The effect of different therapeutic treatments on the frequency of postoperative hypocalcemia in patients with thyroidectomy
Hamdi Burak Piyade1, Mahmut Başoğlu2, Ersan Gürsoy3
1Clinic of General Surgery, Gümüşhane State Hospital, Gümüşhane, Türkiye
2Department of General Surgery, Ondokuz Mayıs University Faculty of Medicine, Samsun, Türkiye
3Department of Family Medicine, Binali Yıldırım University Faculty of Medicine, Erzincan, Türkiye
Objective: Thyroid gland surgery and its surgical complications are situations that a surgeon frequently encounters in his daily practice. In our study, it was aimed to examine the effect of different treatment methods given to patients who underwent thyroidectomy on hypocalcemia.
Material and Methods: Three hundred and seventy-one patients who underwent thyroidectomy at Ondokuz Mayıs University Medical Faculty General Surgery clinic between December 2016 and January 2021 were retrospectively included in the study. Parameters such as surgery indications, fine needle aspiration biopsy results, preoperative serum calcium values, type of surgery, serum calcium values at postoperative 1st day and 1st month, postoperative hospital stay, drugs prescribed at discharge, histopathological diagnosis of the patient, and whether there was incidental parathyroidectomy or not were included.
Results: Mean age of 371 patients who underwent thyroidectomy was 49 (19-82) years. Total thyroidectomy was the most common type of thyroidectomy with 61% (n= 225) of the patients. There was a significant decrease in pre-op and post-op calcium values in all three types of surgery performed on the patients, and there was no significant difference between the different types of surgery. Post-operative day one and month one serum calcium values were significantly increased in all groups (p= .000). The increase in post-op serum calcium level was most common in the group using calcium carbonate + cholecalciferol + calcitriol.
Conclusion: The use of post-op calcitriol in patients undergoing thyroidectomy seems to be quite effective in preventing the development of hypocalcemia.
Keywords: Thyroidectomy, hypocalcemia, calcitriol, thyroid diseases
Thyroid gland diseases are conditions affecting approximately 5% of the population and are frequently encountered by a surgeon in his/her daily practice (1). Although thyroid surgery is considered a low-risk and safe approach today, the patient should be followed closely for postoperative complications (2).
The first successful thyroid surgery in humans was performed and documented by Ebu’l Kasım El Zehravi (963-1013) (3). It is also called Albucasis or Elzahawi in European sources. These methods were published by Roger Frugardi in 1170 (4). Thyroid surgery, which had a mortality rate of approximately 40% until the 1850s, became much less mortal and effective especially after the 1850s (5).
However, another problem is hypothyroidism, which develops in patients who survive thyroidectomy. This condition was first treated with subcutaneous injection of the thyroid extract in 1891, and after the effectiveness of the treatment was proven, it was discovered that oral therapy had similar efficacy, and oral replacement therapy was started (6).
Today, oral replacement therapy is not only for hypothyroidism, but also for calcium deficiencies (7,8). Postoperative hypocalcaemia can be affected by many conditions such as the surgeon, the center, and the risk factors of the patient, and it can be seen in the literature at rates up to 50% (2,8,9). Postoperative hypocalcaemia may be asymptomatic or may be of varying severity ranging from tetany, aryngospasm, cardiac arrhythmias and death (10). Therefore, surgeons should diagnose and treat postoperative hypocalcaemia in a timely manner. On the other hand, preoperative and postoperative calcium and vitamin D preparations are recommended in the American Thyroid Association guidelines although there is no consensus on a standard prevention treatment (10). In our study, it was aimed to examine the effect of prophylactic hormone therapy given to patients who underwent thyroidectomy on hypocalcaemia.
Material and Methods
The study retrospectively included 371 patients who underwent bilateral total thyroidectomy, completion thyroidectomy, and intrathoracic substernal thyroidectomy by the same surgeon in the General Surgery clinic of Ondokuz Mayıs University Faculty of Medicine between December 2016 and January 2021.
