Preoperative Vitamin D Levels as a Predictor of Transient Hypocalcemia and Hypoparathyroidism After Parathyroidectomy

Hypocalcemia is a common problem after parathyroidectomy and/or thyroidectomy. The complication may be transient or permanent. Most cases occur as a result of removal of the parathyroid glands or damage to the glands during neck surgery. The purpose of this study was to evaluate the effect of preoperative vitamin D deficiency in predicting transient hypocalcemia and hypoparathyroidism after parathyroidectomy.Retrospective evaluation was made of 180 patients with primary hyperparathyroidism in respect of serum 25(OH)D, calcium and parathyroid hormone before and after parathyroidectomy. Transient hypocalcemia was defined as corrected calcium ≤ 8.4 mg/dL, and these cases were then evaluated for preoperative 25(OH)D values. Transient hypoparathyroidism has been described as low PTH level immediately after surgery before beginning any supplementation. Permanent hypoparathyroidism is accepted as the need for medical treatment is necessary over 12 months.Both transient hypocalcemia and hypoparathyroidism developed at statistically significantly higher rates in patients with preoperative vitamin D deficiency and vitamin D insufficiency.Vitamin D deficiency is an independent contributor to transient hypocalcemia and hypoparathyroidism following parathyroidectomy.

Vitamin D3 is made in the skin from 7-dehydrocholesterol under the influence of UV light. Vitamin D is metabolized first to 25 hydroxyvitamin D (25OHD), then to 1,25-dihydroxyvitamin D (1,25(OH)2D). 1,25(OH)2 vitamin D, the active metabolite of vitamin D, also known as calcitriol, regulates not only calcium and phosphate homeostasis but also cell proliferation and differentiation, and has a key a role to play in the responses of the immune and nervous systems. Also, in vivo novel pathways of vitamin D3 metabolism were defined generating D3-hydroxy derivatives different from 25-hydroxyvitamin D3 [25(OH)D3] and 1,25(OH)(2)D3 in placenta, adrenal gland, and epidermal keratinocytes [8][9][10][11] .
Surgery is always an appropriate option for individuals with PHPT and operative management is more effective and less costly than either long-term observation or medical treatment. After a parathyroidectomy, nephrolithiasis incidence decreases, the bone mass densities of the lumbar spine and femoral neck increase compared to preoperative values, and fractures frequency decrease 12 .
Hypocalcemia is a common problem after parathyroidectomy and/or thyroidectomy. Gambardella et al. reported transient hypoparathroidism rates of 11.4% in total thyroidectomy vs 21.4% in total thyroidectomy with prophylactic central neck dissection and permanent hypoparathyroidism rates of 1.5% in total thyroidectomy vs 6.4% in total thyroidectomy with prophylactic central neck dissection 13 .
There are no specific data for the prediction and management of hypocalcemia in patients with parathyroidectomy. The hypothesis of the study was that preoperative vitamin D deficiency indicates higher risk for postoperative transient hypoparathyroidism and hypocalcemia in patients following parathyroidectomy.

Materials and methods
Study population. This retrospective study included a total of 180 patients with primary hyperparathyroidism. Patients who underwent concomitant thyroidectomy, permanent hypoparathyroidism or were aged <18 years were not included in the study (Fig. 1). The study was performed at the Endocrinology Department of Diskapi Yildirim Beyazit Training and Research Hospital between November 2014 and December 2018. The Corporation, NY, USA). The Kolmogorov-Smirnov test was used to assess the conformity of the data to normal distribution. Categorical data were presented with frequencies and percentages (%). All continuous data with normal distribution were presented as mean ± standard deviation (SD), and in the case of non-normally distributed data were presented as median (range) values. The Kruskal-Wallis test was performed to compare non-normally distributed data. The relationships between categorical variables were examined using Chi-square analysis. A value of p < 0.05 was considered statistically significant.

Results
Initially, 256 patients with primary hyperparathyroidism were enrolled in the study, and after the exclusion of 76 patients for various reasons (Fig. 1), and the study was continued with 180 patients. Only patients who underwent minimally invasive parathyroidectomy or unilateral parathyroidectomy were included in the study. The mean age of patients was 54.9 ± 12.2 years, and the majority 147/180, (81.7%) were female. The demographic characteristics and biochemical parameters of the patients are shown in Table 1. Postoperative histopathological examination demonstrated adenoma in 156 (%87,3) cases, hyperplasia in 13 (%10,5) cases, carcinoma in 2 (%1.1) cases, and double adenoma in 2 cases (%1,1). Vitamin D deficiency was determined in 62.22% of patients and vitamin D insufficiency 25.56% of patients (Fig. 2). Preoperatively, 22 patients (12.2%) had normal levels of vitamin D. At the end of the study, 37% of patients were determined with transient hypocalcemia and 24% with transient hypoparathyroidism (Figs. 3 and 4). After the parathyroidectomy median calcium levels were low in both vitamin D deficiency and insufficiency groups compared with the normal D vitamin group (p = 0,02) ( Table 2). The rate of transient hypocalcemia and transient hypoparathyroidism was statistically significantly higher in the groups with vitamin D deficiency or insufficiency compared to the normal vitamin D level group (p = 0.02, p = 0.04, respectively) ( Table 3).

