Percentage Decline of Parathyroid Hormone Level is a Predictor for Post-thyroidectomy Symptomatic Hypocalcemia

Dami Jung; Jong-kyu Kim; Hyungju Kwon; Woosung Lim; Byung-In Moon

doi:10.16956/jes.2017.17.4.168

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Jung, Kim, Kwon, Lim, and Moon: Percentage Decline of Parathyroid Hormone Level is a Predictor for Post-thyroidectomy Symptomatic Hypocalcemia

Original Article

Journal of Endocrine Surgery 2017; 17(4): 168-174.

Published online: 18 December 2017

DOI: https://doi.org/10.16956/jes.2017.17.4.168

Percentage Decline of Parathyroid Hormone Level is a Predictor for Post-thyroidectomy Symptomatic Hypocalcemia

Dami Jung

, Jong-kyu Kim, Hyungju Kwon

, Woosung Lim, Byung-In Moon

Department of Surgery, Ewha Womans University College of Medicine, Seoul, Korea.

Correspondence to Hyungju Kwon. Department of Surgery, Ewha Womans University School of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul 07985, Korea. hkwon@ewha.ac.kr

Received 22 October 2017 Revised 10 December 2017 Accepted 14 December 2017

Korean Association of Thyroid and Endocrine Surgeons

(open-access):

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/).

Abstract

Purpose

Postoperative hypocalcemia is one of the most common complications after thyroid surgery. However, the predictive efficacy of parathyroid hormone (PTH) level was still controversial. We investigated the cut-off value of perioperative PTH level for postoperative hypocalcemia after total thyroidectomy.

Methods

Four hundred eighty-two patients performed total thyroidectomy from January 2015 to December 2016 were enrolled. Demographics, operative variables and the development of symptomatic hypocalcemia were collected and evaluated.

Results

Transient symptomatic hypocalcemia occurred in 83 (17.2%) patients and 5 (1.0%) patients have progressed to the permanent hypocalcemia. Patients with transient symptomatic hypocalcemia showed significantly lower postoperative day 1 PTH level than those without hypocalcemia (7.7±6.5 vs. 13.1±10.4 pg/mL; P<0.001), while correlation between postoperative PTH level and development of symptomatic hypocalcemia was not found in a multivariate analysis (P=0.122). Percentage decline of the preoperative PTH only showed significant association with transient hypocalcemia and the recommended cut-off value was 75.0%. When percentage decline of 75.0% was used, the incidence of transient hypoparathyroidism was 3.4 times (95% confidence interval, 2.1–5.6) higher in high percentage decline group (P<0.001). In regard to the permanent hypoparathyroidism, there were no significant differences in all factors.

Conclusion

Percentage decline of PTH can be used as a predictive factor for postoperative hypocalcemia. Cautions against preventing injury of the parathyroid glands with careful surgical technique should be recommended.

Keywords: Parathyroid hormone, Hypoparathyroidism, Thyroidectomy, Hypocalcemia, Sequelae

INTRODUCTION

Thyroid cancer is the most prevalent cancer in Korea, and its incidence has rapidly increased over the past 10 years (1). As thyroidectomy is the mainstay of therapy for thyroid cancer, postoperative complication is the major concern of surgeons and patients (2). Postoperative hypocalcemia is one of the most common complications after thyroid surgery, with the varying incidence from 1.6% to >50.0% (3 4 5 6). The causes of the postoperative hypocalcemia included surgical trauma to the parathyroid glands, large extent of surgery, inexperience of the surgeon, and concomitant thyroid disease including Graves' disease.

As postoperative hypocalcemia can cause increased length of hospital stay, additional medication, extra blood test, and cost burden on the patients, many researchers have tried to predict postoperative hypocalcemia after thyroid surgery (3). Recent systematic review indicated that perioperative parathyroid hormone (PTH) level, preoperative vitamin D, and postoperative changes of calcium were biochemical predictors of postoperative hypocalcemia (7). Of these factors, postoperative PTH was considered as the most useful predictor of hypocalcemia. However, the predictive ability of PTH level can be affected by the timing of PTH measurement and the cut-off value.

