Long-Term Follow-Up and Treatment of Postoperative Permanent Hypoparathyroidism in Patients with Medullary Thyroid Carcinoma: Differences in Complete and Partial Disease

Abstract

This study aimed to identify factors influencing long-term outcome in complete or partial postoperative hypoparathyroidism (parathyroid hormone ≤10 or >10 ng/l, respectively) in medullary thyroid carcinoma (MTC). It was designed as retrospective, long-term follow-up with single-center outpatient visits. Quality of treatment, renal calcification, and function were evaluated. In 33 patients with MTC and postoperative hypoparathyroidism, current medication includes: calcium (73%), calcitriol (73%), alfacalcidol (6%), dihydrotachysterol (3%), and cholecalciferol supplements (21%). Mean hypoparathyroidism duration was 15.9±9.4 years. Initially, 15% of patients received high cholecalciferol dosages. Initial calcium dosages were higher (1 542±1 179 mg/day) than final dosages (1 188 ± 595 mg/day) (p<0.05); calcitriol dosages remained constant. Over the median observation period of about 12 years it was found that serum calcium was within the target range (2.0–2.3 mmol/l) in 63% of visits, decreased (<2.0 mmol/l) in 20.4%, high-normal (2.4–2.6 mmol/l) in 15.8%, and increased (>2.65 mmol/l) in 0.9% of visits. Calcitriol dosages were 0.73±0.22 μg/day and 0.47±0.20 μg/day in patients with complete (n=13) and partial (n=20) hypoparathyroidism, respectively (p=0.008). Renal function decreased slightly during follow-up (eGFR: 102±22 vs. 90±27 ml/min). eGFR was negatively correlated with hypoparathyroidism duration (r=−0.35, p=0.05). Of 9 patients with renal calcification, 5 had received high initial cholecalciferol doses. eGFR was lower in patients with than in those without calcification (77±17 vs. 95±29 ml/min) (p=0.07). At least one tetanic episode occurred in 60.6% of patients, and 9% had repeated tetanic complaints. In conclusion, severity of hypoparathyroidism affects treatment: Partial hypoparathyroidism required lower calcitriol dosages than complete hypoparathyroidism. Renal calcifications occurred more frequently in patients treated initially with high cholecalciferol dosages. Impaired renal function was related to hypoparathyroidism duration and renal calcification.

Key words

postoperative hypoparathyroidism - medullary thyroid carcinoma - calcitriol treatment - cholecalciferol - renal calcification and function - tetanic symptoms