Discussion
PHPT is a common endocrine disorder due to a surge in incidental diagnosis with routine laboratory testing. Surgery is always the most suitable option for individuals with PHPT, with focused exploration and bilateral parathyroid exploration as the standard surgical options for patients with primary hyperparathyroidism 14 .
Commonly accepted indications for parathyroidectomy are osteoporosis, fragility fracture, nephrolithiasis, hypercalciuria, renal insufficiency, moderate hypercalcemia, and age <50 years 15 . Hypocalcemia is an important potential complication of parathyroid exploration. Hypocalcemia may be transient or permanent. Parathyroid autotransplantation can be used to reduce the risk of permanent hypocalcemia, although this does not affect transient hypocalcemia, because reimplanted glands achieve normal function after 3 to 14 weeks [16][17][18] . Transient hypoparathyroidism may be due to manipulation of the blood supply to or removal of one or more parathyroid glands during surgery, whereas permanent hypoparathyroidism is due to a decreased parathyroid reserve. The risk of postoperative hypoparathyroidism and hypocalcemia increases in particular with extensive thyroidectomy, www.nature.com/scientificreports www.nature.com/scientificreports/   www.nature.com/scientificreports www.nature.com/scientificreports/ completion procedures, and central neck dissection. Previous studies have shown that bilateral parathyroid exploration is associated with higher rates of postoperative hypocalcemia 14,19,20 . The current study included only patients who underwent minimally invasive parathyroidectomy or unilateral parathyroidectomy. In a previous meta-analysis of 12743 cases, postoperative hypocalcemia was determined at the rate of 1.6% in focused parathyroid exploration vs 13.2% in bilateral exploration 14 .
Philips et al. found PTH to be a significant predictor for hypocalcemia after unplanned parathyroidectomy. PTH ≤ 15.5 significantly increases the risk of developing hypocalcemia, and prophylactic ≥1000 mg elementary calcium is recommended for these patients 12 . In another study, the preoperative PTH level was found to be one of the most important factors associated with postoperative hypocalcemia in patients who underwent thyroidectomy 21 . Soares et al. showed that postoperative hypocalcemia was associated only with parathyroid hormone and the preoperative vitamin D levels of patients were no different in those with or without hypocalcemia. In that study serum 25(OH)D concentrations were not found to be predictors for hypocalcemia 22 25 . Hence, the role of vitamin D level as a predictor for hypocalcemia is still controversial.
Interestingly, in the current study, a relationship was observed between postparathyroidectomy transient hypocalcemia and preoperative 25(OH)D levels, and the 25(OH)D level was seen to predict hypocalcemia in patients with primary hyperparathroidism after parathyroidectomy. Theoretically, patients with reduced serum Vitamin D levels are more prone to develop hypocalcemia due to a higher dependency on PTH-induced bone and renal re-absorption mechanisms 22 . Decreased serum calcium due to functional hypoparathyroidism causes reductions in bone reabsorption and increases in bone formation and an increased influx of calcium into bone. Following parathyroidectomy in patients with primary hyperparathyroidism, hypocalcemia is further exacerbated by increased calcium excretion and decreased intestinal calcium absorption owing to reduced PTH-mediated renal 1,25 dihydroxyvitamin D production further exacerbate a hypocalcemia 12 . In patients with vitamin D deficiency, calcium homeostasis is provided by increasing PTH secretion in the blood. In the current study, transient hypoparathyroidism was determined more in the vitamin D deficiency and insufficiency groups (p = 0.04). This may be related to the higher preoperative PTH level than normal due to the secondary hyperparathyroidism effect. In a previous study, the rate of hypocalcemia was found to be high in patients with preoperative PTH near the upper limit (p < 0.01) 21 . Therefore, the preoperative PTH level in vitamin D deficiency may not reflect the reality.
The main limitation of this study was the retrospective design, and not measured urine calcium creatinine ratio. But we were collected 24 hour urine second time in patients who we do not sure 24 hour urine calcium excretion value. However, to the best of our knowledge, this is the first study in literature to have investigated the relationship between postoperative hypocalcemia and vitamin D after parathyroidectomy.
In conclusion, parathyroidectomy remains the only curative treatment option for PHPT and preoperative vitamin D replacement may significantly reduce postoperative hypocalcemia rates.
The influence of preoperative vitamin D on the development of hypocalcemia occurrence requires more studies on postoperative hypocalcemia relationship with vitamin D after parathyroidectomy.   Table 3. Comparison among three vitamin D groups with chi-square analysis.