In this context, we evaluated the predictive value of perioperative PTH level for postoperative hypocalcemia after total thyroidectomy.

METHODS

1. Patients

The Institutional Review Boards of the Ewha Womans University Medical Center (Approval No. 2017-09-056) approved this retrospective cohort study. Between January 2015 and December 2016, 485 patients with thyroid cancer underwent total thyroidectomy by a single surgeon. After exclusion of 3 patients with concomitant parathyroid disease, 482 patients were finally included in the present study. Demographic data, preoperative thyroid function, extent of operation, stage of tumor, numbers of removed lymph nodes (LNs), and numbers of sacrificed parathyroid glands were analyzed as well as the development of postoperative symptomatic hypocalcemia.

2. Management protocols

Serum levels of calcium, phosphorus, ionized calcium, and PTH were measured on preoperative day 1, postoperative day 1, postoperative day 14, and postoperative 3 months. Postoperative symptomatic hypocalcemia was defined as an ionized calcium level lower than 4.6 mg/dL (normal range, 4.6–5.4 mg/dL) associated with hypocalcemic symptoms. Hypocalcemic symptoms include perioral numbness, tingling sensations in the fingers or toes, and muscle cramps. In case of mild symptomatic hypocalcemia, patients were supplemented with 1,000–2,000 mg of oral calcium and 1,000 IU of cholecalciferol. When hypocalcemic symptoms were severe or showed no improvement after medication, patients received 2.0 g of intravenous calcium gluconate and were supplemented with 3,000–4,000 mg of oral calcium and 1,000–2,000 IU of cholecalciferol for 2 weeks. Hypocalcemia was considered permanent in patients who required calcium and vitamin D supplementation for longer than 6 months after surgery. All patients were followed-up at 2 weeks, 3 months, 6 months, and annually.

3. Statistical analysis

All results are expressed as mean and standard deviation, absolute numbers, or proportions. Statistical analysis including the Student's t-test, Fisher's exact test, and Mann-Whitney U test was performed using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA). Multivariate logistic regression was used to analyze the relationship between PTH level and development of symptomatic hypocalcemia. Recursive Partitioning And Regression Trees (RPART) classification algorithm in R 3.4.2 (R Development Core Team, Vienna, Austria) was used to find the optimal cutting points for PTH level. A 2-sided P value of 0.05 or less were considered statistically significant.

RESULTS

Of the enrolled 482 patients, 406 (84.2%) were female and 76 (15.8%) were male. Mean age of patients was 48.2±12.1 (range, 20–83 years). Total thyroidectomy without neck dissection was performed in 114 patients (23.7%), while combined central neck dissection was done in 368 patients (76.3%). Mean number of retrieved LNs was 5.0±4.2 (range, 0–23), and the median number of sacrificed parathyroid glands was 1.0 (range, 0–3). Preoperative vitamin D level was 36.4±11.3 pg/mL. The mean serum PTH level at preoperative day1 and postoperative day 1 was 32.3±15.2 pg/mL and 23.2±17.0 pg/mL, respectively. Transient symptomatic hypocalcemia occurred in 83 (17.2%) patients and 5 (1.0%) patients have progressed to the permanent hypocalcemia.

Table 1 showed the characteristics of the patients with or without transient symptomatic hypocalcemia. There were no differences in risk factors including extent of surgery, pathologic stage and number of sacrificed parathyroid glands, except laboratory findings at postoperative day 1. Patients with transient symptomatic hypocalcemia showed significantly lower postoperative day 1 PTH level than those without hypocalcemia (7.7±6.5 vs. 13.1±10.4 pg/mL; P<0.001). In a multivariate analysis, however, there was no correlation between postoperative PTH level and development of symptomatic hypocalcemia (odds ratio, 0.965; 95% confidence interval [CI], 0.923–1.009; P=0.122).

