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Morbidity in patients with permanent hypoparathyroidism after total thyroidectomy
Surgery xxx (2019) 1e5
Contents lists available at ScienceDirect
Surgery journal homepage: www.elsevier.com/locate/surg
Morbidity in patients with permanent hypoparathyroidism after total thyroidectomy € m, MD, PhDb, Martin Almquist, MD, PhDb Anders Bergenfelz, MD, PhDa,*, Erik Nordenstro a b
Department of Clinical Sciences-Lund, Lund University, Sweden Department of Surgery, Skåne University Hospital, Lund, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 11 June 2019 Available online xxx
Background: Permanent hypoparathyroidism is common after thyroidectomy. The present study evaluated the risk for morbidity in patients operated with total thyroidectomy with and without permanent hypoparathyroidism. Methods: Data was retrieved from the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery and cross-linked with the Swedish National Prescription Registry for Pharmaceuticals, the National Data Inpatient Registry, and Causes of Death Registry. Patients with benign thyroid disease were included. Permanent hypoparathyroidism was defined as treatment with active vitamin D for more than 6 months after thyroidectomy. Analyzed morbidity was evaluated by multivariable Cox’s regression analysis and presented as hazard ratio and 95% confidence interval. Results: There were 4,828 patients. The mean (standard deviation) follow-up was 4.5 (2.4) years. Some 239 (5.0 %) patients were medicated for permanent hypoparathyroidism. Patients with permanent hypoparathyroidism had an increased risk for renal insufficiency, hazard ratio 4.88 (2.00e11.95), and an increased risk for any malignancy, hazard ratio 2.15 (1.08e4.27). Patients with permanent hypoparathyroidism and known cardiovascular disease at the time of thyroidectomy had an increased risk for cardiovascular events during follow-up, hazard ratio 1.88 (1.02e3.47). Conclusion: Patients with permanent hypoparathyroidism after total thyroidectomy have an increased risk of long-term morbidity. These results are a cause of great concern. © 2019 Elsevier Inc. All rights reserved.
Introduction Permanent hypoparathyroidism is the most common serious complication after total thyroidectomy, with an estimated incidence of less than 3% in high volume centers,1-3 but figures of up to 10% have been reported.4 The true impact on long-term morbidity owing to permanent hypoparathyroidism after total thyroidectomy is not known, but case reports and case series suggest that hypoparathyroidism may be associated with severe morbidity.5,6 Previous studies with long-term follow-up in patients with permanent hypoparathyroidism often included patients with nonsurgical hypoparathyroidism,6,7 making results less valid to evaluate morbidity after thyroid surgery.
Presented at the meeting of the American Association of Endocrine Surgeons April 7 to 9, 2019, Los Angeles, CA. * Reprint requests: Professor Anders Bergenfelz, Kamprad Building 4th floor, Barngatan 4, Skåne University Hospital, 221 85 Lund, Sweden. E-mail address: [email protected] (A. Bergenfelz). https://doi.org/10.1016/j.surg.2019.06.056 0039-6060/© 2019 Elsevier Inc. All rights reserved.
Two large Danish studies8,9 included only patients with permanent hypoparathyroidism after surgery for thyroid and parathyroid disease and reported an increased risk of renal insufficiency (hazard ratio [HR] 4.54), renal stones (HR 4.22), seizures, infection, and depression. However, the patients in these studies were matched with controls from the general population, who had not undergone thyroidectomy or parathyroidectomy. This might give biased estimates of the risk of morbidity after permanent hypoparathyroidism because patients undergoing thyroidectomy have a lower risk for mortality than age- and gender-matched controls from the general population.10 Recently, a study from Scotland11 showed an increase risk for renal insufficiency (HR 2.18) in patients with chronic hypoparathyroidism, although this study compared outcomes with matched controls from the general population and included patients with parathyroid surgery. There are several definitions of permanent hypoparathyroidism; a pragmatic and valid definition is the use of medication with active vitamin D or calcium for more than 6 months after thyroidectomy to maintain normocalcaemia.12 By using the definition of medication
