and associated risks. Surgical eligibility for both symptomatic and asymptomatic patients was determined according to the guidelines from the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism (12).

Figure 1 Flowchart analyzed patients. Group A: preoperative symptom status—symptomatic; Group B: preoperative symptom status—asymptomatic. PHPT, primary hyperparathyroidism.

The inclusion criteria comprised patients with PHPT who had complete clinical data, underwent PTX, and received postoperative pathological confirmation of parathyroid hyperplasia, adenoma, or carcinoma. Exclusion criteria were: (I) postoperative pathology indicating normal parathyroid tissue; (II) preoperative administration of calcium, calcimimetic, vitamin D, or vitamin D analogs; (III) severe renal dysfunction; (IV) secondary or tertiary hyperparathyroidism; (V) incomplete clinical data; and (VI) combined thyroidectomy. Patients were stratified into two groups based on preoperative symptom status: symptomatic (Group A) and asymptomatic (Group B). Specifically, symptomatic disease was defined by the presence of classic objective complications of PHPT, such as nephrolithiasis or overt bone disease. In accordance with these guidelines, non-specific subjective symptoms, including fatigue, depression, anxiety, and concentration difficulties, were not considered definitive criteria for symptomatic classification. Consequently, patients presenting solely with these subjective complaints were categorized as asymptomatic.

Management

A standardized surgical protocol was applied to all 478 patients, consisting of bilateral neck exploration with identification of all four parathyroid glands. The baseline characteristics of the study included demographic parameters, including gender, age, presence of clinical symptoms at admission, the number of affected parathyroid glands, and the pathological findings of the affected parathyroid glands. All patients underwent preoperative fasting biochemical tests, including PTH, serum calcium, serum magnesium, serum phosphorus, serum chloride, and alkaline phosphatase. On the first postoperative day at 6:00 am, PTH and serum calcium levels were measured for all patients. Regular postoperative clinical evaluations were conducted, with a focus on serum calcium levels and symptoms associated with hypocalcemia. Early postoperative hypocalcemia was defined as a serum calcium concentration below 2.1 mmol/L within 48 hours after surgery. As all patients received standard intravenous calcium gluconate supplementation following PTX, those with normal serum calcium levels but presenting with symptoms of hypocalcemia were also classified as having early postoperative hypocalcemia. In this study, patients’ serum calcium levels and hypocalcemia symptoms were monitored throughout their hospital stay until discharge.

Calcium supplementation

After surgery, all patients received an initial intravenous supplementation of 3 g of calcium gluconate. On the first postoperative day, the dosage was adjusted according to postoperative day-1 PTH and serum calcium levels. If both serum calcium levels exceeded 2.1 mmol/L and postoperative day-one PTH exceeded 15 pg/mL, the intravenous calcium supplementation was reduced as appropriate. If serum calcium levels range between 2.0 and 2.1 mmol/L, patients should be instructed to take 1,500 mg of oral calcium carbonate every 8 hours. If serum calcium levels drop below 2.0 mmol/L, an additional 2–3 g of intravenous calcium gluconate is required.

Statistical analysis

Statistical analyses were conducted using IBM SPSS Statistics 25.0 (IBM Corp., Armonk, NY, USA). Categorical variables were expressed as counts (percentages), normally distributed continuous variables as mean ± standard deviation (SD), and ordinal or non-normally distributed continuous variables as median [interquartile range (IQR)]. Student’s t-test or the Mann-Whitney U test was used to compare continuous datasets, while the Chi-squared test or Fisher’s exact test was applied for categorical datasets. Univariate analyses were performed on all relevant factors, and variables with a P<0.05 were included in multivariate models to identify independent predictors. Additionally, factors reported in the literature to have predictive value were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of association between each variable and the development of postoperative hypocalcemia. All tests were two-tailed, and statistical significance was defined as P<0.05.


Results

Characteristics of study cohort

Between July 2012 and August 2024, a total of 478 patients underwent parathyroid surgery. Of these patients, 361 (75.5%) were female, and 117 (24.5%) were male, with a median age of 59 years. All patients underwent preoperative localization with at least one imaging modality. The standard imaging techniques employed were neck ultrasound and Technetium-99m sestamibi (MIBI) scintigraphy. Specifically, 419 patients underwent ultrasound, 367 patients underwent MIBI scintigraphy, and 308 patients received both studies for complementary assessment. The detailed results of preoperative localization are summarized in Figure S1. The demographic data, surgical details, pathological findings, and preoperative and postoperative biochemical parameters of the patients are summarized in Table 1.