Table 1

Comparison of clinicopathological features between patients with and without symptomatic hypocalcemia

Characteristics		Patients with symptomatic hypocalcemia (n=83)	Patients without symptomatic hypocalcemia (n=399)	P value
Age at operation (yr)		47.7±12.0	48.2±11.9	0.720
Female sex		75 (90.4)	331 (83.0)	0.092
Extent of surgery				0.643
	Total thyroidectomy	18 (21.7)	96 (24.1)
	Total thyroidectomy with central LN dissection	65 (78.3)	303 (75.9)
Operative findings
	Tumor size (cm)	0.9±0.6	0.9±0.6	0.844
	No. of LN retrieval	4.8±3.7	5.1±4.3	0.682
	Median No. of parathyroid glands sacrificed	1.0 (0–3)	1.0 (0–3)	0.170
Pathologic TNM stage				0.429
	T1N0	24 (28.9)	92 (23.1)
	T1N1a	6 (7.2)	36 (9.0)
	T1Nx	3 (3.6)	18 (4.5)
	T2N1a	0 (0.0)	2 (0.5)
	T2Nx	1 (1.2)	0 (0.0)
	T3N0	23 (27.7)	108 (27.1)
	T3N1a	21 (25.3)	115 (28.8)
	T3Nx	5 (6.0)	28 (7.0)
Laboratory findings
	Preoperative vitamin D level (ng/mL)	35.6±10.9	36.6±11.8	0.596
	Preoperative day 1 PTH level (pg/mL)	31.5±14.6	32.5±15.3	0.592
	Postoperative day 1 PTH level (pg/mL)	7.7±6.5	13.1±10.4	<0.001
	Postoperative day 1 ionized calcium level (pg/mL)	1.0±0.1	1.1±0.1	<0.001
	Postoperative day 1 total calcium level (pg/mL)	7.5±0.5	8.1±0.6	<0.001

Data shown are mean±standard deviation, number (%), or mean (range).

LN = lymph node; PTH = parathyroid hormone; TNM = tumor, node, and metastasis.

Using the tree classification algorithm by RPART model, there was no cut-off value for postoperative day 1 PTH measurement. In RPART model, percentage decline of the preoperative PTH only showed significant association with transient hypocalcemia and the recommended cut-off value was 75.0%. When percentage decline of 75.0% was used, the incidence of transient symptomatic hypocalcemia was 3.4 times (95% CI, 2.1–5.6) higher in high percentage decline group (P<0.001). There were no differences in other risk factors, including age, sex, combined central neck dissection, and number of sacrificed parathyroid glands (Table 2). There was no significant difference in all factors, because only 5 patients experienced permanent hypocalcemia.

Table 2

Comparison of clinicopathological features between patients with high percentage decline of PTH and control group

Characteristics		PTH decline over 75% (n=195)	Control (n=287)	P value
Age at operation (yr)		49.3±11.1	47.3±12.4	0.081
Female sex		171 (87.7)	235 (81.9)	0.086
Extent of operation				0.643
	Total thyroidectomy	44 (22.6)	70 (24.4)
	Total thyroidectomy with central neck dissection	151 (77.4)	217 (75.6)
Pathologic characteristics
	Tumor size (cm)	0.9±0.7	0.9±0.6	0.188
	No. of LN retrieval	5.1±4.2	5.0±4.3	0.763
	Median No. of parathyroid glands sacrificed	1.0 (0–3)	1.0 (0–3)	0.488
Laboratory data
	Preoperative vitamin D level (ng/mL)	35.4±10.8	37.4±11.8	0.179
	Preoperative day 1 PTH level (pg/mL)	38.3±13.8	28.3±14.7	<0.001
	Postoperative day 1 PTH level (pg/mL)	5.8±2.2	16.5±10.9	<0.001
Transient hypoparathyroidism		54 (27.7)	29 (10.1)	<0.001

Data shown are mean±standard deviation, number (%), or mean (range).