Parameters such as patients’ indications for surgery, fine needle aspiration biopsy results, preoperative serum calcium values, type of surgery, serum calcium (n= 8.5-10.3 mg/dL) values at postoperative 1st day and 1st month, postoperative hospital stay, drugs prescribed at discharge, histopathological diagnosis, and whether there was an incidental parathyroidectomy or not were included in the study.
Patients who had deficiencies in these parameters, did not come to their follow-ups, cases with accompanying parathyroid surgery or those who did not use the prescribed drugs were excluded from the study.
The patients were divided into three groups according to the treatments they received (or did not receive). No drugs, calcium carbonate + cholecalciferol or calcium carbonate + cholecalciferol + calcitriol. Only calcium carbonate + cholecalciferol was started in patients with symptomatic hypocalcaemia. If the patient had symptomatic hypocalcaemia at discharge and parathormone levels were below the normal range, calcitriol was added. The treatment was terminated if parathormone values were found to be normal in the postoperative onemonth follow-up.
Since the center where the study was conducted is an education clinic dealing with oncological cases, central lymph node dissection with nerve monitoring is routinely performed in all cases.
IBM SPSS (Statistical Package for the Social Sciences) 20.0 package program was used for data analysis. Descriptive statistics were summarized as frequency and percentage. Chi-square test was used for comparison of qualitative variables, Student-t test, Mann-Whitney U and ANOVA tests were used for comparisons of independent groups. Wilcoxon test was used for dependent group comparisons. However, corrections were not made for multiple comparisons.
Approval for this study was obtained from the Clinical Research Ethics Committee of Ondokuz Mayıs University with the application dated 16.04.2020 and application number 2020000416-5.
Statistical significance level was taken as p< .05.
Mean age of 371 patients who underwent thyroidectomy was 49 (19-82) years. Total thyroidectomy was the most common type of total thyroidectomy with 61% (n= 225) of the patients (Table 1).
Incidental parathyroidectomy was seen in 20.1% of the patients (n= 72), and no significant correlation was found between the types of surgery and the incidence of incidental parathyroidectomy (p= .453). Hypocalcaemia was observed in 69.4% (n= 50) of 72 patients with incidental parathyroidectomy and 47.4% (n= 136) of 287 patients without incidental parathyroidectomy. Mean serum calcium level of the patients with incidental parathyroidectomy was 8.2 (min= 6.1, max= 9.9) while the mean of patients without incidental parathyroidectomy was 8.5 (min= 5.8, max= 11.5). Presence of incidental parathyroidectomy has a statistically significant effect on hypocalcaemia (p= 0.001).
Serum PTH levels were measured on post-op day one from 346 patients. Median value was found to be 24.66 pg/mL (min= 1.2, max= 168.6) (normal value= 15-65 pg/mL). There was a statistically significant difference between the groups with and without incidental parathyroidectomy (p< 0.001).
In 71% (n= 262) of the patients, the biopsy result was malignancy or suspected malignancy, and no suspicion of malignancy was found in 29% (n= 109). Of the patients, 88% (n= 325) were hospitalized for less than one postoperative day. Calcium levels observed in the postoperative 1st day and 1st month controls of the patients are given in Table 2.
Mean post-op calcium values of 325 patients who were discharged one day after the operation were 8.45 ± 0.613, and the average of 46 patients who were discharged more than two days later was 7.793 ± 0.796, and the difference between them was statistically significant (p< 0.001) (Table 3).
There was a significant decrease in preoperative and postoperative calcium values in all three types of surgery, and no significant difference was observed between the different types of surgery (Table 4).
In 98% (n= 364) of the patients, levothyroxine 100 microgram was started on the 1st postoperative day. Likewise, 2500 mg calcium carbonate + 9.68 mg cholecalciferol was started in 90% (n= 334) of the patients, and calcitriol 0.25 microgram was started in 23% (n= 86) of the patients.
Regardless of the drug effect, there is a time-dependent increase in serum calcium values even if the patients do not use any drugs. The change in serum calcium values over time according to the drug groups used is given in Table 5, and post-op 1st day and 1st month serum calcium values increased significantly in all groups (p< 0.001).
