Predictive value of parathyroid hormone levels for permanent hypoparathyroidism at different time points after papillary thyroid cancer surgery

doi:10.21203/rs.3.rs-3130484/v1

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Predictive value of parathyroid hormone levels for permanent hypoparathyroidism at different time points after papillary thyroid cancer surgery

https://doi.org/10.21203/rs.3.rs-3130484/v1

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Purpose

To investigate the relationship between parathyroid hormone (PTH) levels on day 1 after radical thyroid surgery for papillary carcinoma and permanent hypoparathyroidism (PHPP) and the predictive value of the relationship between them.

Methods

Eighty patients with papillary thyroid cancer who underwent total thyroidectomy and lymph node dissection in the central area admitted to the General Surgery Department of Gansu Provincial People’s Hospital from January 2021 to January 2022 were collected and analyzed. Patients were divided into hypoparathyroidism and normal parathyroid groups according to whether PHPP occurred after surgery, and the correlation between parathyroid hormone (PTH) and serum calcium levels and permanent hypoparathyroidism (PHPP) on postoperative day 1 in both groups was analyzed using univariate and binary logistics regression. The area under the subject operating curve (ROC) was used to assess the predictive validity of PTH for the occurrence of PHPP in the postoperative period.

Results

PHPP occurred in 10 of the 80 patients with papillary thyroid cancer included, with an incidence of 12.5%; binary logistic regression analysis showed that PTH on a postoperative day 1 (OR = 14.534, 95% CI: 2.377 to 88.858, P = 0.004), was an independent predictive risk factor for the development of PHPP after surgery. The area under the curve (AUC) was 0.874 (95% CI: 0.79–0.958, P = 0.000) with a sensitivity of 71.4%, specificity of 100%, and Jorden index of 0.714, using PTH = 8.75ng/L on postoperative day 1 as the threshold value.

Conclusions

PTH levels on day 1 after total thyroid papillary carcinoma are strongly associated with permanent hypoparathyroidism and are an independent predictor of the development of PHPP.

Parathyroid hormone

Radical thyroid cancer surgery

Permanent hypoparathyroidism

Hypocalcemia caused by hypoparathyroidism is one of the common complications after thyroidectomy, which is the main treatment for malignant thyroid tumors[1–2]. According to the literature, the incidence of postoperative transient hypocalcemia in patients undergoing bilateral thyroid surgery was 23.6% and the incidence of permanent hypoparathyroidism was 7.2%[3–4]. Clinical symptoms of hypocalcemia[5] may manifest as facial and hand numbness, and in severe cases, seizures, Tracheal spasms, laryngospasm, and cardiac arrhythmias. The current main treatment for postoperative hypoparathyroidism patients is calcium and vitamin D supplementation; However, the relevant literature reports[6–7], Even with adequate calcium and vitamin D supplementation some hypoparathyroid patients will still have recurrent symptoms of low blood calcium, which affects their quality of life. Therefore, it is important to accurately predict PHPP at an early stage. This study aimed to see whether the detection of parathyroid hormone (PTH) levels at different time points after total thyroidectomy could be a reliable predictor of hypoparathyroidism.

2.1 Study design

Patients with papillary thyroid cancer admitted to the General Surgery Department of Gansu Provincial People's Hospital from January 2021 to January 2022 were collected and analyzed, and all procedures were performed by the same surgeon. Inclusion criteria: (1) Patients undergoing total lumpectomy for thyroid cancer and lymph node dissection in the central region with a thoracic breast approach; (2) Patients with postoperative pathology of papillary thyroid cancer; (3) The postoperative follow-up period is not less than six months. Exclusion Criteria: (1) Prior history of thyroid or neck surgery; (2) Absence of postoperative PTH and blood calcium test results; (3) Those with previous disorders of calcium and phosphorus metabolism; (4) Postoperative follow-up interrupted patients. Eighty patients met the criteria for inclusion in this study through screening and were divided into hypoparathyroidism and normal parathyroidism groups according to whether permanent hypoparathyroidism occurred after surgery. The study was approved by the ethics committee. The patient's family and I have accepted and signed the informed consent form.