Table 1

Characteristics of 478 patients undergoing PTX for PHPT

Variables Whole cohort Non-hypocalcemia group (n=364) Hypocalcemia group (n=114) P value
Age (years) 59 [48, 68] 60 [48, 69] 57 [45, 64] 0.08
Age groups (years)
   <60 255 (53.3) 181 (49.7) 71 (62.3) 0.03
   ≥60 233 (46.7) 183 (50.3) 43 (37.7)
Sex <0.001
   Male 117 (24.5) 102 (28.0) 15 (13.2)
   Female 361 (75.5) 262 (72.0) 99 (86.8)
Underlying medical condition <0.001
   No 330 (69.0) 234 (64.3) 96 (84.2)
   Hypertension 122 (25.5) 105 (28.8) 17 (14.9)
   Diabetes 10 (2.1) 9 (2.0) 1 (0.9)
   Both 16 (3.3) 16 (4.4) 0 (0.0)
Presence or absence of clinical symptoms 0.001
   Absence 207 (43.3) 174 (47.8) 33 (28.9)
   Presence 271 (56.7) 190 (52.2) 81 (71.1)
Preoperative serum Ca (mmol/L) 2.73 [2.60, 2.90] 2.74 [2.62, 2.91] 2.68 [2.52, 2.87] 0.003
First postoperative serum Ca (mmol/L) 2.28 [2.15, 2.46] 2.33 [2.22, 2.50] 2.07 [2.00, 2.19] <0.001
Decrease of serum Ca (%) 16.36 [11.06, 21.37] 14.65 [10.18, 19.47] 21.92 [17.36, 25.20] <0.001
Serum P (mmol/L) 0.84 [0.72, 0.96] 0.84 [0.73, 0.96] 0.80 [0.65, 0.96] 0.047
Serum Mg (mmol/L) 0.89 [0.82, 0.96] 0.89 [0.81, 0.95] 0.91 [0.84, 0.97] 0.10
Serum Cl (mmol/L) 105.8 [104.0, 107.0] 105.0 [103.5, 107.0] 106.1 [104.6, 108.0] 0.001
Serum Cl/Ca 38.50 [36.24, 40.80] 38.20 [36.08, 40.39] 39.46 [37.24, 42.08] <0.001
Alkaline phosphatase (U/L) 101.5 [74.0, 147.0] 97.0 [74.0, 138.0] 114.5 [75.5, 185.5] 0.03
Preoperative PTH (pg/mL) 167.20 [115.10, 326.73] 153.70 [106.45, 302.63] 222.25 [130.50, 541.95] 0.001
First postoperative PTH level (pg/mL) 13.79 [7.48, 26.97] 12.00 [7.01, 22.54] 22.37 [12.63, 38.61] <0.001
Percentage decrease of PTH (%) 92.52 [80.79, 97.34] 93.35 [83.58, 97.26] 88.05 [73.59, 97.64] 0.048
Number of diseased parathyroid glands 0.73
   Single 470 (98.3) 357 (98.1) 113 (99.1)
   Multiple 8 (1.7) 7 (1.9) 1 (0.9)
Location of diseased parathyroid glands 0.51
   Superior 111 (23.2) 89 (24.5) 22 (19.3)
   Inferior 363 (75.9) 272 (74.7) 91 (79.8)
   Both 4 (0.8) 3 (0.8) 1 (1.9)
Pathology 0.37
   Adenoma 346 (72.4) 270 (74.2) 76 (66.7)
   Atypical adenoma 41 (8.6) 30 (8.2) 11 (9.6)
   Hyperplasia 85 (17.8) 59 (16.2) 26 (22.8)
   Carcinoma 6 (1.3) 5 (1.4) 1 (0.9)

Data are presented as median [Q1, Q3] or n (%). Ca, calcium; Cl, chlorine; Cl/Ca, chloride/calcium; Mg, magnesium; P, phosphorus; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone; PTX, parathyroidectomy; Q, quartile.

