Does vitamin D deficiency really increase the risk of post-surgical hypoparathyroidism?

doi:10.21203/rs.3.rs-2095976/v1

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Does vitamin D deficiency really increase the risk of post-surgical hypoparathyroidism?

https://doi.org/10.21203/rs.3.rs-2095976/v1

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BACKGROUND: Postoperative hypoparathyroidism is the most frequent complication after total thyroidectomy. The identification of preoperative predictors could be helpful to identify patients at risk. The aim of this study is to determine if preoperative vitamin D levels are related to transient, protracted, and permanent hypoparathyroidism.

METHOD: A prospective, observational study that includes 100 patients who underwent total thyroidectomy.

RESULTS: Transient hypoparathyroidism was present in 42% of patients, 11% developed protracted hypoparathyroidism and 5% permanent hypoparathyroidism.

The median preoperative Vitamin D levels were higher in patients who developed transient hypoparathyroidism than in patients without this complication (24 ng/mL [RIQ 13-31] vs. 17 ng/mL [RIQ 10-24]; p=0.024). Patients with preoperative vitamin D levels below 20 ng/mL had a lower percentage of transient hypoparathyroidism (31.4% vs. 53.1%; p=0.028). The prevalence of protracted and permanent hypoparathyroidism in both groups was similar. Patients with preoperative vitamin D levels lower than 20 pg/mL had higher median PTH levels 24 hours after surgery, (37.7 ± 28.2 pg/ml vs. 23.6 ± 18.6 pg/ml; p=0.037), and suffered a lower postoperative PTH decline (46.2 ± 35.4 % vs. 61 ± 29 %; p=0.026).

CONCLUSIONS:Patients with vitamin D deficiency had a lower transient hypoparathyroidism rate, higher median PTH levels 24 hours after surgeryand a lower postoperative PTH decline. We found no association between preoperative vitamin D and the development of protracted or permanent hypoparathyroidism.

total thyroidectomy

postoperative hypoparathyroidism

vitamin D deficiency

protracted hypoparathyroidism

permanente hypoparathyroidism

A total thyroidectomy is considered as a procedure of low morbidity and mortality, but does present complications, such as postoperative hypoparathyroidism, which represents the most frequent complication (1).

Hypoparathyroidism is caused by multiple factors, some of which are patient-dependent, such as sex, age, or comorbidities; others are associated with the surgical indication and technique. It is usually a consequence of manipulation or thermal lesion of the parathyroid glands causing a de-vascularization or inadvertent resection, which occurs in 5-20% of cases (2,3).

The incidence of postsurgical hypoparathyroidism varies between 1.6% and 68% depending on different series, which shows the heterogenicity of the studies and lack of definition consensus (4,5). Permanent hypoparathyroidism is present 1 year after surgery in 0.5-3% of the cases (6).

Postoperative hypoparathyroidism results in a longer hospital stay and increased health costs. Patients with permanent hypoparathyroidism suffer a lower quality of life, with use of chronic medication, continuous specialist consultations and emergency room visits.

The identification of possible factors that may predict postoperative hypoparathyroidism could have clinical relevance, and especially classifying patients according to their risk of postoperative hypoparathyroidism.

Vitamin D deficiency is a highly prevalent condition in our population (7). One of the factors that can be related to postoperative hypoparathyroidism is vitamin d deficiency.

However, its influence in the development of hypoparathyroidism is still controversial. Some studies have found a relationship between preoperative vitamin D deficiency and the development of hypoparathyroidism (8-11); whereas, other studies did not show any association (12-14), even demonstrating an inverse relationship between preopertive vitamin D levels and the risk of hypoparathyroidism (15).

The aim of this study is to determine if preoperative vitamin D levels are related to transient, protracted, and permanent hypoparathyroidism.

Patients and study design

A prospective, longitudinal, observational study of a series of 100 consecutive patients who underwent a total thyroidectomy between September 2018 and September 2020 was carried out. The patients had a follow-up of at least 1 year after surgery. The study was approved by the Institutional review board at Ramon y Cajal University Hospital.

Exclusion criteria included: previous thyroid or parathyroid surgery, hemithyroidectomy, patients with primary or secondary hyperparathyroidism, and those who rejected participating in the study.

