Abstract
Purpose
Current guidelines for calcium supplementation for parathyroid function recovery after thyroidectomy are based on low-quality evidence. The present trial compared the effects of oral calcium and vitamin D supplementation on the recovery of parathyroid function when administered routinely or exclusively to symptomatic patients.
Methods
This prospective, randomized, open-label clinical trial analyzed 203 patients who underwent total thyroidectomy and developed hypoparathyroidism on postoperative day 1 (POD1) with median age of 41 years and proportion of women of 77.8%. Participants were randomized to group A (calcium and vitamin D supplementation administered only to symptomatic patients) and group B (routine supplementation). The primary outcome was the incidence of protracted hypoparathyroidism in the two groups. Secondary outcomes included risk factors for postoperative protracted hypoparathyroidism and the incidence of symptomatic hypocalcemia.
Results
The incidence of protracted hypoparathyroidism was not significantly different between group A and group B (11 of 99 vs. 17 of 104, P = 0.280). Parathyroid hormone (PTH) in group B exhibited a better recovery tendency. The incidence of postoperative symptomatic hypocalcemia in group B was significantly lower than group A (26.92% vs. 42.42%, P = 0.020). Independent factors predicting protracted hypoparathyroidism included sex, preoperative serum calcium, and POD1 PTH.
Conclusion
Calcium and vitamin D supplementation administered exclusively to symptomatic patients achieved the same effect on protracted hypoparathyroidism as routine supplementation. However, routine supplementation significantly reduced postoperative hypocalcemia. Extra attention is necessary in female patients with high preoperative serum calcium and patients with low POD1 PTH.
Trial registration
Chinese Clinical Trial Registry (ChiCTR), ChiCTR1900022194. Registered March 30, 2019.
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Data availability
The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request.
References
L.A. Orloff, S.M. Wiseman, V.J. Bernet, T.J. Fahey 3rd, A.R. Shaha, M.L. Shindo, S.K. Snyder, B.C. Stack Jr., J.B. Sunwoo, M.B. Wang, American thyroid association statement on postoperative hypoparathyroidism: Diagnosis, prevention, and management in adults. Thyroid 28(7), 830–841 (2018). https://doi.org/10.1089/thy.2017.0309
O. Edafe, R. Antakia, N. Laskar, L. Uttley, S. Balasubramanian, Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br. J. Surg. 101(4), 307–320 (2014). https://doi.org/10.1002/bjs.9384
H.S. Kazaure, J.A. Sosa, Surgical hypoparathyroidism. Endocrinol. Metab. Clin. North Am. 47(4), 783–796 (2018). https://doi.org/10.1016/j.ecl.2018.07.005
R.A. Dedivitis, F.T. Aires, C.R. Cernea, Hypoparathyroidism after thyroidectomy: Prevention, assessment and management. Curr. Opin. Otolaryngol. Head Neck Surg. 25(2), 142–146 (2017). https://doi.org/10.1097/moo.0000000000000346
A. Sitges-Serra, S. Ruiz, M. Girvent, H. Manjón, J. Dueñas, J. Sancho, Outcome of protracted hypoparathyroidism after total thyroidectomy. Brit. J. Surg. 97(11), 1687–1695 (2010). https://doi.org/10.1002/bjs.7219
