Intact Parathyroid Hormone Levels in Predicting Postoperative Hypocalcaemia After Total Thyroidectomy in South Indian Population: Cross Sectional Study

Abstract

Hypocalcaemia being one of the most common complications after total thyroidectomy may not be avoidable in all cases. This study evaluated the effectiveness of intact Parathyroid hormone (iPTH) measured at 1-h after total thyroidectomy in predicting postoperative hypocalcaemia in early postoperative period in South Indian population. Patients who underwent total thyroidectomy in our institute from 2016 to 2018 were included. Preoperative calcium and iPTH levels were measured. Patients’ iPTH level was measured 1 h after surgery and serum calcium level was measured at 24 h after surgery. Patients were also monitored clinically for any symptoms and signs of hypocalcaemia. A total of 57 patients were studied. The malignant causes accounted for 75.4% with papillary carcinoma thyroid being the most common cause. 65.7% of patients who underwent total thyroidectomy and 100% of patients who underwent total thyroidectomy with neck dissection developed hypocalcaemia. 70% of patients with low iPTH developed hypocalcaemia and none of the patients who had normal iPTH developed hypocalcaemia. This relation was statistically significant with p value of 0.018 (< 0.05). The positive predictive value is 70% and negative predictive value is 100%. Though our study supports the hypothesis that iPTH is effective in predicting hypocalcaemia after total thyroidectomy in the early postoperative period, a larger sample study is needed to further support this. It can be used to consider patients for early discharge or to prophylactically start oral calcium and Vitamin D supplementation based on iPTH levels at 1 h after surgery.

Introduction

Total thyroidectomy is a procedure commonly indicated for both benign and malignant pathologies of the thyroid gland. Hypocalcemia is a common complication which can occur in the early or the late postoperative periods. Permanent hypocalcemia adversely affects the patients’ quality of life and causes considerable financial loss [1].

Hypocalcemia in the early postoperative period can particularly be morbid to the patient as it prolongs hospital stay and has the potential to add to significant complications. Hence early identification and timely management of postoperative hypocalcaemia becomes crucial. Of the patients undergoing total thyroidectomy 1.6–50% experience temporary hypocalcaemia while permanent hypocalcaemia persists in 0–13% of cases [2]. While some centres prophylactically administer calcium and Vitamin D supplements, it can add to patients’ financial and mental stress.

Various studies have been undertaken to identify factors which can be used to predict hypocalcaemia in patients after total thyroidectomy. Preoperative calcium levels, postoperative calcium levels at different time periods (serial calcium level monitoring), intact Parathyroid hormone (iPTH) measurement—intraoperative and postoperative at different time periods, preoperative Vitamin D level, intraoperative identification of fewer parathyroid glands, fewer parathyroid glands preserved in-situ, higher number of parathyroid glands autotransplanted, inadvertent parathyroid gland excision, greater blood loss, longer duration of surgery are some of the parameters which have been studied [3–5].

Among all the parameters studied, iPTH measurement in predicting postoperative hypocalcaemia has been promising. However timing of the iPTH measurement has not been standardized worldwide. Some of the previous studies have done iPTH measurements in time period ranging from 30 min till 24 h after surgery and also they further recommend population based studies [3–6]. We believe this study can add to the pool of population-based studies on similar topic.

Objective

To study the efficacy of iPTH levels measured at 1 h after surgery in predicting postoperative hypocalcaemia in the early postoperative period after total thyroidectomy in South Indian population.

Materials and Methods

Study Design

Cross-sectional study conducted in the Department of Otolaryngology and General Surgery from August 2016 to May 2018.

Inclusion Criteria

All patients above the age of 18 years, undergoing total thyroidectomy for benign and malignant thyroid disorders in the Department of Otolaryngology and General Surgery during the aforementioned study period.

Exclusion Criteria

Patients with pre-existing

• Hypo/hyperparathyroidism.

• Hypoalbuminemia.

• Renal dysfunction.

Sample Size Calculation

Considering the sensitivity of iPTH in early detection of postoperative hypocalcemia as 89% from the previous study with a relative precision of 15% and 95% confidence level, the number of hypocalcaemic patients post total thyroidectomy required for the study was estimated as 21 using nMaster 2.0 software [6]. It was expected that approximately 30% of all patients undergoing total thyroidectomy would develop hypocalcemia [7].