Biochemical analysis

Serum levels of albumin, calcium, phosphorus, magnesium, alkaline phosphatase, intact PTH, TSH and Vitamin D-25, as well as glomerular filtration rate were measured before surgery.

Definitions

Transient hypoparathyroidism was defined as total serum calcium levels lower than 8.0 mg/dL, or patients whose PTH levels were less than 15 pg/mL 24 hours after surgery.

Protracted hyperparathyroidism was defined as cases in which PTH levels continued being lower than 15 pg/mL one month after surgery, or if oral supplements of calcium or vitamin D were necessary to maintain calcium levels above 8.5 mg/dL (16).

The cases in which medication was necessary 12 months after surgery were considered as permanent hypoparathyroidism.

Statistical analysis

Statistics data was analyzed using SPSS 20.0 for Windows (SPSS Inc, Chicago, IL). Student’s t-test was used for the comparison between quantitative and qualitative variables when samples were independent (comparison between two means) and ANOVA (comparison between more than two means) when the quantitative variables followed a normal distribution. When quantitative variables did not follow a Gaussian distribution, Mann-Whitney test was used to compare two means and Kruskal-Wallis to compare more than two means. The Pearson correlation method was used for the analysis of two normal quantitative variables, whereas Spearman’s test was used if one or more of the variables did not follow a Gaussian distribution. A p-value of < 0.05 was considered statistically significant.

The distribution by sex in our sample was 84 women (84%) and 16 men (16%). The global average age was 54.9 ± 14.8 years old. The main indication of total thyroidectomy was multinodular goiter, in 57% of the cases. A total thyroidectomy and central compartment lymph node dissection was done in 18% of the cases.

The average postoperative hospital stay was 1.78 ± 1.4 days (range 1-8 days). The most frequent complication was transient hypoparathyroidism, in 42% of the patients. The prevalence of protracted hypoparathyroidism one month after surgery was 11% of the entire sample. Seventy-four percent of the patients who developed transient hypoparathyroidism recovered parathyroid function one month after surgery, but the remaining 26% developed protracted hypoparathyroidism.

The prevalence of permanent hypoparathyroidism one year after surgery was 5%. Twelve percent of the patients who had transient hypoparathyroidism after surgery developed permanent hypoparathyroidism. Among the 11 patients who had protracted hypoparathyroidism, parathyroid function improved before 12 months after surgery in 54.5%, and the remaining 45.5% developed permanent hypoparathyroidism.

There were no statistically significant differences in the incidence of hypoparathyroidism regarding to sex, age, initial diagnosis and/or surgical technique. The descriptive analysis of the study population is summarized in table 1.

The median preoperative Vitamin D levels were higher in patients who developed transient hypoparathyroidism than in patients without this complication (24 ng/mL [RIQ 13-31] vs. 17 ng/mL [RIQ 10-24]; p=0.024). There were no statistically significant differences in the median preoperative vitamin D between patients with protracted and permanent hypoparathyroidism (13 ng/ml (RIQ 10-27) vs. 20 ng/ml (RIQ 12-29,2); p=0.396) and (13 ng/ml [RIQ 9-33] vs. 20 ng/ml [RIQ 12-28.7]; p=0.590).

The sample was distributed into three groups based on their preoperative vitamin D levels. A ROC curve was constructed, and the AUC was shown to be 0.62. The group distribution was done as follows:

Group 1: preoperative vitamin D lower than 20 pg/mL (n=51)
Group 2: preoperative vitamin D higher than 20 pg/mL (n=49)

Patients with preoperative vitamin D levels below 20 ng/mL had a lower percentage of transient hypoparathyroidism (31.4% vs. 53.1%; p=0.028). The prevalence of protracted and permanent hypoparathyroidism in both groups was similar (11.8% vs. 10.2%; p=0.803) and (5.9% vs. 4.1%; p=0.680). These results are shown in Table 2.

Patients in group 1, with a preoperative vitamin D lower than 20 pg/mL, had a higher median preoperative PTH, but these differences were not statistically significant (75.2 ± 34.3 pg/ml vs. 66.3 ± 26.7 pg/ml; p=0.259).