Upon admission, 271 patients (56.7%) presented with clinical symptoms affecting various organ systems, while 207 patients (43.3%) were referred due to elevated PTH levels or the discovery of a neck mass during routine examinations. Single-lesion PTX (98.3%) was more common than multi-lesion PTX (1.7%). The majority of patients (72.4%) had pathological results indicating parathyroid adenoma. The majority of patients (75.9%) had the affected parathyroid glands located in the inferior parathyroids. Overall, 114 patients (23.4%) experienced early hypocalcemia or hypocalcemia-related symptoms during their postoperative hospital stay. In contrast, the majority of patients maintained normal serum calcium levels without hypocalcemic symptoms during the same period (Table 1).

Characteristics of non-hypocalcemia and hypocalcemia patients

This study identified 19 factors that could potentially influence postoperative serum calcium levels in patients with PHPT (Table 1). These factors included gender, age, BMI, presence of preoperative clinical symptoms, preoperative levels of serum calcium, phosphorus, magnesium, chloride, PTH, postoperative PTH levels, the PTH reduction rate and characteristics of the affected parathyroid glands (number, location, pathology).

Significant differences in biochemical parameters were observed between patients with normal postoperative calcium levels and those who developed postoperative hypocalcemia. The postoperative serum calcium level in hypocalcemic patients was 2.07 (2.00, 2.19) mmol/L, significantly lower than the 2.33 (2.22, 2.50) mmol/L observed in patients with normal calcium levels (P<0.001).

Other statistically significant factors included age (P=0.03), preoperative serum calcium (P=0.003), percentage reduction in serum calcium (P<0.001), preoperative serum phosphorus (P=0.047), preoperative serum chloride (P=0.001), chloride-to-calcium ratio (P<0.001), preoperative intact PTH (P=0.001), PTH levels on the first postoperative day (P<0.001), and alkaline phosphatase levels (P=0.03). Additionally, patients presenting with clinical symptoms at admission had a higher incidence of postoperative hypocalcemia (P=0.001), and female patients were more likely to develop postoperative hypocalcemia (P<0.001).

Comparison of baseline characteristics between symptomatic and asymptomatic patients

Patients were divided into symptomatic and asymptomatic groups according to their preoperative clinical presentation. The baseline characteristics and laboratory parameters of the symptomatic (n=271) and asymptomatic (n=207) groups are presented in Table 2. No significant difference was observed in age (P=0.27) and sex (P=0.25) between the two groups. Regarding calcium metabolism, preoperative serum calcium levels were significantly higher in the symptomatic group compared to the asymptomatic group (P=0.004). The percentage decrease in serum calcium after surgery was also greater in the symptomatic group (P<0.001). In contrast, no significant difference was found in the first postoperative serum calcium levels between the two groups (P=0.98). Significant differences were also noted in other electrolyte levels. Serum phosphorus (P<0.001) and magnesium (P=0.10) were lower in the symptomatic group, while serum chloride was higher (P=0.004). Alkaline phosphatase levels were significantly elevated in the symptomatic group (P<0.001). Preoperative PTH levels were markedly higher in the symptomatic group than in the asymptomatic group (P<0.001). Although both groups exhibited a substantial reduction in PTH after surgery, the first postoperative PTH level remained slightly higher in the symptomatic group (P=0.01), and the percentage decrease in PTH was more pronounced in the symptomatic group (P=0.04).

Table 2

Comparison of baseline characteristics and laboratory parameters between symptomatic and asymptomatic groups

Variables Group A (n=271) Group B (n=207) P value
Age (years) 59 [51, 67] 56 [46, 68] 0.27
Sex 0.25
   Male 61 (22.5) 56 (27.1)
   Female 210 (77.5) 151 (72.9)
Preoperative serum Ca (mmol/L) 2.75 [2.61, 2.98] 2.71 [2.57, 2.84] 0.004
First postoperative serum Ca (mmol/L) 2.28 [2.14, 2.48] 2.28 [2.17, 2.41] 0.98
Decrease of serum Ca (%) 17.69 [11.85, 22.78] 14.87 [10.75, 19.47] <0.001
Serum P (mmol/L) 0.80 [0.68, 0.95] 0.88 [0.78, 0.98] <0.001
Serum Mg (mmol/L) 0.88 [0.81, 0.94] 0.91 [0.83, 0.97] 0.01
Serum Cl (mmol/L) 106.0 [104.0, 108.0] 105.0 [103.4, 107.0] 0.004
Alkaline phosphatase (U/L) 110 [80, 173] 93 [69, 129] <0.001
Preoperative PTH (pg/mL) 205.0 [124.2, 484.3] 138.0 [100.9, 227.8] <0.001
First postoperative PTH level (pg/mL) 15.41 [8.04, 30.49] 12.66 [6.82, 23.70] 0.01
Percentage decrease of PTH (%) 93.51 [81.52, 97.91] 91.43 [80.13, 96.26] 0.04