Therefore, the sample size for this study was calculated as 70 patients. However, only 57 patients were included in the study from the Department of Otolaryngology and General Surgery.

List of variables studied:

1. Independent variables Age, gender, preoperative calcium levels, iPTH level 1 h after total thyroidectomy (low or normal).

2. Dependent variable Serum calcium levels at 24 h after surgery, symptoms and signs of hypocalcaemia (hypocalcaemia present or absent).

Study Procedure

After obtaining PGRMC and Institute Ethics committee approval, patients who satisfied the Inclusion criteria were selected, and informed consent was taken. Preoperative investigations including serum calcium and iPTH were done. Patients underwent total thyroidectomy under General anesthesia (GA). Patients who underwent total thyroidectomy as part of total laryngectomy were also included.

Though attempts were made to identify the parathyroid glands and preserve them, they were resected along with the surgical specimen in some instances (Fig. 1).

Fig. 1.

Superior parathyroid gland (yellow arrow) and recurrent laryngeal nerve (black arrowhead) preserved in-situ on the right side with an enlarged right lobe of the thyroid gland

One-hour post completion of surgery, the patients’ blood samples were collected. Whole blood samples for iPTH were immediately centrifuged, and serum was separated. Serum samples were then stored at − 18 to – 20 °C and pooled for processing in batches [8, 9]. Serum iPTH levels were measured using the Beckman Coulter UniCel DxI 600 access immunoassay system and were expressed in terms of pg/mL. Serum calcium levels were measured using the Beckman Coulter AU 680 system.

Patients were monitored for symptoms and signs of hypocalcemia and serum Calcium levels were measured after 24 h. Clinical symptoms and signs which were considered as positive for hypocalcemia were perioral numbness, positive Chvostek, Trousseau signs, cardiac arrhythmias, muscle spasm, stridor [10].

The measured calcium levels were then corrected using the formula,

• Corrected calcium level = Serum calcium + 0.8 × (4-Patient’s albumin) [11].

• Normal serum calcium levels were considered to be 8.7–10.2 mg/dL [12] and

• Normal iPTH levels as 1.5–6.9 pmol/L (10–55 pg/mL) [6–13].

A patient was considered to be having hypocalcemia if his/her corrected serum calcium level was less than 8.5 mg/dL and/or had clinical symptoms and signs [7–12].

Daily serum calcium level was measured, and the patient monitored for symptoms or signs of hypocalcaemia for an average period of one week. Correlation between preoperative and postoperative iPTH and serum calcium values was evaluated. Any patient who was considered to be hypocalcaemic was treated with oral calcium and calcitriol.

• Age was expressed in mean (S.D i.e. Standard deviation) as it followed a normal distribution.

• Preoperative serum calcium levels, postoperative iPTH levels were expressed in median (IQR i.e. Interquartile range) as they followed a non-normal distribution.

• Postoperative 24-h calcium levels, preoperative iPTH levels were described using mean (S.D i.e. Standard deviation) as they followed a normal distribution.

• The correlation between iPTH levels at 1 h and postoperative hypocalcaemia was measured using Fisher’s exact test.

• Sensitivity, Specificity, Positive predictive value (PPV) and Negative predictive value (NPV) of iPTH (low) in predicting postoperative hypocalcaemia were reported with 95% confidence interval.

• All the statistical tests were considered statistically significant at a p value of less than or equal to 0.05.

• Statistical analysis was done using IBM PASW statistics v19.0 (SPSS version 19.0).

Results

• After satisfying the inclusion criteria, 57 patients were included in the study, of whom 37 were female (65%), and 20 were male (35%).

• The patients who underwent total thyroidectomy for benign conditions were 14 (24.6%) and for malignant conditions were 43 patients (75.4%).

• Papillary carcinoma thyroid was the most common indication for patients who underwent total thyroidectomy in this study accounting for 59.9% of the study participants.

• Other diagnoses included multinodular goiter (24.5%), follicular carcinoma thyroid (1.7%), Hurthle cell carcinoma thyroid (1.7%), carcinoma larynx (12.2%) who underwent total thyroidectomy as the primary modality of treatment or as part of another surgery.

