Does Vitamin D Deficiency Really Increase the Risk of Post-surgical Hypoparathyroidism?

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. A prospective, observational study that includes 100 patients who underwent total thyroidectomy. 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 h 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). Patients with vitamin D deficiency had a lower transient hypoparathyroidism rate, higher median PTH levels 24 h after surgery and a lower postoperative PTH decline. We found no association between preoperative vitamin D and the development of protracted or permanent hypoparathyroidism.


Introduction
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 relevance, and especially classifying patients according to their risk of postoperative hypoparathyroidism.
One of the factors that can be related to postoperative hypoparathyroidism is 25-OH Vitamin D deficiency which is a highly prevalent condition in our population [7].
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][9][10][11]; whereas, other studies did not show any association [12][13][14], even demonstrating an inverse relationship between preoperative 25-OH 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 associated to high serum calcium levels, and those who rejected participating in the study.

Definitions
Transient hypoparathyroidism was defined as cases in which PTH levels were less than 15 pg/mL 24 h after surgery.
Protracted hypoparathyroidism 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 25-OH 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.

Results
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.
We compared the biochemical parameters analyzed preoperatively in patients with and without hypoparathyroidism in the postoperative period, no statistically significant differences were found in preoperative serum levels of albumin, calcium, phosphorus, magnesium, alkaline phosphatase, TSH and glomerular filtration rate.
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. 74% 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%. 12% 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% of cases 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 and demographics parameters of the study population are summarized in Table 1.
The sample was distributed into two groups based on their preoperative 25-OH Vitamin D levels. A ROC curve was constructed, and the AUC was shown to be 0.62, the cut-point of 20 pg/mL had a sensitivity of 62% and 64.5% specificity.
We analyze the preoperative calcium levels in both groups. There were no statistically significant differences in 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 25-OH Vitamin D and postoperative PTH levels. Patients with preoperative 25-OH Vitamin D < 10 ng/mL had higher PTH levels 24 h after surgery, a lower percentage of PTH decrease at 24 h and a lower rate of postoperative hypoparathyroidism than patients with 25-OH Vitamin D above 20 ng/mL [15]. In our study, patients with transient hypoparathyroidism had significantly higher median preoperative 25-OH Vitamin D levels than patients without this complication. Furthermore, patients with 25-OH 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 h and a higher percentage of PTH decrease than patients with 25-OH Vitamin D below 20 ng/mL, in line with the results of Lang et al.
One 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 25-OH Vitamin D levels inhibit the synthesis of PTH, so these patients could have less PTH synthesis during the immediate postoperative period [17], however serum calcium is the most important driver of parathyroid hormone secretion. We did not find an association between 25-OH Vitamin D and the development of protracted or permanent hypoparathyroidism.
This study supports the hypothesis that clinicians might be encouraged to withdraw vitamin D supplementation in subjects with vitamin D deficiency.
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 25-OH 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.

Conclusions
The best way to preserve parathyroid function continues to be a meticulous surgical technique. Patients with 25-OH Vitamin D deficiency had a lower transient hypoparathyroidism rate, higher median PTH levels 24 h after surgery the median preoperative calcium levels (Group 1; 9.33 mg/ dL ± 0.41 vs. Group 2; 9.43 ± 0.43 mg/dL; p = 0.23).
We measure the calcium levels 24 h after surgery and there were no statistically significant differences in the median postoperative calcium levels comparing both groups (8.67 ± 0.67 mg/dL vs. 8.49 mg/dL ± 0.62; p = 0.19).

Discussion
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 25-OH Vitamin D levels and development of postoperative hypoparathyroidism, but its role remains controversial.
Erbil et al. determined in a 2009 study that preoperative 25-OH 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 25-OH Vitamin D levels above 15 ng/mL [8]. Erbil et al. group had published similar conclusions previously, showing that patients with preoperative 25-OH 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 25-OH Vitamin D levels, describing a hypoparathyroidism rate over 35% in patients with 25-OH 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 25-OH Vitamin D levels as a factor of postsurgical hypoparathyroidism. They reported a significantly higher incidence of transient hypocalcemia in patients with preoperative severe 25-OH Vitamin D deficiency (serum 25-OH Vitamin D levels < 10 ng/ml) and in patients with preoperative 25-OH Vitamin D deficiency (serum 25-OH Vitamin D levels < 20 ng/ml). Therefore, preoperative supplementation of oral 25-OH Vitamin D should be considered a way of minimizing hypocalcemia in these patients [11].
Manzini et al. found that patients with severe preoperative 25-OH 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 25-OH Vitamin and a lower postoperative PTH decline. We found no association between preoperative vitamin D and the development of protracted or permanent hypoparathyroidism.
Funding No financial support is needed.

Data Availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate All the procedures were followed in accordance with Declaration of Helsinki. Ramon y Cajal Hospital ethics committee approved the study. Written informed consent was obtained from all subjects and/or their legal guardian(s).

Consent for publication
Written informed consent was obtained from all subjects and/or their legal guardian(s). Manuscript has not been published previously and is not under consideration elsewhere.