O. Edafe, C.E. Mech, S.P. Balasubramanian, Calcium, vitamin D or recombinant parathyroid hormone for managing post-thyroidectomy hypoparathyroidism. Cochrane Database Systematic Rev. 5(5), Cd012845 (2019). https://doi.org/10.1002/14651858.CD012845.pub2
A. Sanabria, A. Rojas, J. Arevalo, Meta-analysis of routine calcium/vitamin D3 supplementation versus serum calcium level-based strategy to prevent postoperative hypocalcaemia after thyroidectomy. Brit. J. Surg. 106(9), 1126–1137 (2019). https://doi.org/10.1002/bjs.11216
T. Xing, Y. Hu, B. Wang, J. Zhu, Role of oral calcium supplementation alone or with vitamin D in preventing post-thyroidectomy hypocalcaemia: A meta-analysis. Medicine 98(8), e14455 (2019). https://doi.org/10.1097/md.0000000000014455
G. Mercante, A. Anelli, D. Giannarelli, D. Giordano, I. Sinopoli, F. Ferreli, G. Digiesi, M.L. Appetecchia, A. Barnabei, G. Cristalli, L. Conti, R. Pellini, F. Piazza, D. Lombardi, A. De Virgilio, G. Spriano, Cost-effectiveness in transient hypocalcemia post-thyroidectomy. Head Neck 41(11), 3940–3947 (2019). https://doi.org/10.1002/hed.25934
B.C. Stack Jr., D.N. Bimston, D.L. Bodenner, E.M. Brett, H. Dralle, L.A. Orloff, J. Pallota, S.K. Snyder, R.J. Wong, G.W. Randolph, American association of clinical endocrinologists and American College of endocrinology disease state clinical review: Postoperative hypoparathyroidism–definitions and management. Endocr. Pract. 21(6), 674–685 (2015). https://doi.org/10.4158/EP14462.DSC
V. Walker Harris, S. Jan De Beur, Postoperative hypoparathyroidism: medical and surgical therapeutic options. Thyroid 19(9), 967–973 (2009). https://doi.org/10.1089/thy.2008.0306
J. Järhult, K. Landerholm, Outcome of hypocalcaemia after thyroidectomy treated only in symptomatic patients. Brit. J. Surg. 103(6), 676–683 (2016). https://doi.org/10.1002/bjs.10086
J. Bollerslev, L. Rejnmark, C. Marcocci, D. Shoback, A. Sitges-Serra, W. Biesen, O. Dekkers, European society of endocrinology clinical guideline: Treatment of chronic hypoparathyroidism in adults. Eur. J. Endocrinol. 173(2), G1–G20 (2015). https://doi.org/10.1530/eje-15-0628
P. McCullough, J. Amend, Results of daily oral dosing with up to 60,000 international units (iu) of vitamin D3 for 2 to 6 years in 3 adult males. J. Steroid Biochem. Mol. Biol. 173, 308–312 (2017). https://doi.org/10.1016/j.jsbmb.2016.12.009
A. Adorni, G. Lussignoli, C. Geroldi, O. Zanetti, Extensive brain calcification and dementia in postsurgical hypoparathyroidism. Neurology 65(9), 1501 (2005). https://doi.org/10.1212/01.wnl.0000182293.34015.a9
B. Abboud, G. Sleilaty, S. Zeineddine, C. Braidy, R. Aouad, C. Tohme, R. Noun, R. Sarkis, Is therapy with calcium and vitamin D and parathyroid autotransplantation useful in total thyroidectomy for preventing hypocalcemia? Head Neck 30(9), 1148–1154 (2008). https://doi.org/10.1002/hed.20836. discussion 1154-1145
M.B. Albuja-Cruz, N. Pozdeyev, S. Robbins, R. Chandramouli, C.D. Raeburn, J. Klopper, B.R. Haugen, R. McIntyre Jr, A “safe and effective” protocol for management of post-thyroidectomy hypocalcemia. Am. J. Surg. 210(6), 1162–1168 (2015). https://doi.org/10.1016/j.amjsurg.2015.07.010. discussion 1168-1169
A. Alhefdhi, H. Mazeh, H. Chen, Role of postoperative vitamin D and/or calcium routine supplementation in preventing hypocalcemia after thyroidectomy: A systematic review and meta-analysis. Oncologist 18(5), 533–542 (2013). https://doi.org/10.1634/theoncologist.2012-0283