2.2 Information on the surgical procedure

Patients in both groups underwent conventional lumpectomy for total thyroidectomy. After general anesthesia, the patient is placed in the supine position and the surgical area is routinely disinfected and toweled. The expansion fluid is injected in the proposed free area, the separation rod separates the observation channel, the expansion fluid is squeezed out, the trocar is placed, and CO2 gas is injected. The anterior interstitial space is separated and freed upward to the level of the thyroid cartilage, the anterior, inferior pole, and lateral aspect of the left thyroid gland in the lax gap between the true and false peritoneum, the anterior cervical musculature is pulled away to fully expose the left thyroid gland, the anterior tracheal space is separated and the isthmus is disconnected. The left inferior pole of the thyroid gland is separated, the inferior thyroid vessels are disconnected, the thyroid gland is freed to the thyroid suspensory ligament, and the cricothyroid gap is entered to complete the freeing of the lateral thyroid gland. The separation of the recurrent laryngeal nerve is completed near the tracheoesophageal groove until it is separated until the recurrent laryngeal nerve is probed into the larynx and the left thyroid is removed. The right thyroid gland was removed in the same way, followed by clearing the lymph nodes in the central region, placing drainage, and closing the incision at the end of the operation. The parathyroid glands were preserved in situ in full accordance with the refined perineural separation technique[8]. For parathyroid glands that were incorrectly excised or hemorrhage damaged, the parathyroid glands were autografted to the brachioradialis muscle of the forearm by homogenous injection[9].

2.3 Observation index and postoperative treatment

PTH and serum calcium levels were recorded and analyzed in both groups before surgery, 8 hours after surgery, 1 day and 3 days after surgery, and 6 months after surgery. Hypoparathyroidism defined as PTH < 15ng/mL for more than six months can be defined as permanent hypoparathyroidism (PHPP)[10–11]. The normal range of serum calcium level is 2.13–2.65 mmol/L. The blood calcium concentration is less than 2.00 mmol/L, hypocalcemia can be considered [12–13]. A blood calcium concentration of 1.90-2.00 mmol/L is considered mild hypocalcemia; blood calcium < 1. 90 mmol/L or the presence of the facial, hand, and foot numbness is considered severe hypocalcemia.

Patients were routinely given 2 to 4 g of calcium gluconate intravenously postoperatively. Oral calcium and osteopontin were also given if postoperative symptoms of hand and foot numbness or twitching occurred. If there are no obvious symptoms after surgery, but laboratory tests suggest blood calcium < 2.0 mmol/L, still take oral calcium routinely to prevent clinical manifestations such as numbness of hands and feet; after blood calcium rises to 2.0 mmol/L, discontinue calcium and osteochondral.

2.4 Statistical analysis

SPSS 26.0 statistical software was applied to process and analyze the data, and the measurement data were expressed as (s), and the independent samples t-test was used if the variance between groups was the same, and the corrected t-test was used if the variance was not the same; a chi-square test was used for univariate analysis, and significant variables were included in the binary logistic regression analysis. Analysis of the relationship between the variables and the occurrence of hypoparathyroidism in patients; and using the operating characteristic curve (ROC) to find the best diagnostic value of PTH at 1 day postoperatively to predict PHPP, P < 0.05 was considered a statistically significant difference.

3.1 Baseline information

The 80 patients included in the study were followed up six months after the procedure. There were 10 patients in the permanent hypoparathyroidism group, with an incidence of 12.5%, including 4 male patients and 6 female patients, age ranged from 22 to 58 years, with a mean age of (43.90 ± 13.18) years. There were 70 patients in the normal parathyroid function group, including 22 male patients and 48 female patients, aged 26–68 years, with a mean age of (49.13 ± 10.19) years.

3.2 Risk factors associated with PHPP

Univariate analysis showed no statistically significant differences in gender, age, comorbidity, and tumor size between the two groups (P > 0.05). Age was grouped by 55 years, and studies have shown that below 55 years is the optimal cut-off age for low-risk patients treated with TNM staging[14–15],27 patients with hypoparathyroidism on a postoperative day 1 (X2 = 19.175, P < 0.05), an incidence of 33.75%; there were 35 patients with hypocalcemia on postoperative day 1 (X2 = 4.535, P < 0.05), with an incidence of 43.75%.PTH and blood calcium levels on postoperative day 1 (P < 0.05) were influential factors for PHPP (Table 1). Factors affecting PHPP in the univariate analysis were included in a binary logistic regression analysis, which showed that PTH level on a postoperative day 1 was an independent factor affecting PHPP (Table 2).