Data are presented as median [Q1, Q3] or n (%). Group A: preoperative symptom status—symptomatic; Group B: preoperative symptom status—asymptomatic. Ca, calcium; Cl, chlorine; Mg, magnesium; P, phosphorus; PTH, parathyroid hormone; Q, quartile.

Analysis of factors influencing early postoperative hypocalcemia

In the asymptomatic group, the preoperative blood calcium levels were significantly lower than those in the symptomatic group (P=0.004) (Figure 2A). There was no significant difference in the first postoperative blood calcium levels between the two groups (P=0.98) (Figure 2B). However, the incidence of early hypocalcemia was significantly higher in the symptomatic group (Table 1). Variables from both groups were analyzed for differences (Table 3).

Figure 2 Comparison of serum calcium levels between asymptomatic and symptomatic patient groups. (A) Raincloud plot of preoperative serum calcium levels. (B) Raincloud plot of the first postoperative serum calcium levels. Ca, calcium; PHPT, primary hyperparathyroidism.

Table 3

Regression analysis of factors influencing postoperative hypocalcemia in different groups

Variables Group A (n=271) Group B (n=207)
Non-hypocalcemia group (n=190) Hypocalcemia group (n=81) P value Non-hypocalcemia group (n=174) Hypocalcemia group (n=33) P value
Age (years) 60 [51, 68] 57 [50, 66] 0.21 58 [46, 69] 52 [43, 63] 0.12
Age groups (years) 0.10 0.05
   <60 92 (48.4) 48 (59.3) 89 (51.1) 23 (69.7)
   ≥60 98 (51.6) 33 (40.7) 85 (48.9) 10 (30.3)
Sex 0.003 0.21
   Male 52 (27.4) 9 (11.1) 124 (71.3) 27 (81.8)
   Female 138 (72.6) 72 (88.9) 50 (28.7) 6 (18.2)
Preoperative serum Ca (mmol/L) 2.77 [2.62, 3.00] 2.70 [2.56, 2.88] 0.06 2.73 [2.62, 2.85] 2.58 [2.43, 2.72] <0.001
First postoperative serum Ca (mmol/L) 2.34 [2.22, 2.55] 2.06 [2.00, 2.24] <0.001 2.30 [2.21,2.46] 2.07 [2.02, 2.10] <0.001
Decrease of serum Ca (%) 14.96 [9.80, 20.67] 22.75 [17.97, 27.29] <0.001 14.09 [10.27, 18.50] 19.84 [15.61, 23.20] <0.001
Serum P (mmol/L) 0.83 [0.71, 0.95] 0.77 [0.62, 0.94] 0.06 0.88 [0.78, 0.97] 0.93 [0.73, 0.99] 0.68
Serum Mg (mmol/L) 0.87 [0.80, 0.94] 0.91 [0.84, 0.97] 0.03 0.91 [0.83, 0.97] 0.89 [0.86, 0.99] 0.52
Serum Cl (mmol/L) 105.8 [104.0, 107.0] 107.0 [105.0, 108.0] 0.01 105.0 [103.2, 107.0] 106.0 [104.0, 107.0] 0.13
Serum Cl/Ca 37.94 [34.94, 40.38] 38.88 [36.52, 41.37] 0.02 38.35 [36.60, 40.40] 40.94 [38.14, 43.92] <0.001
Alkaline phosphatase (U/L) 101.0 [78.0, 157.3] 121.0 [87.5, 214.5] 0.05 93.0 [69.8, 125.0] 86.0 [68.5, 154.5] 0.98
Preoperative PTH (pg/mL) 189.2 [122.1, 408.2] 294.5 [133.5, 808.6] 0.02 134.8 [99.9, 212.3] 148.3 [119.9, 258.4] 0.29
First postoperative PTH level (pg/mL) 12.68 [7.35, 27.41] 21.86 [12.38, 38.91] <0.001 11.26 [6.54, 21.05] 22.55 [12.74, 42.84] <0.001
Percentage decrease of PTH (%) 94.07 [85.11, 97.82] 91.88 [74.41, 98.09] 0.34 92.49 [82.84, 96.49] 80.86 [65.10, 93.60] 0.005

Data are presented as median [Q1, Q3] or n (%). Group A: preoperative symptom status—symptomatic; Group B: preoperative symptom status—asymptomatic. Ca, calcium; Cl, chlorine; Cl/Ca, chloride/calcium; Mg, magnesium; P, phosphorus; PTH, parathyroid hormone; Q, quartile.