Post hoc multiple comparison test was performed to determine the difference between the groups. Accordingly, the difference in post-op 1st day and post-op 1st month serum calcium levels was significantly higher in the group using calcium carbonate + cholecalciferol + calcitriol compared to the other two groups (p= .004, p= .041, respectively) (Table 6).
Thyroid pathologies are one of the most common endocrine pathologies after diabetes mellitus, and therefore, thyroid operations are very vital in the general surgical practice (11). Postoperative hypocalcemia after thyroidectomy is one of the most common complications, and it has been reported in the literature that temporary hypocalcemia can occur at a rate of 6-50% and permanent hypocalcemia at a rate of 1-2% (2,9,12,13). In our study, it was aimed to evaluate the efficacy of drug treatments for hypocalcemia in 371 patients operated in our center.
In patients with positive malignancy, the rate of bilateral total thyroidectomy and complementary thyroidectomy surgery increases, on the contrary, the rate of intrathoracic-substernal thyroidectomy decreases (14,15). In our study, 71% (n= 262) of the patients had biopsy results as malignancy or suspected malignancy, therefore, the rates of total thyroidectomy were higher than intrathoracic-substernal thyroidectomy.
Due to its anatomical variations, even with careful dissection and sufficient anatomical information, it is very difficult to recognize and preserve the parathyroid tissue during the operation. In the literature, it has been reported that incidental parathyroidectomy occurs in 6-28% of thyroidectomy operations (16). Similarly, incidental parathyroidectomy was found in 20.1% of the patients in our study. In addition, it was observed that the surgical method applied did not make a statistically significant difference in the incidence of incidental parathyroidectomy in the pathology specimen.
Various strategies have been used to diagnose and manage hypocalcaemia after thyroidectomy. The traditional approach to inpatient clinical assessment and monitoring of serum calcium levels is still used by many institutions around the world (17). When the literature is reviewed, many studies have shown that the measurement of serum PTH levels after surgery can be used as a predictor of the development of hypocalcaemia after thyroidectomy (17-19). Although there are studies suggesting PTH measurement routinely post-op, this approach is not costeffective. However, since our clinic is an education clinic, serum PTH levels were measured in 93.2% (n= 346) of the patients, and most of them were found to be within the normal range (median= 24.66 pg/mL) (min= 1.2, max= 168.6).
Mean serum calcium (mean= 7.793 ± 0.796) in patients with a hospital stay of two days or longer was found to be lower than the mean calcium (mean= 8.45 ± 0.613) of patients discharged on the 1st postoperative day. In this respect, it has been observed that low calcium levels on the first postoperative day are a significant indicator for prolonged hospitalization. However, considering the final serum calcium values, hypocalcemia was observed in only 1.2% (n= 4) of the patients in the post-op 1st month controls.
A significant decrease was observed in the mean of pre-op and post-op serum calcium values after thyroidectomy in all age groups, regardless of the type of surgery. The main factor affecting serum calcium values in post-op 1st month controls was the type of drug used.
When the postoperative 1st month control calcium values were examined, an increase in serum calcium levels was observed even if the patients did not use any medication. Although the lowest increase was observed in this group, the difference in calcium levels between the post-op 1st day and 1st month was still statistically significant. The highest increase was in the group using calcium carbonate + cholecalciferol + calcitriol.
On the other hand, the difference in calcium levels between the 1st day and 1st month was not statistically significant between the group that did not use drugs and the group that used only calcium carbonate + cholecalciferol. In a meta-analysis involving 2.285 patients in 2013, it was stated that the use of post-op vitamin D preparations had an effective role in preventing postop hypocalcemia and its use was recommended (20). In another study involving 200 patients, the use of vitamin D has been found to be effective in preventing post-op hypocalcemia (21). Similarly, in our study, the increase in serum calcium levels in the group receiving calcitriol + calcium carbonate + cholecalciferol was significantly higher than in both groups.