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with active vitamin D for more than 6 months postoperatively, an incidence of chronic hypoparathyroidism of approximately 5% in Sweden after thyroidectomy for benign disease was previously reported.10 In patients below 18 years of age, the incidence was more than 7%.13 Importantly, adult patients operated owing to benign thyroid disease with permanent hypoparathyroidism had a 2-fold increased risk of death compared to patients without hypoparathyroidism.10 In this study, the risk for morbidity in patients with permanent hypoparathyroidism after total thyroidectomy for benign disease was analyzed. Methods This study was approved by the ethical committee at Lund University (2011/740, 2015/543, 2016/83) and is reported according to STROBE guidelines.14 Patients were registered in the Scandinavian Quality Registry for Thyroid, Parathyroid, and Adrenal Surgery (SQRTPA), which is recognized as the Swedish National Quality Registry within the field. Data on patients operated with total thyroidectomy were extracted from the SQRTPA (January 27, 2016). Data were crosslinked with the Swedish National Prescription Registry for Pharmaceuticals. This registry contains all pharmaceutical prescriptions as of July 1, 2005. The study period was July 1, 2005 to December 31, 2014. Information on all hospital discharge diagnoses was collected from the Swedish National Data Inpatient Registry (going back to January 1, 1964), and date and cause of death were retrieved from the Causes of Death Registry. Definitions The need for medication with active vitamin D for more than 6 months after surgery was defined as permanent hypoparathyroidism. There were 3 pharmaceutical compounds registered for treatment: dihydrotachysterol, Anatomical Therapeutic Chemical Classification System (ATC) A11CC02; alfacalcidol, ATC A11CC03; and calcitriol, ATC A11CC04. These drugs are the only ones approved in Sweden for treatment of renal osteodystrophy, osteomalacia, idiopathic and postoperative hypoparathyroidism, and rickets. They are not approved for treating low levels of 25 OH vitamin D. Patients who were registered as being prescribed and having collected active vitamin D analogues both within the first 180 days and after 180 days after thyroidectomy were defined as having permanent hypoparathyroidism. Patients with follow-up of less than 180 days and with surgery before 1 July 2005 were excluded, as were patients treated with active vitamin D before thyroidectomy. Patients with previous thyroid or parathyroid surgery were also excluded, as were patients undergoing concomitant parathyroid surgery and patients aged <18 years. Lastly, patients with thyroid malignancy were excluded. In SQRTPA, patients are registered with 1 main and up to 3 secondary diagnoses. If any of them contained a malignant diagnosis, the patients were deemed to have been operated owing to malignancy and excluded from analysis. Patients with ICD-10 code C73 (thyroid cancer) as the discharge diagnosis in the National Inpatients Registry or as the underlying cause of death in the Cause of Death Registry were also excluded.
Fig 1. Flowchart according to STROBE guidelines.
Postoperative morbidity was defined using ICD codes in the discharge diagnoses of the National Inpatients Registry for the following diseases: cardiovascular disease (CVD), fracture, nephrolithiasis, renal insufficiency, cardiac arrhythmia, and any malignancy (for definitions see Appendix A, online version). Prevalent morbidity was defined as any hospitalization with the specific discharge diagnosis before the date of thyroidectomy. Incident morbidity was defined as the first (if any) hospitalization with the specific discharge diagnosis after the date of thyroidectomy. Statistics Continuous data are presented as mean (standard deviation [SD]), median and interquartile range (IQR), and categorical data as numbers with percentages. Univariable analysis was performed with c2 test. Multivariable analysis of morbidity in relation to permanent hypoparathyroidism (as defined above) was analyzed by Cox’s regression analysis and presented as HRs and 95% confidence intervals (95% CI). Patients were censored at incident morbidity, death, or end-of-follow-up (December 31, 2014), whichever came first. Patients were analyzed without and with prevalent morbidity. The analysis was adjusted for factors that were deemed to potentially influence morbidity: age at surgery (continuous variable), sex, and for thyrotoxicosis. Statistical tests were 2-sided and significance set at P < .05, and STATA version 13.0 (StataCorp, College Station, TX) was used for statistical analysis.
Analysis Results Patients with benign thyroid disease were subdivided into thyrotoxicosis and other benign disease based on the indication for surgery and histology as registered in SQRTPA.