Analysis of factors influencing early postoperative hypocalcemia in the symptomatic group

Variables showing significant associations (P<0.05) were further analyzed using multivariate stepwise logistic regression. The results indicated that three variables (Figure 3), preoperative serum chloride/calcium (Cl/Ca) ratio (OR =1.104; 95% CI: 1.025–1.190; P=0.009), alkaline phosphatase (OR =1.002; 95% CI: 1.001–1.003; P=0.001), and female gender (OR =0.257; 95% CI: 0.103–0.641; P=0.004), were significantly associated with early postoperative hypocalcemia (Table 4).

Figure 3 Multivariate logistic regression analysis of forest plots of the two groups. CI, confidence interval; Cl/Ca, chloride/calcium; OR, odds ratio.

Table 4

Regression analysis of factors influencing postoperative hypocalcemia in the symptomatic group

Variables Multivariate
OR (95% CI) P value
Sex 0.257 (0.103–0.641) 0.004
Alkaline phosphatase 1.002 (1.001–1.003) 0.001
Serum Cl/Ca 1.104 (1.025–1.190) 0.009

CI, confidence interval; Cl/Ca, chloride/calcium; OR, odds ratio.

Analysis of factors influencing early postoperative hypocalcemia in the asymptomatic group

In contrast to the symptomatic group, regression analysis revealed that age was an independent factor influencing postoperative hypocalcemia in asymptomatic patients. Patients younger than 60 years had a higher likelihood of developing hypocalcemia (OR =0.379) (Figure 3). Additionally, higher preoperative serum Cl/Ca ratios were associated with an increased likelihood of postoperative hypocalcemia (OR =1.335; 95% CI: 1.170–1.523; P<0.001). These factors were predictive of postoperative calcium disturbances (Table 5).

Table 5

Regression analysis of factors influencing postoperative hypocalcemia in the asymptomatic group

Variables Multivariate
OR (95% CI) P value
Age groups (<60 vs. ≥60 years) 0.379 (0.161–0.894) 0.03
Serum Cl/Ca 1.335 (1.170–1.523) <0.001

CI, confidence interval; Cl/Ca, chloride/calcium; OR, odds ratio.


Discussion

Hypocalcemia is a common complication following PTX in patients with PHPT. Although the mechanisms underlying early postoperative hypocalcemia have been extensively investigated, research identifying predictive factors for its occurrence remains limited, particularly concerning variations across clinical subtypes. Consequently, a comprehensive analysis of factors influencing early postoperative hypocalcemia is essential for optimizing clinical management.

In this study, 487 patients were divided into two groups according to the presence or absence of clinical symptoms at admission. We assessed factors that might be associated with postoperative serum calcium levels and hypocalcemia in PHPT patients. Although no statistically significant difference in serum calcium levels was observed between the two groups, this finding may be attributed to routine postoperative intravenous calcium supplementation (Figure 2B). The results demonstrated that the incidence of early postoperative hypocalcemia differed significantly between the two groups, and the factors contributing to early postoperative hypocalcemia also varied.