Our study has some strengths and weaknesses. First, since the patient group followed up with calcitriol in isolation in our clinic is not crowded, the therapeutic and efficacy of calcitriol was demonstrated by comparing three patient groups who did not receive replacement, only calcium carbonate + cholecalciferol, and took both drugs. On the other hand, although Graves’ disease is a risk factor for postoperative hypocalcemia, there is no relevant data in our study and we do not have preoperative vitamin D levels of patients for whom we planned total thyroidectomy. In addition, it may be more appropriate to include not only the 1st month but also the future follow-ups of the patients. However, after this period, patients either do not come for follow-ups or continue their follow-ups in internal clinics. On the other hand, the selection of patients operated by the same surgeon is one of the strengths of our study in order to include and standardize all patients within a period of more than four years. In addition, the large number of patients included is also statistically significant. However, there is a need for further studies that include patients followed up with calcitriol in isolation and include long-term follow-up results.
In our study, we found that incidental parathyroidectomy was independent of the type of surgery. In the early postoperative period, serum PTH levels of most patients were found to be within the normal range. However, the use of calcitriol appears to be quite effective in patients with decreased PTH levels. On the other hand, even if no post-operative medication was given to the patients, it was observed that the serum calcium levels of the patients increased, which was statistically similar to the group using calcium carbonate + cholecalciferol. The highest increase was in the group using carbonate + cholecalciferol + calcitriol, which was found to be significantly higher than the other groups. The use of post-op calcitriol in patients undergoing thyroidectomy seems to be quite effective in preventing the development of hypocalcemia.
Cite this article as: Piyade HB, Başoğlu M, Gürsoy E. The effect of different therapeutic treatments on the frequency of postoperative hypocalcemia in patients with thyroidectomy. Turk J Surg 2023; 39 (1): 70-75.
This study was approved by Ondokuz Mayıs University Clinical Research Ethics Committee (Decision no: OMÜ KAEK 2020/416, Date: 27.08.2020).
Concept - All of authors; Design - All of authors; Supervision - All of authors; Fundings - All of authors; Materials - All of authors; Data Collection and/ or Processing - All of authors; Analysis and/or Interpretation - All of authors; Literature Search - All of authors; Writing Manuscript - All of authors; Critical Reviews - All of authors.
The authors have no conflicts of interest to declare.
The authors declared that this study has received no financial support.
- Lorenz K, Raffaeli M, Barczyński M, Lorente-Poch L, Sancho J. Volume, outcomes, and quality standards in thyroid surgery: An evidencebased analysis. ESES positional statement Langenbecks Arch Surg 2020; 405(4): 401-25. https://doi.org/10.1007/s00423-020-01907-x
- Medas F, Tuveri M, Canu GL, Erdas E, Calò PG. Complications after reoperative thyroid surgery: Retrospective evaluation of 152 consecutive cases. Updates Surg 2019; 71(4): 705-10. https://doi.org/10.1007/ s13304-019-00647-y
- Shuja A. History of thyroid surgery. Professional Med J 2008; 15(02): 295-7. https://doi.org/10.29309/TPMJ/2008.15.02.2813
- Sarkar S, Banerjee S, Sarkar R, Sikder B. A review on the history of ‘thyroid surgery’. Indian J Surg 2016; 78(1): 32-6. https://doi.org/10.1007/ s12262-015-1317-5