A flow chart according to STROBE guidelines is presented in Fig 1. The final cohort consisted of 4,828 patients operated with
A. Bergenfelz et al. / Surgery xxx (2019) 1e5
3
Table I Baseline data and prevalent and incident morbidity of the 4,828 patients included in the study. Factor/variable
All, n (%) 4,828 (100)
Men, n (%) 809 (16.8)
Women, n (%) 4,019 (83.2)
Age, y, mean (SD) Type of thyroid disease Thyrotoxicosis Other benign disease Permanent hypoparathyroidism Prevalent morbidity at the time of thyroidectomy Cardiovascular disease Fracture Nephrolithiasis Renal insufficiency Cardiac arrhythmia Malignancy (any) Incident morbidity after thyroidectomy Cardiovascular disease Fracture Nephrolithiasis Renal insufficiency Cardiac arrhythmia Malignancy (any)
46.2 (15.7)
49.8 (16.1)
45.5 (15.6)
2,919 (46.9) 1,909 (30.7) 239 (5.0)
429 (53.0) 380 (47.0) 33 (4.1)
2,490 (62.0) 1,529 (38.0) 206 (5.1)
433 (9.0) 345 (7.2) 66 (1.4) 6 (0.1) 146 (3.0) 209 (4.3)
145 (17.9) 73 (9.0) 21 (2.6) 3 (0.4) 51 (6.3) 40 (4.9)
288 (7.2) 272 (6.8) 45 (1.1) 3 (0.1) 95 (2.4) 169 (4.2)
320 (6.6) 102 (2.1) 16 (0.3) 37 (0.8) 172 (3.6) 144 (3.0)
97 (12.0) 22 (2.7) 8 (1.0) 15 (1.8) 55 (6.8) 35 (4.3)
223 (5.5) 80 (2.0) 8 (0.2) 22 (0.6) 117 (2.9) 109 (2.7)
total thyroidectomy for benign disease. Characteristics of the cohort is shown in Table I. The mean (SD) follow-up was 4.5 (2.4) years. Permanent hypoparathyroidism was diagnosed in 239 (5.0 %) patients. Patients collected the prescribed vitamin D analogue within a median of 4 (IQR 2e9) days. The univariable analysis of the incidence of morbidity and its association with permanent hypoparathyroidism, excluding prevalent morbidity, is shown in Table II. The incidence for renal insufficiency during follow-up in the whole cohort was 36 of 4,822 (0.8%) patients; for patients with permanent hypoparathyroidism, the incidence was 6 of 239 (2.5%) patients and for patients without permanent hypoparathyroidism 30 of 4,583 (0.7%) patients, P < .001. In the whole cohort, the fracture incidence was 87 of 4,483 (1.9%) patients; for patients with permanent hypoparathyroidism the fracture incidence was 1 of 223 (0.5%) patients vs 86 of 4,260 (2.0%) patients without permanent hypoparathyroidism, P ¼ .097. The incidence of any new diagnosis of malignancy in patients with permanent hypoparathyroidism was 9 of 230 (3.9%) vs 95 of 4389 (2.2%) in patients without permanent hypoparathyroidism, P ¼ .081. Multivariable Cox regression analysis was performed adjusted for sex, age, and for thyrotoxicosis (Table III). Analysis was performed for patients without and with prevalent disease at the time of surgery. After excluding prevalent disease, permanent hypoparathyroidism was associated with a significant increased risk for renal insufficiency (HR 4.88 [95 % CI 2.00e11.95]). Permanent hypoparathyroidism was associated with a 2-fold increased risk for any malignancy during follow-up (HR 2.15 [95 % CI 1.08e4.27]). To evaluate the impact of permanent hypoparathyroidism on the risk for incident morbidity in patients with known (prevalent disease) at the time of thyroidectomy, a multivariable analysis was performed including these patients (Table III). Patients operated with permanent hypoparathyroidism and with known CVD at the time of surgery had an increased risk of cardiovascular events during follow-up (HR of 1.88 [1.02e3.47]). Interestingly, patients with permanent hypoparathyroidism operated due to benign thyroid disease and with prevalent malignancy (any malignant diagnosis, excluding ICD code C73) at the time of surgery showed no increased risk for malignancy during follow-up as compared to patients without permanent hypoparathyroidism (HR 0.41 [95 % CI 0.06e3.0]).