Table 1

Results of univariate analysis of the occurrence of permanent hypoparathyroidism at 6 months postoperatively
group	Number of cases	Sex		age		Combined hypertension		Combined heart disease		Combined diabetes		Tumor diameter		PTH 1 day after surgery			Blood calcium 1 day after surgery
		male	Femle	＜55	≥ 55	Yes	No	Yes	No	Yes	No	＜2cm	≥ 2cm	Regular	Reduce	Regular		Reduce
PHPP Group	n = 10	4	6	7	3	7	3	2	8	4	6	6	4	0	10	2		8
Non-PHPP group	n = 70	22	48	42	28	30	40	25	45	18	52	29	41	53	17	43		27
X²value		0.033		0.369		1.616		0.391		0.322		0.588		19.175			4.535
Pvalue		0.570		0.544		0.204		0.532		0.570		0.443		0.001			0.033

Table 2

Multifactorial analysis of the occurrence of permanent hypoparathyroidism at 6 months postoperatively
Characteristics	β-value	Standard error	wald value	P value	OR	95%CI
Sex	-0.692	1.072	0.416	0.519	0.501	0.061 ~ 4.092
age	-0.917	0.895	1.050	0.306	0.400	0.069 ~ 2.311
Tumour diamete＞2cm	-0.571	0.848	0.454	0.500	0.565	0.107 ~ 2.977
Hypertension	1.204	0.918	1.722	0.189	3.333	0.552 ~ 20.131
Heart disease	-1.318	1.072	1.509	0.219	0.268	0.033 ~ 2.191
Diabetes	1.309	0.984	1.770	0.183	3.702	0.538 ~ 25.466
1 day postoperative PTH	2.677	0.924	8.395	0.004	14.534	2.377 ~ 88.858
1 day postoperatively Blood calcium	0.885	1.073	0.679	0.410	2.422	0.295 ~ 19.860

3.3 Dynamics of PTH in patients with papillary thyroid cancer at different time points after surgery

PTH values at 8 hours, 1 day, 3 days, and 6 months after surgery were observed in patients with papillary thyroid cancer. PTH levels were measured in patients at 8 hours, 1 day, 3 days, and 6 months postoperatively, there were 38 (47.5%) with low PTH at 8 hours; 28 (35%) with low PTH 1 day after surgery, and 18 (22.5%) with low PTH 3 days after surgery; and 10 (12.5%) with low PTH at the 6-month postoperative review. PTH values are returning to normal levels as the postoperative recovery time increases. Those with low PTH were PTH < 15 pg/ml (Table 3)

Table 3

Dynamics of PTH in patients with papillary thyroid cancer at different time points after surgery
	PTH values	Low PTH people
8 hours postoperative	17.46 ± 8.642	38(47.5%)
1 day postoperative	19.03 ± 10.311	28(35.0%)
3 days postoperative	25.53 ± 13.509	18(22.5%)
6 months postoperative	50.18 ± 20.167	10(12.5%)

3.4 ROC curve analysis

ROC curves of PTH levels at 8 hours, 1 day, and 3 days postoperatively to predict hypoparathyroidism showed that: the area under the curve AUC at 1 day postoperatively was the largest with a cut-off value of 8.75 ng/L, an area under the curve AUC of 0.874 (95% CI: 0.79–0.958, P = 0.000), a sensitivity of 71.4%, a specificity of 100% and a Jorden index of 0.714 (Fig. 1).