I.M. Arer, M. Kus, N. Akkapulu, H.O. Aytac, H. Yabanoglu, K. Caliskan, M.A. Tarim, Prophylactic oral calcium supplementation therapy to prevent early post thyroidectomy hypocalcemia and evaluation of postoperative parathyroid hormone levels to detect hypocalcemia: A prospective randomized study. Int. J. Surg. 38, 9–14 (2017). https://doi.org/10.1016/j.ijsu.2016.12.041
R. Bellantone, C.P. Lombardi, M. Raffaelli, M. Boscherini, P.F. Alesina, C. De Crea, E. Traini, P. Princi, Is routine supplementation therapy (calcium and vitamin D) useful after total thyroidectomy? Surgery 132(6), 1109–1112 (2002). https://doi.org/10.1067/msy.2002.128617. discussion 1112-1103
J.H. Choe, W.W. Kim, S.K. Lee, H.I. Lim, J.H. Choi, J.E. Lee, J.H. Kim, S.J. Nam, J.H. Yang, J.S. Kim, Comparison of calcitriol versus cholecalciferol therapy in addition to oral calcium after total thyroidectomy with central neck lymph node dissection: a prospective randomized study. Head Neck 33(9), 1265–1271 (2011). https://doi.org/10.1002/hed.21619
G. Docimo, S. Tolone, D. Pasquali, G. Conzo, A. D’Alessandro, G. Casalino, S. Gili, L. Brusciano, A. Gubitosi, G. Del Genio, R. Ruggiero, L. Docimo, Role of pre and post-operative oral calcium and vitamin D supplements in prevention of hypocalcemia after total thyroidectomy. Il Giornale di Chirurgia 33(11-12), 374–378 (2012)
L. Genser, C. Trésallet, G. Godiris-Petit, S. Li Sun Fui, H. Salepcioglu, C. Royer, F. Menegaux, Randomized controlled trial of alfacalcidol supplementation for the reduction of hypocalcemia after total thyroidectomy. Am. J. Surg. 207(1), 39–45 (2014). https://doi.org/10.1016/j.amjsurg.2013.05.007
A. Grzegory, L. Pomorski, Perioperative calcium and vitamin D supplementation in patients undergoing thyroidectomy - literature review. Polski przeglad chirurgiczny 90(4), 46–50 (2018). https://doi.org/10.5604/01.3001.0012.0975
M. Khan Bhettani, M. Rehman, M. Ahmed, H.N. Altaf, U.K. Choudry, K.H. Khan, Role of pre-operative vitamin D supplementation to reduce post-thyroidectomy hypocalcemia; Cohort study. Int. J. Surg. 71, 85–90 (2019). https://doi.org/10.1016/j.ijsu.2019.08.035
E. Langner, A.J. Tincani, A.D. Negro, Use of prophylactic oral calcium after total thyroidectomy: A prospective study. Arch. Endocrinol. Metab. 61(5), 447–454 (2017). https://doi.org/10.1590/2359-3997000000286
J.W. Lee, J.K. Kim, H. Kwon, W. Lim, B.I. Moon, N.S. Paik, Routine low-dose calcium supplementation after thyroidectomy does not reduce the rate of symptomatic hypocalcemia: a prospective randomized trial. Annals Surg. Treat. Res. 96(4), 177–184 (2019). https://doi.org/10.4174/astr.2019.96.4.177
A.K. Maxwell, D.C. Shonka Jr., D.J. Robinson, P.A. Levine, Association of preoperative calcium and calcitriol therapy with postoperative hypocalcemia after total thyroidectomy. JAMA Otolaryngol.– Head Neck Surg. 143(7), 679–684 (2017). https://doi.org/10.1001/jamaoto.2016.4796
S.V. Nemade, V.V. Rokade, N.A. Pathak, S.S. Tiwari, S.J. Sonkhedkar, Comparison between perioperative treatment with calcium and with calcium and vitamin d in prevention of post thyroidectomy hypocalcemia. Indian J. Otolaryngol. Head Neck Surg. 66(Suppl 1), 214–219 (2014). https://doi.org/10.1007/s12070-011-0430-4