The results of this study are consistent with those of many previous studies, highlighting the predictive value of preoperative PTH levels and alkaline phosphatase for postoperative hypocalcemia (14-17). In symptomatic PHPT patients, preoperative PTH level demonstrated significant multicollinearity with alkaline phosphatase, leading to its exclusion from the stepwise logistic regression model. Consequently, preoperative PTH level was not retained as an independent predictor of postoperative hypocalcemia in this cohort. While our findings align with prior studies identifying shared risk factors, the serum Cl/Ca ratio emerged as a novel independent predictor. Preoperative serum Ca has been well-established as a factor influencing postoperative hypocalcemia following PTX in several studies (11,18). Patients with higher preoperative serum calcium levels are likely to maintain elevated calcium concentrations postoperatively due to a slower decline in serum calcium levels. In hyperparathyroidism, the effect of PTH reduces renal bicarbonate reabsorption while increasing chloride reabsorption, leading to hyperchloremia (19-21). Elevated preoperative serum chloride levels may contribute to an acidic environment in the blood, potentially causing mild metabolic acidosis. When acidosis is corrected and the acid-base balance shifts toward alkalosis, the body compensates by increasing free calcium to counteract the acidic substances. This results in increased glomerular filtration of calcium ions, while simultaneously inhibiting calcium reabsorption (22). During this period, due to the persistently high levels of PTH, calcium loss through the urinary system remains minimal. However, after the surgical removal of the affected parathyroid glands and the subsequent normalization of PTH levels, the correction of metabolic acidosis can result in hypocalcemia. Therefore, for patients with preoperative hyperchloremia, restricting the supplementation of chloride-containing fluids postoperatively could potentially reduce the incidence of hypocalcemia.

Furthermore, this study extends research in this area by differentiating the risk factors between symptomatic and asymptomatic PHPT patients, an area that has received limited exploration. Migoń et al. reported significantly elevated serum PTH and calcium levels in PHPT patients with urinary tract stones, osteoporosis, or cholelithiasis, reinforcing the well-established link between hyperparathyroid biochemical profiles and clinical presentation in PHPT (23). Compared to studies that focus on overall risk factors, this stratified approach provides more nuanced insights. The presence or absence of symptoms may reflect different stages of disease progression, with symptomatic patients potentially experiencing more severe electrolyte imbalances and metabolic disturbances. Relatively low preoperative serum phosphorus levels may indicate higher bone resorption and mineral uptake after PTX (18), while magnesium metabolism disorders are considered one of the causes of hypocalcemia following total thyroidectomy (24). Postoperative serum magnesium levels are directly associated with the incidence of hypocalcemia (25). Our study found that symptomatic PHPT patients who developed postoperative hypocalcemia demonstrated paradoxically higher preoperative magnesium levels (P=0.03). The relationship between hypermagnesemia and postoperative hypocalcemia may be related to the calcium-sensing receptor (CaSR). When magnesium levels increase, magnesium ions can bind to the CaSR, leading to an increase in intracellular calcium and a reduction in PTH secretion (26). This subtle change may not be apparent when preoperative PTH levels are high, but after PTX, the suppression of PTH release could potentially lead to decreased serum calcium levels (27). In the asymptomatic group, patients over 60 years of age had a lower probability of developing postoperative hypocalcemia. Becerikli et al. suggested that compared to younger individuals, biomarkers associated with osteoblastogenesis are significantly reduced in the elderly (28), indicating that older patients have a diminished ability to transfer calcium from the bloodstream to the bones postoperatively. As a result, they are less likely to experience hypocalcemia after surgery.

The surgical strategy employed in this cohort also warrants discussion, particularly regarding the selective use of intraoperative PTH (ioPTH) monitoring. ioPTH is recognized as a valuable tool for predicting postoperative hypocalcemia following thyroidectomy and for confirming the biochemical cure of PHPT (29-31). Despite this utility, it was not adopted as a universal requirement in our practice. This decision was grounded in a high-confidence diagnostic and surgical pathway. Specifically, over 95% of our patients had a single adenoma conclusively identified on preoperative imaging. This was further corroborated by a standardized intraoperative protocol comprising bilateral exploration with visual identification of all parathyroid glands and immediate histological confirmation of the resected specimen via frozen section. In accordance with guidelines from the American Head and Neck Society Endocrine Surgery Section, techniques such as near-infrared autofluorescence or indocyanine green angiography were able to enhance parathyroid identification and assess gland perfusion (32). The efficacy of this multi-layered approach, which encompassed precise preoperative localization, rigorous intraoperative surgical and histological verification, and definitive postoperative biochemical assessment, was confirmed by normalized PTH levels on postoperative day one. Within this robust framework, ioPTH was reserved for selective use, primarily in cases with inconclusive preoperative imaging.

This study has several limitations. First, its retrospective design may have led to incomplete data collection, including preoperative vitamin D levels. Second, as a single-center investigation, the study is susceptible to selection bias. The analysis revealed no significant difference in the incidence of postoperative hypocalcemia between patients undergoing single-gland vs. multi-gland excision. This finding is likely attributable to the low prevalence of multi-gland disease in our cohort (2%), which falls below the typical range of 15–20% as reported (33). Finally, while the study identifies biochemical predictors, it does not explore their interplay or underlying mechanisms in detail. Future research should focus on validating these findings in multi-center, prospective studies.