• The mean age of patients in the study group was 43.

• The mean preoperative serum calcium level was 9.3 mg/dL, and the mean 24-h postoperative calcium level was 8.4 mg/dL.

• The mean preoperative iPTH level was 27.4 pg/mL.

• The mean preoperative iPTH level was 27.4 pg/mL.

• The mean and median ± IQR postoperative iPTH levels were 2 pg/mL and 0 ± 1 pg/mL respectively. Tables 1, 2 depict the variables studied.

• 66.6% of patients in the study developed postoperative hypocalcaemia. Table 3 depicts the percentage of patients who developed hypocalcaemia in each group.

Table 1.

Variables expressed in mean ± standard deviation

S. no	Variables studied (n = 57)	Minimum	Maximum	Mean ± SD
1	Age (years)	23	78	43 ± 12
2	Preoperative serum iPTH level (pg/mL)	15.3	47	27.4 ± 8
3	Postoperative 24 h serum calcium level (mg/dL)	6.2	9.6	8.4 ± 0.7

Table 2.

Variables expressed in median ± IQR

S. no	Variables studied (n = 57)	Median ± IQR
1	Preoperative serum calcium level (mg/dL)	9.2 ± 0.5
2	Postoperative serum iPTH level (pg/mL)	0 ± 1

Table 3.

Percentage of patients who developed hypocalcaemia in each category

	N = 57	Postoperative hypocalcaemia		p value
		Yes (n = 38)	No (n = 19)
Age in years	18–30 (n = 8)	3 (37.5%)	5 (62.5%)	0.119
	31–50 (n = 36)	27(75%)	9 (25%)
	> 50 (n = 13)	8 (61.5%)	5 (38.5%)
Gender	Male (n = 20)	15 (75%)	5 (25%)	0.326
	Female (n = 37)	23 (62.2%)	14 (37.8%)
Diagnosis	Multinodular goiter (n = 14)	7 (50%)	7 (50%)	0.236
	Papillary carcinoma thyroid (n = 34)	25(73.6%)	9 (26.4%)
	Follicular carcinoma thyroid (n = 1)	1 (100%)	0 (0)
	Hurthle cell carcinoma thyroid (n = 1)	1 (100%)	0 (0)
	Carcinoma larynx (n = 7)	4 (57.1%)	3(42.9%)
Surgery	Total thyroidectomy (n = 35)	23 (65.7%)	12 (34.3%)	0.198
	Total thyroidectomy with neck dissection (n = 6)	6 (100%)	0 (0)
	Completion thyroidectomy (n = 8)	4 (50%)	4 (50%)
	Total laryngectomy with total thyroidectomy (n = 8)	5 (62.5%)	3 (37.5%)
Number of patients with parathyroid glands preserved	≤ 2 Parathyroid glands preserved (n = 24)	16 (66.7%)	8 (33.3%)	1
	≥ 3 Parathyroid glands preserved (n = 33)	22 (66.7%)	11 (33.3%)
1-h postoperative serum iPTH levels	Low iPTH level (n = 54)	38 (70%)	16 (30%)	0.018
	Normal iPTH level (n = 3)	0 (0)	3 (100%)

Bold value indicates a p-value of less than 0.05 which is statistically significant

The sensitivity of iPTH in predicting postoperative hypocalcaemia is 100%.

The specificity of iPTH in predicting postoperative hypocalcaemia is 15%.

The positive predictive value is 70%.

The negative predictive value is 100%.

Discussion

In a study by AlQahtani et al., iPTH levels 1 h, 6 h and 24 h after thyroidectomy were measured. iPTH levels measured 1 h after surgery had PPV and NPV of 97%, 100% respectively for predicting 24 h postoperative hypocalcaemia [6]. Our study’s findings are comparable to this. In that study, it was also concluded that the PTH levels remained relatively stable in the first 24 h post-surgery.

Michael G. White studied patients who underwent total thyroidectomy and found out that iPTH at 1 h and 24 h bear the same implication in predicting postoperative hypocalcaemia [14]. In this study it was also found that age, gender, diagnosis, and surgery being done were not related to postoperative iPTH levels measured at 1 h. However, they have also commented that further studies with large cohort are needed.