Patients in group 1 also, had higher median PTH levels than patients in group 2, 24 hours after surgery, (37.7 ± 28.2 pg/ml vs. 23.6 ± 18.6 pg/ml; p=0.037), and suffered a lower postoperative PTH decline (46.2 ± 35.4 % vs. 61 ± 29 %; p=0.026).

Postoperative hypoparathyroidism is caused by manipulation or thermal injury of the parathyroid glands that become de-vascularizated, or from their inadvertent removal. Surgical experience and knowledge of cervical anatomy are crucial, however, there are other factors that could influence the development of hypoparathyroidism.

Many studies have tried to demonstrate the association between preoperative Vitamin D levels and development of postoperative hypoparathyroidism, but its role remains controversial.

Erbil et al determined in a 2009 study that preoperative vitamin D levels were lower in patients suffering from postoperative hypoparathyroidism. All patients with preoperative levels below 15 ng/mL suffered from hypoparathyroidism, compared to the 9.5% of patients with preoperative vitamin D levels above 15 ng/mL (8). Erbil et al group had published similar conclusions previously, showing that patients with preoperative vitamin D levels lower than 25 ng/mL have a 15-fold increased risk of developing postoperative hypoparathyroidism (9).

Kirkby-Bott et al also found differences between preoperative vitamin D levels, describing a hypoparathyroidism rate over 35% in patients with vitamin D <10 ng/mL, compared to a 15% rate in patients with levels over 20 ng/mL (10).

In the latest metanalysis published in 2021, eight studies analyzed preoperative vitamin D levels as a factor of postsurgical hypoparathyroidism. They reported a significantly higher incidence of transient hypocalcemia in patients with preoperative severe vitamin D deficiency (serum 25OHD levels < 10 ng/ml) and in patients with preoperative vitamin D deficiency (serum 25OHD levels < 20 ng/ml). Therefore, preoperative supplementation of oral vitamin D should be considered a way of minimizing hypocalcemia in these patients (11).

Manzini et al found that patients with severe preoperative vitamin D deficiency (serum 25OHD levels < 10 ng/ml) had a higher tendency to develop transient hypoparathyroidism, but without statistically significant differences, they also concluded that high preoperative vitamin D levels does not reduce the risk of permanent hypoparathyroidism (12).

On the other hand, other studies, have not found this association (13,14). Lang et al analyzed 281 patients who underwent total thyroidectomy and found an inverse relationship between preoperative vitamin D and postoperative PTH levels. Patients with preoperative vitamin D <10 ng/mL had higher PTH levels 24 hours after surgery, a lower percentage of PTH decrease at 24 hours and a lower rate of postoperative hypoparathyroidism than patients with vitamin D above 20 ng/mL (15). In our study, patients with transient hypoparathyroidism had significantly higher median preoperative vitamin D levels than patients without this complication. Furthermore, patients with vitamin D > 20 ng/mL presented a higher percentage of hypoparathyroidism the day after surgery (53.1% vs 31.4%; p=0.028) with a lower PTH at 24 hours and a higher percentage of PTH decrease than patients with vitamin D below 20 ng/mL, in line with the results of Lang et al.

Patients with vitamin D deficiency present secondary hyperparathyroidism, as a compensatory mechanism, and may associate hyperplasia of the parathyroid glands that expose them to greater risk during surgery (17).

Another possible hypothesis could be that the half-life of 25 (OH) vitamin D is approximately two weeks, higher than that of PTH, which is a few minutes; therefore, higher vitamin D levels inhibit the synthesis of PTH, so these patients could have less PTH synthesis during the immediate postoperative period (18). We did not find an association between vitamin D and the development of protracted or permanent hypoparathyroidism.

Even though this study is prospective, it does have its limitations. Patient recruitment was done in only one center. Patients were operated on by different surgeons of the Endocrine Surgery Unit of the General Surgery Department. The preoperative biochemical panel, which included vitamin D and PTH levels, was obtained from an isolated sample. The time elapsed between the preoperative measurements and the surgery, as well as their variations over time, could influence the results. The sample size is small, and some results could reach the statistical significance by increasing the sample size

The best way to preserve parathyroid function continues to be a meticulous surgical technique. Patients with vitamin D deficiency had a lower transient hypoparathyroidism rate, higher median PTH levels 24 hours after surgery and a lower postoperative PTH decline. We found no association between preoperative vitamin D and the development of protracted or permanent hypoparathyroidism.