Conclusions

This study is the first to stratify PHPT patients based on the presence or absence of clinical symptoms and analyze the factors associated with early postoperative hypocalcemia following PTX. Serum Ca/Cl ratio was identified as a common independent predictor of postoperative hypocalcemia in both groups. Additionally, alkaline phosphatase and female gender were identified as potential risk factors for early postoperative hypocalcemia in symptomatic PHPT patients. For asymptomatic patients, age ≤60 years was found to be a significant predictor.


Acknowledgments

None.


Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-426/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-426/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-426/prf

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-2025-426/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. This 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 after comprehensive disclosure of surgical procedures and associated risks.

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/.


References

  1. Walker MD, Silverberg SJ. Primary hyperparathyroidism. Nat Rev Endocrinol 2018;14:115-25. [Crossref] [PubMed]
  2. Assadipour Y, Zhou H, Kuo EJ, et al. End-organ effects of primary hyperparathyroidism: A population-based study. Surgery 2019;165:99-104. [Crossref] [PubMed]
  3. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg 2016;151:959-68. [Crossref] [PubMed]
  4. Walker MD, Shane E. Hypercalcemia: A Review. JAMA 2022;328:1624-36. [Crossref] [PubMed]
  5. Zhu CY, Sturgeon C, Yeh MW. Diagnosis and Management of Primary Hyperparathyroidism. JAMA 2020;323:1186-7. [Crossref] [PubMed]
  6. Turner J, Gittoes N, Selby P, et al. Society for Endocrinology Endocrine Emergency Guidance: Emergency management of acute hypocalcaemia in adult patients. Endocr Connect 2016;5:G7-8. [Crossref] [PubMed]
  7. Orloff LA, Wiseman SM, Bernet VJ, et al. American Thyroid Association Statement on Postoperative Hypoparathyroidism: Diagnosis, Prevention, and Management in Adults. Thyroid 2018;28:830-41. [Crossref] [PubMed]
  8. Samargandy S, Wadie J, Msallak H, et al. Parathyroid hormone-driven algorithms after thyroid surgery: Not one-size-fits-all. Head Neck 2023;45:595-603. [Crossref] [PubMed]
  9. Yeh MW, Zhou H, Kuo EJ, et al. Biochemical Dynamics of Untreated Primary Hyperparathyroidism: An Observational Study. Endocr Pract 2019;25:470-6. [Crossref] [PubMed]
  10. Wu JX, Yeh MW. Asymptomatic Primary Hyperparathyroidism: Diagnostic Pitfalls and Surgical Intervention. Surg Oncol Clin N Am 2016;25:77-90. [Crossref] [PubMed]
  11. Mu Y, Zhao Y, Zhao J, et al. Factors influencing serum calcium levels and the incidence of hypocalcemia after parathyroidectomy in primary hyperparathyroidism patients. Front Endocrinol (Lausanne) 2023;14:1276992. [Crossref] [PubMed]
  12. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab 2014;99:3561-9. [Crossref] [PubMed]
  13. Bilezikian JP, Potts JT Jr. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab 2002;87:5353-61. [Crossref] [PubMed]
  14. Privitera F, Centonze D, La Vignera S, et al. Risk Factors for Hypoparathyroidism after Thyroid Surgery: A Single-Center Study. J Clin Med 2023;12:1956. [Crossref] [PubMed]
  15. Muller O, Bauvin P, Bacoeur O, et al. Machine Learning-Based Algorithm for the Early Prediction of Postoperative Hypocalcemia Risk After Thyroidectomy. Ann Surg 2024;280:835-41. [Crossref] [PubMed]
  16. He C, Zhang Y, Li L, et al. Risk Factor Analysis and Prediction of Severe Hypocalcemia after Total Parathyroidectomy without Auto-Transplantation in Patients with Secondary Hyperparathyroidism. Int J Endocrinol 2023;2023:1901697. [Crossref] [PubMed]