Discussion In this population-based study of almost 5,000 patients undergoing thyroidectomy for benign disease, permanent hypoparathyroidism after thyroidectomy showed an almost 5-fold increased risk of renal insufficiency (HR 4.88, (2.00e11.95) and a doubled risk of a diagnosis of any malignancy (HR 2.15 (1.08e4.27) in the multivariable analysis of patients without prevalent disease. In patients with permanent hypoparathyroidism and with known CVD at the time of surgery (ie, prevalent disease), the multivariable analysis showed an approximately 2-fold increased risk for cardiovascular events (HR 1.88 [1.02e3.47]) during followup. In the context of the overall rate of permanent hypoparathyroidism after total thyroidectomy, 5% in the current series, and the previously shown increased risk for mortality in patients with permanent hypoparathyroidism operated for benign disease,10 the results clearly demonstrate the severity of the problem. The finding that permanent hypoparathyroidism increases the risk of renal insufficiency agrees with previous investigations, as demonstrated by Mitchell et al6 in a small case series and Underbjerg et al and Vadiveloo et al in population-based case-control studies.8,11 The observation that permanent hypoparathyroidism is associated with an increased risk of malignancy has not, to our knowledge, been reported. Patients with benign disease, which excluded all patients with ICD-code C73 (thyroid cancer) either before or after the date of surgery, had an increased risk for a diagnosis of any malignancy during follow-up. The reason for this finding remains obscure, whether by chance, causal relationship with hypoparathyroidism, medical treatment, or an increased surveillance leading to detection bias. However, in the context of renal insufficiency an increased risk for digestive cancer in pre-dialytic patients has recently been reported.15 An increased risk for cardiovascular events during follow-up in patients with permanent hypoparathyroidism with known CVD at the time of surgery has not been reported and should be considered when monitoring vitamin D therapy for patients with hypoparathyroidism with known CVD. It is not known whether low calcium or PTH levels or medical treatment for hypoparathyroidism, or a combination of those, are the cause of the increased risk for morbidity demonstrated in the
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A. Bergenfelz et al. / Surgery xxx (2019) 1e5 Table II Univariable analysis of the risk for morbidity in patients with or without permanent hypoparathyroidism after total thyroidectomy for benign disease. Patients with known (prevalent morbidity) at the time for thyroidectomy were excluded for this analysis. Numbers of total (percentages) are shown. Variable
Number/total morbidity (%)
CVD Fracture Nephrolithiasis Renal insufficiency Cardiac arrhythmia Malignancy (any) *
129/4,395 (2.9) 87/4,483 (1.9) 14/4,762 (0.3) 36/4,822 (0.8) 158/4,682 (3.4) 104/4,619 (2.2)
Benign thyroid disease N ¼ 4,828 Permanent hypoparathyroidism
No permanent hypoparathyroidism
P value*
8/219 1/223 1/238 6/239 8/232 9/230
121/4,176 (2.9) 86/4,260 (2.0) 13/4,524 (0.3) 30/4,583 (0.7) 150/4,450 (3.4) 95/4,389 (2.2)
.519 .097 .712 .001 .949 .081
(3.7) (0.5) (0.4) (2.5) (3.5) (3.9)
c2 test.
Table III Multivariable Cox’s regression of the risk for incident morbidity after permanent hypoparathyroidism, presented separately for patients with and without prevalent morbidity Morbidity
Benign thyroid disease without prevalent morbidity* (N ¼ 4,828) HR (95 % CI)
Benign thyroid disease with prevalent morbidity* (n is different for different morbidities) HR (95 % CI)
Cardiovascular disease Fracture Renal insufficiency Nephrolithiasis Cardiac arrhythmia Malignancy (any)
1.52 0.29 4.88 1.71 1.02 2.15
1.88 (1.02e3.47) 0.88 (0.11e7.00)
* y
(0.74e3.12) (0.04e2.10) (2.00e11.95 (0.22e13.11) (0.50e2.08) (1.08e4.27)
y y y
0.41 (0.06e3.05)
Adjusted for age, sex, and thyrotoxicosis. Numbers were too small to analyze.
present study. Most guidelines for treatment recommend aiming for serum calcium levels in the low normal or just below normal range.16,17 However, in 1 study, 9.4 % of patients experienced hypercalcemic and 15.6 % hypocalcemic episodes, respectively.18 Treatment frequently fails to reach target values for serum calcium, serum phosphorus, calcium-phosphate product, and, especially, for urinary calcium excretion.6,19 Recently, an association between high levels of phosphate and mortality was shown, as was an increased risk for mortality and renal disease with high calciumphosphate product.20 Mortality, cardiovascular disease, and renal disease increased with the number of hypercalcemic episodes in this case-control study.20 Some weaknesses of the present study are acknowledged. Morbidity was evaluated based on ICD discharge codes, and longterm biochemical values, including PTH, calcium, and creatinine, were not analyzed. This could probably lead to an under- or overestimation of risk for several of the analyzed variables. For instance, decreased estimated glomerular filtration rates (< 60 mL/min/1.73 m2) consistent with chronic kidney disease grade 3 or higher has been found in between 12.2% and 41% of patients treated for chronic hypoparathyroidism.6,18-20 Therefore, the impact of treatment for permanent hypoparathyroidism on renal insufficiency is most likely underestimated in the present study. Most patients with renal stones are now treated in the ambulatory setting. Previous studies have shown that nephrolithiasis or nephrocalcinosis occurred in 10.5% to 31% of patients and was often asymptomatic.6,18,19 Therefore, the present study may underestimate the impact of this complication. In the present study, we did not analyze the impact of the 3 pharmaceutical compounds registered for treatment of hypoparathyroidism. A previous study found that calcitriol, compared with calcifediol, showed a higher level of creatinine, and renal failure was twice as common in the calcitriol group.18
This study has several strengths. The cohort was homogenous and included only patients who had been operated with total thyroidectomy. The crosslinking of data enables a robust analysis of the incidence of the studied complications and risk assessment for morbidities that otherwise would be problematic owing to risk for loss to follow-up. In conclusion, this study shows a high incidence of permanent hypoparathyroidism after total thyroidectomy associated with an increased morbidity. Strategies to reduce the risk for postoperative hypoparathyroidism, for instance by reducing the extent of surgery or to develop new intraoperative techniques, are needed.