J.L. Roh, C.I. Park, Routine oral calcium and vitamin D supplements for prevention of hypocalcemia after total thyroidectomy. Am. J. Surg. 192(5), 675–678 (2006). https://doi.org/10.1016/j.amjsurg.2006.03.010
J.L. Roh, J.Y. Park, C.I. Park, Prevention of postoperative hypocalcemia with routine oral calcium and vitamin D supplements in patients with differentiated papillary thyroid carcinoma undergoing total thyroidectomy plus central neck dissection. Cancer 115(2), 251–258 (2009). https://doi.org/10.1002/cncr.24027
A. Sanabria, L.C. Dominguez, V. Vega, C. Osorio, D. Duarte, Routine postoperative administration of vitamin D and calcium after total thyroidectomy: A meta-analysis. Int. J. Surg. 9(1), 46–51 (2011). https://doi.org/10.1016/j.ijsu.2010.08.006
F. Tartaglia, A. Giuliani, M. Sgueglia, F. Biancari, T. Juvonen, F.P. Campana, Randomized study on oral administration of calcitriol to prevent symptomatic hypocalcemia after total thyroidectomy. Am. J. Surg. 190(3), 424–429 (2005). https://doi.org/10.1016/j.amjsurg.2005.04.017
S. Tolone, R. Roberto, G. del Genio, L. Brusciano, D. Parmeggiani, V. Amoroso, G. Casalino, I. Verde, A. Bosco, A. D’Alessandro, R. Pirozzi, G. Rossetti, P. Limongelli, L. Docimo,, The impact of age and oral calcium and vitamin D supplements on postoperative hypocalcemia after total thyroidectomy. A prospective study. BMC Surg. 13(Suppl 2), S11 2013). https://doi.org/10.1186/1471-2482-13-s2-s11
T. Uruno, A. Miyauchi, K. Shimizu, C. Tomoda, Y. Takamura, Y. Ito, A. Miya, K. Kobayashi, F. Matsuzuka, N. Amino, K. Kuma, A prophylactic infusion of calcium solution reduces the risk of symptomatic hypocalcemia in patients after total thyroidectomy. World J. Surg. 30(3), 304–308 (2006). https://doi.org/10.1007/s00268-005-0374-5
S.D. Wu, L. Gao, Is routine calcium supplementation necessary in patients undergoing total thyroidectomy plus neck dissection? Surg. Today 41(2), 183–188 (2011). https://doi.org/10.1007/s00595-010-4230-3
T.P. Griffin, M.S. Murphy, P. Sheahan, Vitamin D and risk of postoperative hypocalcemia after total thyroidectomy. JAMA Otolaryngol.– Head Neck Surg. 140(4), 346–351 (2014). https://doi.org/10.1001/jamaoto.2014.25
G.H. Lee, Y.H. Ku, H.I. Kim, M.C. Lee, M.J. Kim, Vitamin D level is not a predictor of hypocalcemia after total thyroidectomy. Langenbeck’s Arch. Surg. 400(5), 617–622 (2015). https://doi.org/10.1007/s00423-015-1311-1
Y. Lin, H.L. Ross, C.D. Raeburn, P.E. DeWitt, M. Albuja-Cruz, E.L. Jones, R.C. McIntyre Jr, Vitamin D deficiency does not increase the rate of postoperative hypocalcemia after thyroidectomy. Am. J. Surg. 204(6), 888–893 (2012). https://doi.org/10.1016/j.amjsurg.2012.10.001. discussion 893-884
E. Alkhalili, M.D. Ehrhart, H. Ayoubieh, M.R. Burge, Does pre-operative vitamin d deficiency predict postoperative hypocalcemia after thyroidectOMY? Endocr. Pract. 23(1), 5–9 (2017). https://doi.org/10.4158/ep161411.Or
S.F. Al-Dhahri, M. Mubasher, F. Al-Muhawas, M. Alessa, R.S. Terkawi, A.S. Terkawi, Early prediction of oral calcium and vitamin D requirements in post-thyroidectomy hypocalcaemia. Otolaryngol. Head Neck Surg. 151(3), 407–414 (2014). https://doi.org/10.1177/0194599814536848