PTH = parathyroid hormone; LN = lymph node.

DISCUSSION

In the present study, percentage decline of PTH can be used as a predictive factor for postoperative hypocalcemia and percentage decline of 75.0% showed 3.4 times higher incidence for developing symptomatic hypocalcemia. Postoperative hypocalcemia can be divided into 3 types according to the symptom and laboratory status (8). Symptomatic biochemical hypocalcemia is the most critical problem and may progress to the permanent hypocalcemia. Asymptomatic biochemical hypocalcemia has been presumed to be a stunning of parathyroid during the thyroidectomy or perioperative hemodilution. This condition is not a predisposing factor of permanent hypocalcemia. Some patients experienced hypocalcemic symptoms with mismatched biochemical hypocalcemia, defined as decrease of calcium levels despite normal parathyroid function. Asymptomatic or mismatched hypocalcemia can be managed conservatively and make no significant problems. Therefore, prediction of the symptomatic biochemical hypocalcemia is a matter of great interest.

Many studies have tried to predict and prevent postoperative symptomatic hypocalcemia. Laboratory tests including perioperative PTH level, total calcium, ionized calcium, and phosphorus level were evaluated (3 9 10 11 12 13 14 15 16). In most of these studies, postoperative serum PTH was recommended as the most powerful predictor for post-thyroidectomy hypocalcemia, with a sensitivity ranging from 64% to 100% and a specificity ranging from 72% to 100%. However, some studies questioned the role of the postoperative PTH. Lombardi et al. (17) showed that PTH lacked accuracy to predict hypocalcemia. Del Rio et al. (18) also demonstrated that measurement of PTH was not predictive of hypocalcemia by evaluating more than 1,000 patients. These results indicated that the postoperative PTH alone was not sufficient as a predictor of hypocalcemia. In the present study, PTH level at postoperative day 1 also showed no predictive cut-off value for detecting symptomatic hypocalcemia after total thyroidectomy for thyroid cancer.

The single measurement of PTH conflicted with a lack of sensitivity or specificity, depending on the threshold maintained (17 19). To resolve this threshold problem, some investigators studied the PTH decline of the perioperative periods. Lecerf et al. (19) indicated that the PTH decline was more precise than the PTH level alone in early diagnosis of hypocalcemia. Other several studies also have reported that percentage decline of the perioperative PTH level in the immediate postoperative period was useful to predict hypocalcemia, using the thresholds of PTH decline from 50.0% to 75.7% (20 21 22 23). We demonstrated that the percentage decline of preoperative PTH level, using the cut-off value 75.0%, showed significant difference in the chance of transient hypocalcemia (P<0.001). Our result suggested that clinicians could use the percentage decline of PTH level, to predict symptomatic hypocalcemia early and properly after thyroid surgery.

There are some limitations in this study. First of all, the definition of hypocalcemic symptom is subjective and arbitrary, and many previous studies have used their own definitions (13 24 25 26 27 28 29). The result of this study may be biased by the threshold for pain or tingling sensation of the patients. Second, we did not evaluate the role of intraoperative or immediate postoperative PTH measurement. As early measurement of PTH can allow patients early and safe discharge, further study for the role of early PTH measurement is warranted.

CONCLUSION

Notes

^{Author Contributions}

Conceptualization: Dami Jung, Hyungju Kwon, Woosung Lim.
Data curation: Dami Jung, Jong-kyu Kim, Hyungju Kwon.
Formal analysis: Jong-kyu Kim, Hyungju Kwon.
Methodology: Jong-kyu Kim, Woosung Lim.
Supervision: Byung-In Moon.
Validation: Woosung Lim, Byung-In Moon.
Writing - original draft: Hyungju Kwon.
Writing - review & editing:

^{Conflict of Interest} No potential conflict of interest relevant to this article was reported.

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ORCID iDs

Dami Jung
https://orcid.org/0000-0002-4128-5562

Hyungju Kwon
https://orcid.org/0000-0003-4979-8749

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