  17. Zuberi KA, Urquhart AC. Serum PTH and ionized calcium levels as predictors of symptomatic hypocalcemia after parathyroidectomy. Laryngoscope 2010;120:S192. [Crossref] [PubMed]
  18. Xu J, Kong N, Bai N, et al. Identification of novel risk factors for postoperative severe hypocalcemia in patients with primary hyperparathyroidism undergoing parathyroidectomy: a case control study. BMC Endocr Disord 2024;24:88. [Crossref] [PubMed]
  19. Weger W, Kotanko P, Weger M, et al. Prevalence and characterization of renal tubular acidosis in patients with osteopenia and osteoporosis and in non-porotic controls. Nephrol Dial Transplant 2000;15:975-80. [Crossref] [PubMed]
  20. Wright C, King D, Small M, et al. The Utility of the Cl:PO4 Ratio in Patients With Variant Versions of Primary Hyperparathyroidism. Otolaryngol Head Neck Surg 2021;164:308-14. [Crossref] [PubMed]
  21. Tang W, Jia H, Wang B, et al. Evaluating distal renal tubular acidification function in primary hyperparathyroidism and its effects on bone mineral density. BMC Musculoskelet Disord 2021;22:69. [Crossref] [PubMed]
  22. Kennedy AC, Allam RF, Rooney PJ, et al. Hypercalcaemia in rheumatoid arthritis: investigation of its causes and implications. Ann Rheum Dis 1979;38:401-12. [Crossref] [PubMed]
  23. Migoń J, Miciak M, Pupka D, et al. Analysis of Clinical and Biochemical Parameters and the Effectiveness of Surgical Treatment in Patients with Primary Hyperparathyroidism: A Single-Center Study. J Clin Med 2025;14:996. [Crossref] [PubMed]
  24. Brophy C, Woods R, Murphy MS, et al. Perioperative magnesium levels in total thyroidectomy and relationship to hypocalcemia. Head Neck 2019;41:1713-8. [Crossref] [PubMed]
  25. Garrahy A, Murphy MS, Sheahan P. Impact of postoperative magnesium levels on early hypocalcemia and permanent hypoparathyroidism after thyroidectomy. Head Neck 2016;38:613-9. [Crossref] [PubMed]
  26. Quinn SJ, Thomsen AR, Egbuna O, et al. CaSR-mediated interactions between calcium and magnesium homeostasis in mice. Am J Physiol Endocrinol Metab 2013;304:E724-33. [Crossref] [PubMed]
  27. Allgrove J. Physiology of Calcium, Phosphate, Magnesium and Vitamin D. Endocr Dev 2015;28:7-32. [Crossref] [PubMed]
  28. Becerikli M, Jaurich H, Schira J, et al. Age-dependent alterations in osteoblast and osteoclast activity in human cancellous bone. J Cell Mol Med 2017;21:2773-81. [Crossref] [PubMed]
  29. Scurry WC Jr, Beus KS, Hollenbeak CS, et al. Perioperative parathyroid hormone assay for diagnosis and management of postthyroidectomy hypocalcemia. Laryngoscope 2005;115:1362-6. [Crossref] [PubMed]
  30. Rutledge J, Siegel E, Belcher R, et al. Barriers to same-day discharge of patients undergoing total and completion thyroidectomy. Otolaryngol Head Neck Surg 2014;150:770-4. [Crossref] [PubMed]
  31. Lee DR, Hinson AM, Siegel ER, et al. Comparison of Intraoperative versus Postoperative Parathyroid Hormone Levels to Predict Hypocalcemia Earlier after Total Thyroidectomy. Otolaryngol Head Neck Surg 2015;153:343-9. [Crossref] [PubMed]
  32. Silver Karcioglu AL, Triponez F, Solórzano CC, et al. Emerging Imaging Technologies for Parathyroid Gland Identification and Vascular Assessment in Thyroid Surgery: A Review From the American Head and Neck Society Endocrine Surgery Section. JAMA Otolaryngol Head Neck Surg 2023;149:253-60. [Crossref] [PubMed]
  33. Insogna KL. Primary Hyperparathyroidism. N Engl J Med 2018;379:1050-9. [Crossref] [PubMed]
Cite this article as: Lin Z, Lin Q, Yang H, Kang J, Yu F, Pan L, Wu B. Identifying risk factors for postoperative hypocalcemia in primary hyperparathyroidism: 12-year experience in a tertiary hospital. Gland Surg 2026;15(1):8. doi: 10.21037/gs-2025-426

Download Citation