Authors’ Contributions:

Study conception and design: José Alberto Vilar Tabanera, Joaquín Gómez.

Acquisition of data: José Alberto Vilar Tabanera; Ana Puerta.

Analysis and interpretation of data: José Alberto Vilar Tabanera; Alberto González Barranquero.

Drafting of manuscript: José Alberto Vilar Tabanera; Philip Brabyn.

Critical revision of manuscript: Joaquín Gómez; José María Cebrián.

Conflict of Interest: The authors declare that they have no conflict of interest.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Thomusch O, Machens A, Sekulla C, Ukkat J, Lippert H, Gastinger I, Dralle H. Multivariate analysis of risk factors for postoperative complications in benign goiter surgery: prospective multicenter study in Germany. World J Surg. 2000 Nov;24(11):1335-41.
Sakorafas GH, Stafyla V, Bramis C, Kotsifopoulos N, Kolettis T, Kassaras G. Incidental parathyroidectomy during thyroid surgery: an underappreciated complication of thyroidectomy. World J Surg. 2005 Dec;29(12):1539-43.
Gourgiotis S, Moustafellos P, Dimopoulos N, Papaxoinis G, Baratsis S, Hadjiyannakis E. Inadvertent parathyroidectomy during thyroid surgery: the incidence of a complication of thyroidectomy. Langenbecks Arch Surg. 2006 Nov;391(6):557-60.
Pattou F, Combemale F, Fabre S, Carnaille B, Decoulx M, Wemeau J-L, et al. Hypocalcemia following Thyroid Surgery: Incidence and Prediction of Outcome. World Journal of Surgery. 1998 Jul 1;22(7):718–24.
Asari R. Hypoparathyroidism After Total Thyroidectomy. Archives of Surgery. 2008 Feb 1;143(2):132.
Qin Y, Sun W, Wang Z, Dong W, He L, Zhang T, et al. A Meta-Analysis of Risk Factors for Transient and Permanent Hypocalcemia After Total Thyroidectomy. Frontiers in Oncology. 2021 Feb 24;10.
Arabi A, El Rassi R, El-Hajj Fuleihan G (2010) Hypovitaminosis D in developing countries - prevalence, risk factors and outcomes. Nat Rev Endocrinol 6(10):550–561
Erbil Y, Barbaros U, Temel B, Turkoglu U, Işsever H, Bozbora A, et al. The impact of age, vitamin D3 level, and incidental parathyroidectomy on postoperative hypocalcemia after total or near total thyroidectomy. Am J Surg. 2009;197(4):439–46.
Erbil Y, Bozbora A, Ozbey N, Issever H, Aral F, Ozarmagan S, et al. Predictive value of age and serum parathormone and vitamin d3 levels for postoperative hypocalcemia after total thyroidectomy for nontoxic multinodular goiter. Arch Surg. 2007;142(12):1182–7.
Kirkby-Bott J, Markogiannakis H, Skandarajah A, Cowan M, Fleming B, Palazzo F. Preoperative vitamin D deficiency predicts postoperative hypocalcemia after total thyroidectomy. World J Surg. 2011;35(2):324–30.
Vaitsi KD, Anagnostis P, Veneti S, Papavramidis TS, Goulis DG. Preoperative vitamin D deficiency is a risk factor for postthyroidectomy hypoparathyroidism: A systematic review and meta-analysis of observational studies. J Clin Endocrinol Metab. 2021;106(4):1209–24.
Manzini G, Malhofer F, Weber T. Can preoperative vitamin D deficiency predict postoperative hypoparathyroidism following thyroid surgery? Langenbeck’s Arch Surg. 2019;404(1):55–61.
Lin Y, Ross HL, Raeburn CD, DeWitt PE, Albuja-Cruz M, Jones EL, et al. Vitamin D deficiency does not increase the rate of postoperative hypocalcemia after thyroidectomy. The American Journal of Surgery. 2012 Dec;204(6):888–94.
Cherian AJ, Ponraj S, Gowri S M, Ramakant P, Paul T V., Abraham DT, et al. The role of Vitamin D in post-thyroidectomy hypocalcemia: Still an enigma. Surg (United States). 2016;159(2):532–8.
Lang BHH, Wong KP, Cheung CY, Fong YK, Chan DKK, Hung GKY. Does preoperative 25-hydroxyvitamin D status significantly affect the calcium kinetics after total thyroidectomy? World J Surg. 2013;37(7):1592–8.
Lorente-Poch L, Sancho JJ, Muñoz-Nova JL, Sánchez-Velázquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surg. 2015 Feb;4(1):82-90.
Vibhatavata P, Pisarnturakit P, Boonsripitayanon M, Pithuksurachai P, Plengvidhya N, Sirinvaravong S. Effect of preoperative vitamin D deficiency on hypocalcemia in patients with acute hypoparathyroidism after thyroidectomy. Int J Endocrinol. 2020; 2020:5162496.
Boullata JI. Vitamin D supplementation: a pharmacologic perspective. Curr Opin Clin Nutr Metab Care. 2010 Nov;13(6):677-84.