In our study the relationship between the number of parathyroid glands preserved and the risk of development of postoperative hypocalcaemia was studied and it was found to be statistically insignificant with a p value of > 0.05. On the contrary in the study by Dr. Pattou et al. the number of parathyroid glands preserved did have a significant role in predicting postoperative hypocalcemia in the early postoperative period [10]. This difference can be possibly explained by temporary hypocalcaemia due to ischaemia or avascular necrosis of the preserved parathyroid gland [15].

Sousa et al. in their study found out that the extent of surgery and re-surgery were risk factors for postoperative hypocalcaemia [16]. In our study also the patients with extensive surgery had more incidence of hypocalcaemia compared to the ones with less extensive surgeries. However, the relation was not statistically significant. This may be explained by the relatively small sample size in our study.

In our study age, gender and malignant conditions did not have statistically significant relationship with developing hypocalcaemia. Baldassarre et al. stated in their study that younger age (less than 45 years), female gender, malignancy increases the risk of developing hypocalcaemia. It was concluded in that study that ethnicity can be a risk factor for hypocalcaemia with Hispanic population being at higher risk than other population groups. It also stated that population-based studies are needed before applying predictors for hypocalcaemia in different population groups. They found that routine Calcium / Vitamin D supplements can reduce the incidence of hypocalcaemia particularly in those patients who were at risk of developing hypocalcaemia [17].

Edafe et al. in their study “Incidence and predictors of post-thyroidectomy hypocalcaemia in a tertiary endocrine surgical unit” found that the preoperative diagnosis did not have significant relation to postoperative hypocalcaemia [5]. This finding is similar to our study.

In “Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia” by Edafe et al. it was found that low postoperative iPTH increases the risk of transient hypocalcaemia and normal iPTH excludes the risk of permanent hypoparathyroidism. However, they did not mention the superiority of any specific timing over another in measuring iPTH. They also concluded that Vitamin D can be considered as an independent predictor despite uncertainty regarding its precision supporting the routine administration of Vitamin D supplementation in patients who are at risk of hypocalcaemia. Fewer identification of parathyroid glands was another risk factor identified. It postulated that female gender can be a risk factor probably due to Vitamin D deficiency in females [3].

Noureldine et al. in their study found that male patients and African American patients had increased iPTH levels offering protection against postoperative hypocalcaemia. This adds to the justification for need of population based studies [4]. Our study is on South Indian population. In this study group, age and gender did not have statistically significant relationship with postoperative hypocalcaemia. However large sample size study in South Indian population is needed to validate this statement.

Le et al. stratified patients into high-risk and low-risk groups for development of hypocalcaemia based on serum PTH levels measured at 1 h after surgery [18]. The cut off taken for low iPTH is less than12 pg/mL. In high risk groups prophylactic calcium and calcitriol supplementation was started. It was concluded that the PTH level measured at 1 h after surgery had a negative predictive value of 98%. Patients in the high-risk group were given calcium supplementation before the development of symptoms hence a valid positive predictive value (PPV) could not be derived. In contrast, in our study the cut off was taken as less than 10 pg/mL and prophylactic calcium and Vitamin D supplementation was not started based on iPTH levels. The PPV and NPV in our study was 97% and 100% respectively which is comparable to this study.

Conclusion

In our study iPTH measured at 1 h after surgery has a positive predictive value of 70% and a negative predictive value of 100% in the occurrence of hypocalcemia in the early postoperative period. We believe that a patient with normal iPTH level measured at 1 h after surgery can safely be considered for early discharge and that additional monitoring in the form of serial calcium levels and monitoring for symptoms/signs of hypocalcemia may be avoided. This would reduce the duration of in-hospital stay and consequently result in decreased patient expenditure while simultaneously conserving hospital resources. At the same time, in patients with low iPTH levels at 1 h after surgery, early supplementation with calcium and Vitamin D may be commenced thereby reducing the risk of developing postoperative hypocalcaemia. However large sample size study in our population is needed to further validate this statement.

Funding

This study was funded from the intramural research funds of JIPMER.

Data Availability

Available.

Declarations

Conflict of interest

The authors declared that they have no conflict of interest.

Ethical Approval

Institute ethics committee approval was taken.

Informed Consent

Informed consent was taken from all participants for data collection and publication.