W.W. Kim, S.H. Chung, E.J. Ban, C.R. Lee, S.W. Kang, J.J. Jeong, K.H. Nam, W.Y. Chung, C.S. Park, Is preoperative vitamin D deficiency a risk factor for postoperative symptomatic hypocalcemia in thyroid cancer patients undergoing total thyroidectomy plus central compartment neck dissection? Thyroid 25(8), 911–918 (2015). https://doi.org/10.1089/thy.2014.0522
G. Dağlar, M. Kiliç, C. Çelik, C. Yüksel, S.G. Terzioğlu, S. Özden, D. İçen, IS there a relationship between vitamin d status and hypocalcemia after total thyroidectomy? Acta. Endocrinol. (Bucharest, Romania: 2005) 12(3), 291–296 (2016). https://doi.org/10.4183/aeb.2016.291
A. Deffain, F. Scipioni, B. De Rienzo, S. Allal, M. Castagnet, J.L. Kraimps, G. Donatini, Preoperative vitamin D levels do not relate with the risk of hypocalcemia following total thyroidectomy. A cohort study. Minerva chirurgica 74(1), 14–18 (2019). https://doi.org/10.23736/s0026-4733.18.07456-4
D. Machin, M.J. Campbell, S.B. Tan, S.H. Tan, Comparing Two Independent Groups for Continuous Data. In: Sample Size Tables for Clinical Studies. (Wiley‐Blackwell, Oxford, UK, 2008), pp. 47–57
R. Lehr, Sixteen S-squared over D-squared: A relation for crude sample size estimates. Stat. Med. 11(8), 1099–1102 (1992)
D. Fliser, A. Stefanski, E. Franek, P. Fode, A. Gudarzi, E. Ritz, No effect of calcitriol on insulin-mediated glucose uptake in healthy subjects. Eur. J. Clin. Investig. 27(7), 629–633 (1997). https://doi.org/10.1046/j.1365-2362.1997.1520699.x
R.I. Gafni, M.T. Collins, Hypoparathyroidism. New Engl. J. Med. 380(18), 1738–1747 (2019). https://doi.org/10.1056/NEJMcp1800213
B. Clarke, E. Brown, M. Collins, H. Jüppner, P. Lakatos, M. Levine, M. Mannstadt, J. Bilezikian, A. Romanischen, R. Thakker, Epidemiology and diagnosis of hypoparathyroidism. J. Clin. Endocrinol. Metabol. 101(6), 2284–2299 (2016). https://doi.org/10.1210/jc.2015-3908
L. Cianferotti, G. Marcucci, M. Brandi, Causes and pathophysiology of hypoparathyroidism. Best Pract. Res. Clin. Endocrinol. Metab. 32(6), 909–925 (2018). https://doi.org/10.1016/j.beem.2018.07.001
Author contributions
AP, Su designed the study and reviewed the paper. Z Li and Y Fei analyzed the clinical data and wrote the paper. Z Li, Y Fei, ZH Li, T Wei, and JQ Zhu performed clinical studies. All authors read and approved the final paper.
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This work was supported by the Bethune Charitable Foundation (HZB-20181119-41).
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Researchers informed all eligible patients about the trial, and patients who agreed to participate gave informed written consent.
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The study was a randomized controlled trial approved by the Biomedicine Ethics Committee of West China Hospital, Sichuan University (approval number: 2018-574).
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Li, Z., Fei, Y., Li, Z. et al. Outcome of parathyroid function after total thyroidectomy when calcium supplementation is administered routinely versus exclusively to symptomatic patients: A prospective randomized clinical trial. Endocrine 75, 583–592 (2022). https://doi.org/10.1007/s12020-021-02921-9
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DOI: https://doi.org/10.1007/s12020-021-02921-9