Table 1: Transient hypoparathyroidism (TH) Protracted hypoparathyroidism (ProH) Permanent hypoparathyroidism (PH)

	Transient	No TH	P-value	Protracted	No ProH	P-value	Permanent	No PH	P-value
Sex
Female	33/84 (39.3%)	51/84 (60.7%)	0.208	9/84 (10.7%)		0.76	3/84 (3.6%)		0.18
Male	9/16 (56.3%)	7/16 (43.7%)	0.208	2/16 (12.5%)			2/16 (12.5%)
Age	55.88 ± 13.87	54.16 ±15.48	0.566	55 ±15	53.5±13.3	0.736	49.8 ± 13.3	55.2 ± 14.9	0.428
Diagnosis			0.465			0.953			0.915
Multinodular goiter	21/57 (36.8%)	36/57 (63.2%)		7/57(12.5%)	50/57 (87.5%)		3/57 (5.3%)	54/57 (94.7%)
Papillary Carcinoma	14/30 (46.7%)	16/30 (53.3%)		3/30 (10%)	27/30 (90%)		1/30 (3.3%)	29/30 (96.7%)
Graves’ disease	6/12 (50%)	6/6 (50%)		1/12 (8.3%)	11/12 (91.7%)		1/12 (8.3%)	11/12 (91.7%)
Medullary Carcinoma	1/1 (100%)	0 (0%)		0/1 (0%)	1/1 (100%)		0/1 (0%)	1/1 (100%)
Surgery performed			0.198			0.987			0.905
Total Thyroidectomy (TT)	32/82 (39%)	50/82 (61%)		9/82 (11%)	73/82 (89%)		4/82 (4.9%)	78/82 (95.1%)
TT + lymph node dissection	10/18 (55.6%)	8/10 (44.4%)		2/18 (11.1%)	16/18 (88.9)		1/18 (5.6%)	17/18 (94.4%)
Hospital stay (days)	2.71 ± 1.7	1.1 ± 0.3	0.000

Table 2: Preoperative Vitamin D.

	Transient	No TH	P-value	Protracted	No ProH	P-value	Permanent	No PH	P-value
Median preoperative Vitamin D	24 ng/mL [RIQ 13-31]	17 ng/mL [RIQ 10-24]	p=0,024	13 ng/ml (RIQ 10-27)	20 ng/ml (RIQ 12-29,2)	0,396	13 ng/ml (RIQ 9-33)	20 ng/ml (RIQ 12-28,7)	0,590
< 20 ng/dl (N=51)	16/51 (31,4%)	35/51 (78,6%)	0,028	6/51 (11,8%)	45/51 (82,2%)	0,803	3/51 (5,9%)	48/51 (94,1%)	0,680
>20 ng/dL (N=49)	26/49 (53,1%)	23/49 (46,9%)	0,028	5/49 (10,2%)	44/49 (89,8%)	0,803	2/49 (4,1%)	47/49 (95,9%)	0,680

No competing interests reported.

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Does vitamin D deficiency really increase the risk of post-surgical hypoparathyroidism?

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