Funding/Support This study was supported by Research Grant from Region Skåne, Sweden, 2018-2020. Participating clinics in the Scandinavian Quality Registry for Thyroid, Parathyroid, and Adrenal Surgery (SQRTPA).
Conflict of interest/Disclosure The authors have no conflict of interest to disclose.
Supplementary materials Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.1016/j.surg.2019. 06.056.
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References 1. 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;101:307e320. 2. Asari R, Passler C, Kaczirek K, Scheuba C, Niederle B. Hypoparathyroidism after total thyroidectomy: a prospective study. Arch Surg. 2008;143:132e137. € m W, Bergenfelz A. Prediction of 3. Almquist M, Hallgrimsson P, Nordenstro permanent hypoparathyroidism after total thyroidectomy. World J Surg. 2014;38:2613e2620. 4. Chadwick DR. Hypocalcaemia and permanent hypoparathyroidism after total/ bilateral thyroidectomy in the BAETS Registry. Gland Surg. 2017;6:S69eS74. 5. Agarwal R, Lahiri D, Biswas A, Mukhopadhyay J, Maity P, Roy MK. A rare cause of seizures, Parkinsonian, and cerebellar signs: Brain calcinosis secondary to thyroidectomy. N Am J Med Sci. 2014;10:540e542. 6. Mitchell DM, Regan S, Cooley MR, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab. 2012;97:4507e4514. 7. Marcucci G, Cianferotti L, Parri S, et al. HypoparaNet: A database of chronic hypoparathyroidism based on expert medical surgical centers in Italy. Calcif Tissue Int. 2018;103:151e163. 8. 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;28:2277e2285. 9. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Postsurgical hypoparathyroidism-risk of fractures, psychiatric diseases, cancer, cataract, and infections. J Bone Miner Res. 2014;29:2504e2510. €m E, Bergenfelz A. Mortality in patients 10. Almquist M, Ivarsson K, Nordenstro with permanent hypoparathyroidism after total thyroidectomy. Br J Surg. 2018;105:1313e1318.
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11. Vadiveloo T, Donnan PT, Leese CJ, Abraham KJ, Leese GP. Increased mortality and morbidity in patients with chronic hypoparathyroidism: A populationbased study. Clin Endocrinol. 2019;90:285e292. ~ oz-Nova JL, S 12. Lorente-Poch L, Sancho JJ, Mun anchez-Vel azquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surg. 2015;1:82e90. €m E, Bergenfelz A, Almquist M. Permanent hypoparathyroidism 13. Nordenstro after total thyroidectomy in children: Results from a national registry. World J Surg. 2018;42:2858e2863. 14. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, the STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007;335:806e808. 15. Oh HJ, Lee HA, Moon CM, Ryu DR. Incidence risk of various types of digestive cancers in patients with pre-dialytic chronic kidney disease: A nationwide population-based cohort study. PLoS One. 2018;13:e0207756. 16. Bollerslev J, Rejnmark L, Marcocci C, et al. and the European Society of Endocrinology. European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol. 2015;173:G1eG20. 17. Bilezikian JP, Brandi ML, Cusano NE, et al. Management of hypoparathyroidism: Present and future. J Clin Endocrinol Metab. 2016;101:2313e2324. 18. Lorente-Poch L, Sancho JJ, Carballo L, Sitges-Serra A. Clinical profile and longterm follow-up of 32 patients with postoperative permanent hypoparathyroidism. Gland Surg. 2017;6:S3eS10. 19. Meola A, Vignali E, Matrone A, Cetani F, Marcocci C. Efficacy and safety of longterm management of patients with chronic post-surgical hypoparathyroidism. J Endocrinol Invest. 2018;41:1221e1226. 20. Underbjerg L, Sikjaer T, Rejnmark L. Long-Term complications in patients with hypoparathyroidism evaluated by biochemical findings: A case-control study. J Bone Miner Res. 2018;33:822e831.