Identification and protection of the parathyroid glands during thyroid surgery is a skill that every surgeon must be proficient in. However, there is still a risk of early hypocalcemia and PHPP after total thyroidectomy[16]. Because of its fragile blood supply and complex anatomical location, the parathyroid glands are easily damaged during surgery, resulting in hypoparathyroidism, which has a serious impact on postoperative quality of life[17–18].Several studies have shown that operator inexperience, disruption of the blood supply, and miscutting can damage the parathyroid glands leading to hypoparathyroidism^[19–22]. Almquist^[23] obtained from a surveillance follow-up analysis of a large sample of post-thyroidectomy patients that PTH and blood calcium concentrations on day 1 after total thyroidectomy were independent predictors of the risk of permanent hypoparathyroidism after thyroidectomy. In the present study it was concluded by analysis that PTH level on day 1 after total thyroidectomy was an independent influence on hypoparathyroidism, which is the same conclusion as reported by Cai et al ^[13].There is a controversy about when to perform PTH measurement after total thyroid cancer resection, and experts in the country have different opinions about this, with the main statements ranging from 10 min to 24 h after surgery^[24–25].It has been shown that a PTH concentration of 15 pg /mL on postoperative day 1 is not accurate as a threshold value to predict the occurrence of hypoparathyroidism^[26].Some scholars in the relevant literature reported a sensitivity of 100% and a specificity of 92% for predicting hypocalcemia with PTH < 12 ng / L 20 min after thyroidectomy^[27]; Sywak et al^[28]. reported a sensitivity of 90% and a specificity of 84% for PTH (3–10 ng/mL) at 4 h after thyroidectomy. In this study, the ROC curve analysis yielded a PTH value of 8.75 ng/mL as the threshold value on postoperative day 1, with an area under the curve AUC of 0.874 (95% CI: 0.79–0.958, P = 0.000), at which time the sensitivity was 71.4% and specificity was 100%, which is similar to the conclusion reached by Dong et al.^[29].When PTH is measured < 8.75 pg/mL, a value below the normal threshold of 15 pg/mL, there is a greater risk of permanent hypoparathyroidism, the reason for this may be that although the attending surgeon carefully identifies and protects the parathyroid glands during the surgical operation, accidental damage to the parathyroid glands does occur from time to time, and intraoperative miscutting, contusion, thermal injury, or disruption of the blood supply can cause a significant degree of damage to parathyroid function. The lower the PTH value measured on the first postoperative day, the greater the possibility that the function of the parathyroid glands has been affected by damage and that it is difficult to return to normal levels within a short period, and the greater the risk of PHPP occurring after surgery. When PTH > 8.75 pg/mL, the PTH concentration at this time is close to the normal critical value, suggesting that little intraoperative paracrine injury occurred, good recovery of blood supply, and little risk of PHPP. It has been reported that parathyroid function is in dynamic recovery after total thyroidectomy and potentially impaired parathyroid function may slowly recover over time^[30].Therefore, the closer the PTH value is to normal on postoperative day 1, the less likely it is that the parathyroid glands have been damaged. However, the determination of PTH values on postoperative day 1 in the study also has some shortcomings, because each person does not start the procedure at the same time, resulting in different time points for the end of the procedure, but all of them check the PTH values on postoperative day 1, which is less rigorous compared to specific time points such as 8 hours postoperatively, but has the advantage that the method is relatively simple. The results of this study showed that the incidence of PHPP after total thyroidectomy was 12.5%, which was significantly different from the results reported in the survey by Ponce et al[31]. The analysis may be due to the small sample size in this study, which led to a large error.

In conclusion, hypoparathyroidism is one of the common complications after total removal of papillary thyroid cancer. PTH on a postoperative day 1 can be used as a major predictor of hypoparathyroidism, but there are limitations in analyzing patients' PTH and blood calcium levels by testing them only from several time points before and after surgery, and their sample selection is limited by regional and sample size factors. Therefore, we need to further expand the sample size and investigation to confirm that PTH level on day 1 after total thyroid papillary carcinoma is a reliable predictor of hypoparathyroidism.

Authors’ Contributions

Study conception and design Drafting of manuscript:Jinwei Gao

Analysis and interpretation of data:Qi Zhang,Zesheng Wang

Acquisition of data:Shengchang Liang,Yibin Guo,Jinlian Wang

Critical revision of manuscript:Tingbao Cao,Yupeng Zhang,Kunpeng Qu

Ethical Approval

This study was exempted by the Medical Ethics Committee of Gansu Provincial People's Hospital. (Approval number 2022-195).

Conflicts of Interest

The authors declare no conflict of interest.

Funding

This research received no specifc grant from any funding agency in the public, commercial, or not-for-proft sectors.

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No competing interests reported.

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Predictive value of parathyroid hormone levels for permanent hypoparathyroidism at different time points after papillary thyroid cancer surgery

Status:

Version 1

Abstract

Purpose

Methods

Results

Conclusions

Figures

1. Introduction

2. Material and methods

2.1 Study design

2.2 Information on the surgical procedure

2.3 Observation index and postoperative treatment

2.4 Statistical analysis

3. Results

3.1 Baseline information

3.2 Risk factors associated with PHPP

3.3 Dynamics of PTH in patients with papillary thyroid cancer at different time points after surgery

3.4 ROC curve analysis

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

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