- Hannan SA. The magnificent seven: A history of modern thyroid surgery. Int J Surg 2006; 4(3): 187-91. https://doi.org/10.1016/j. ijsu.2006.03.002
- Duntas LH. Seven decades of levothyroxine: A comprehensive profile. Springer; 2019; 27-9. https://doi.org/10.1007/s12325-019-01081-7
- Collins R, Lafford G, Ferris R, Turner J, Tassone P. Improving the management of post-operative hypocalcaemia in thyroid surgery. Cureus 2021; 13(5). https://doi.org/10.7759/cureus.15137
- Sözen S, Emir S, Alıcı A, Aysu F, Yıldız F, Aziret, et al. Complications after thyroidectomy and the affecting factors related with the surgeon. Turk Surg J 2010; 26: 13-7. https://doi.org/10.5097/1300-0705. UCD.315-10.02
- Christou N, Mathonnet M. Complications after total thyroidectomy. J Visc Surg 2013; 150(4): 249-56. https://doi.org/10.1016/j.jviscsurg.2013.04.003
- Orloff LA, Wiseman SM, Bernet VJ, Fahey III TJ, Shaha AR, Shindo ML, et al. American Thyroid Association statement on postoperative hypoparathyroidism: Diagnosis, prevention, and management in adults. Thyroid 2018; 28(7): 830-41. https://doi.org/10.1089/ thy.2017.0309
- Harness JK, Fung L, Thompson NW, Burney RE, McLeod MK. Total thyroidectomy: Complications and technique. World J Surg 1986; 10(5): 781-5. https://doi.org/10.1007/BF01655238
- Thomusch O, Machens A, Sekulla C, Ukkat J, Lippert H, Gastinger I, et al. Multivariate analysis of risk factors for postoperative complications in benign goiter surgery: Prospective multicenter study in Germany. World J Surg 2000; 24(11): 1335-41. https://doi.org/10.1007/ s002680010221
- Kalyoncu D, Gönüllü D, Gedik ML, Er M, Kuroğlu E, İğdem AA, et al. Analysis of the factors that have an effect on hypocalcemia following thyroidectomy. Ulus Cerrahi Derg 2013; 29(4): 171-6. https://doi. org/10.5152/UCD.2013.2438
- Cannizzaro MA, Borzì L, Lo Bianco S, Okatyeva V, Cavallaro A, Buffone A, et al. Comparison between focus harmonic scalpel and other hemostatic techniques in open thyroidectomy: A systematic review and meta-analysis. Head Neck 2016; 38(10): 1571-8. https://doi. org/10.1002/hed.24449
- Makay Ö, Özdemir M, Şenyürek YG, Tunca F, Düren M, Uludağ M, et al. Surgical approaches for papillary microcarcinomas: Turkey’s perspective. Turk J Surg 2018; 34(2): 89-93. https://doi.org/10.5152/turkjsurg.2018.3596
- Bai B, Chen Z, Chen W. Risk factors and outcomes of incidental parathyroidectomy in thyroidectomy: A systematic review and metaanalysis. PLoS One 2018; 13(11): e0207088. https://doi.org/10.1371/ journal.pone.0207088
- Mazotas IG, Wang TS. The role and timing of parathyroid hormone determination after total thyroidectomy. Gland Surg 2017; 6(Suppl 1): 38-48. https://doi.org/10.21037/gs.2017.09.06
- Reddy AC, Chand G, Sabaretnam M, Mishra A, Agarwal G, Agarwal A, et al. Prospective evaluation of intra-operative quick parathyroid hormone assay as an early predictor of post thyroidectomy hypocalcaemia. Int J Surg 2016; 34: 103-8. https://doi.org/10.1016/j. ijsu.2016.08.010
- Lecerf P, Orry D, Perrodeau E, Lhommet C, Charretier C, Mor C, et al. Parathyroid hormone decline 4 hours after total thyroidectomy accurately predicts hypocalcemia. Surgery 2012; 152(5): 863-8. https://doi. org/10.1016/j.surg.2012.03.011
- Alhefdhi A, Mazeh H, Chen H. Role of postoperative vitamin D and/or calcium routine supplementation in preventing hypocalcemia after thyroidectomy: A systematic review and meta-analysis. Oncologist 2013; 18(5): 533-42. https://doi.org/10.1634/theoncologist.2012-0283
- Tolone S, Roberto R, del Genio G, Brusciano L, Parmeggiani D, Amoroso V, et al. The impact of age and oral calcium and vitamin D supplements on postoperative hypocalcemia after total thyroidectomy. A prospective study. BMC Surg 2013; 13(2): 1-6. https://doi. org/10.1186/1471-2482-13-S2-S11