^* These authors contributed equally to this study

• References

• 1 Shoback D. Clinical practice. Hypoparathyroidism. N Eng J Med 2008; 359: 391-403
• 2 Bilezikian JP, Khan A, Potts Jr. JT, Brandi ML, Clarke BL, Shoback D, Juppner H, D’Amour P, Fox J, Rejnmark L, Mosekilde L, Rubin MR, Dempster D, Gafni R, Collins MT, Sliney J, Sanders J. Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res 2011; 26: 2317-2337
• 3 Powers J, Joy K, Ruscio A, Lagast H. Prevalence and incidence of hypoparathyroidism in the United States using a large claims database. J Bone Miner Res 2013; 28: 2570-2576
• 4 Raue F, Pichl J, Dorr HG, Schnabel D, Heidemann P, Hammersen G, Jaursch-Hancke C, Santen R, Schofl C, Wabitsch M, Haag C, Schulze E, Frank-Raue K. Activating mutations in the calcium-sensing receptor: genetic and clinical spectrum in 25 patients with autosomal dominant hypocalcaemia - a German survey. Clin Endocrinol (Oxf) 2011; 75: 760-765
• 5 Levy I, Licht C, Daneman A, Sochett E, Harrington J. The Impact of Hypoparathyroidism Treatment on the Kidney in Children: Long-Term Retrospective Follow-Up Study. J Clin Endocrinol Metab 2015; 100: 4106-4113
• 6 Thomusch O, Machens A, Sekulla C, Ukkat J, Brauckhoff M, Dralle H. The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 2003; 133: 180-185
• 7 Edafe O, Antakia R, Laskar N, Uttley L, Balasubramanian SP. Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg 2014; 101: 307-320
• 8 Lorente-Poch L, Sancho JJ, Munoz-Nova JL, Sanchez-Velazquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surg 2015; 4: 82-90
• 9 Abboud B, Sargi Z, Akkam M, Sleilaty F. Risk factors for postthyroidectomy hypocalcemia. J Am Coll Surg 2002; 195: 456-461
• 10 Bergenfelz A, Jansson S, Kristoffersson A, Martensson H, Reihner E, Wallin G, Lausen I. Complications to thyroid surgery: results as reported in a database from a multicenter audit comprising 3,660 patients. Langenbecks Arch Surg 2008; 393: 667-673
• 11 Moley JF, Skinner M, Gillanders WE, Lairmore TC, Rowland KJ, Traugott AL, Jin LX, Wells Jr. SA. Management of the Parathyroid Glands During Preventive Thyroidectomy in Patients With Multiple Endocrine Neoplasia Type 2. Annals of surgery 2015; 262: 641-646
• 12 Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, van Biesen W, Dekkers OM. European Society of E . European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol 2015; 173: G1-G20
• 13 Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow-up study. J Bone Miner Res 2013; 28: 2277-2285
• 14 Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Postsurgical hypoparathyroidism–risk of fractures, psychiatric diseases, cancer, cataract, and infections. J Bone Miner Res 2014; 29: 2504-2510
• 15 Winer KK, Sinaii N, Reynolds J, Peterson D, Dowdy K, Cutler Jr. GB. Long-term treatment of 12 children with chronic hypoparathyroidism: a randomized trial comparing synthetic human parathyroid hormone 1–34 versus calcitriol and calcium. J Clin Endocrinol Metab 2010; 95: 2680-2688
• 16 Sikjaer T, Rejnmark L, Rolighed L, Heickendorff L, Mosekilde L. Hypoparathyroid Study G. The effect of adding PTH(1–84) to conventional treatment of hypoparathyroidism: a randomized, placebo-controlled study. J Bone Miner Res 2011; 26: 2358-2370
• 17 Cusano NE, Rubin MR, McMahon DJ, Irani D, Anderson L, Levy E, Bilezikian JP. PTH(1–84) is associated with improved quality of life in hypoparathyroidism through 5 years of therapy. J Clin Endocrinol Metab 2014; 99: 3694-3699
• 18 Cho NL, Moalem J, Chen L, Lubitz CC, Moore FD, Ruan DT. Surgeons and patients disagree on the potential consequences from hypoparathyroidism. Endocr Pract 2014; 20: 427-446
• 19 Hadker N, Egan J, Sanders J, Lagast H, Clarke BL. Understanding the burden of illness associated with hypoparathyroidism reported among patients in the paradox study. Endocr Pract 2014; 20: 671-679
• 20 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41
• 21 Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, Burnett-Bowie SA, Mannstadt M. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab 2012; 97: 4507-4514
• 22 Cusano NE, Anderson L, Rubin MR, Silva BC, Costa AG, Irani D, Sliney Jr. J, Bilezikian JP. Recovery of parathyroid hormone secretion and function in postoperative hypoparathyroidism: a case series. J Clin Endocrinol Metab 2013; 98: 4285-4290
• 23 Ritter K, Elfenbein D, Schneider DF, Chen H, Sippel RS. Hypoparathyroidism after total thyroidectomy: incidence and resolution. J Surg Res 2015; 197: 348-353
• 24 Spivacow FR, Negri AL, del Valle EE, Calvino I, Zanchetta JR. Clinical and metabolic risk factor evaluation in young adults with kidney stones. Int Urol Nephrol 2010; 42: 471-475
• 25 Girndt M, Trocchi P, Scheidt-Nave C, Markau S, Stang A. Prävalenz der eingeschränkten Nierenfunktion. Deutsch Ärzteblatt 2016; 113: 85-91
• 26 Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. The Epidemiology of Nonsurgical Hypoparathyroidism in Denmark: A Nationwide Case Finding Study. J Bone Miner Res 2015; 30: 1738-1744
• 27 Ronnefarth G, Misselwitz J. Nephrocalcinosis in children: a retrospective survey. Members of the Arbeitsgemeinschaft fur padiatrische Nephrologie. Pediatr Nephrol 2000; 14: 1016-1021
• 28 Winer KK, Ko CW, Reynolds JC, Dowdy K, Keil M, Peterson D, Gerber LH, McGarvey C, Cutler Jr. GB. Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1–34) versus calcitriol and calcium. J Clin Endocrinol Metab 2003; 88: 4214-4220
• 29 Arlt W, Fremerey C, Callies F, Reincke M, Schneider P, Timmermann W, Allolio B.. Well-being, mood and calcium homeostasis in patients with hypoparathyroidism receiving standard treatment with calcium and vitamin D. Eur J Endocrinol 2002; 146: 215-222
• 30 Cusano NE, Rubin MR, McMahon DJ, Irani D, Tulley A, Sliney Jr. J, Bilezikian JP. The effect of PTH(1–84) on quality of life in hypoparathyroidism. J Clin Endocrinol Metab 2013; 98: 2356-2361