Discussion Dr Scott Wilhelm (Cleveland, OH): A lot of your patients had benign disease. I think almost 50% had hyperthyroidism, and of them 90% were due to Graves' disease. Do you think that had a very large impact in your study? We certainly know the higher rate of finding parathyroids in total thyroidectomy specimens after Graves' disease. Also, do you think there is a relationship with the bone hunger problems we see in these patients affecting the use of vitamin D? That makes me wonder if your definition of hypoparathyroidism is correct here. Dr Anders Bergenfelz: There is no impact, actually, of the rate of thyrotoxicosis within the study group, although it was included in the adjusted multivariable model. As a matter of fact, we have done some other analyses on these data, and the risk for mortality and for morbidity is actually increased in the multinodular disease patients that had operation due to compressive symptoms. Also, most of the patients having operation for Graves' disease are young patients, perhaps between 20 and 35. Dr Barry Inabnet (New York, NY): Your data emphasizes the importance of large registries and the ability to cross link them and map the data to other registries to allow for some meaningful observations. There is one additional point that you should include, and that's the experience of the surgeon. So, in your data, were you able to drill down to a level to better understand practice patterns and the volume of the surgeons and perhaps address that potential issue of low-volume surgeons contributing to this problem? Thank you. Dr Anders Bergenfelz: That's a very good question, and of course there are differences between surgeons and between institutions. But as far as I can see from our initial data, the differences, at least between institutions, are not as big as you may think.
Dr Jennifer Rosen (Washington, DC): I found it interesting that you excluded patients who had vitamin D supplementation before surgery because, in fact, it's our practice and many people's practice to actively check and replace the vitamin D before surgery. Why did you exclude those patients, and would you consider looking at them? Because I tell my patients that's one of the modifiable risk factors. Dr Anders Bergenfelz: But they were not excluded. Those who were excluded were those treated with specific medications, and the treatment with these compounds is fairly restricted. So those who had supplementation because they had, let's say, borderline 25-hydroxy vitamin D levels were not excluded. Dr Jennifer Rosen: Why not, therefore, look at the outcomes in those patients who were replaced? And maybe we should be replacing patients more actively with those compounds to prevent these complications. Dr Anders Bergenfelz: I really doubt that this is the reason for these figures because all of those patients were treated immediately after surgery. And even if there is a slight correlation between low or borderline 25-hydroxy vitamin D levels and slightly low calcium levels, in the long run, this doesn’t imply they were being treated with the effective drugs that are very restricted. Dr Jennifer Rosen (Washington, DC): So careful surgical technique still outweighs drug replacement before surgery? Dr Anders Bergenfelz: Well, I guess so. But the problem is that if you ask colleagues, everyone tells you they are very careful. They do high capsular dissection and so on and so forth, and still we have these kind of results.
Contents lists available at ScienceDirect
Surgery journal homepage: www.elsevier.com/locate/surg
Morbidity in patients with permanent hypoparathyroidism after total thyroidectomy € m, MD, PhDb, Martin Almquist, MD, PhDb Anders Bergenfelz, MD, PhDa,*, Erik Nordenstro a b
Department of Clinical Sciences-Lund, Lund University, Sweden Department of Surgery, Skåne University Hospital, Lund, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history: Accepted 11 June 2019 Available online xxx
Background: Permanent hypoparathyroidism is common after thyroidectomy. The present study evaluated the risk for morbidity in patients operated with total thyroidectomy with and without permanent hypoparathyroidism. Methods: Data was retrieved from the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery and cross-linked with the Swedish National Prescription Registry for Pharmaceuticals, the National Data Inpatient Registry, and Causes of Death Registry. Patients with benign thyroid disease were included. Permanent hypoparathyroidism was defined as treatment with active vitamin D for more than 6 months after thyroidectomy. Analyzed morbidity was evaluated by multivariable Cox’s regression analysis and presented as hazard ratio and 95% confidence interval. Results: There were 4,828 patients. The mean (standard deviation) follow-up was 4.5 (2.4) years. Some 239 (5.0 %) patients were medicated for permanent hypoparathyroidism. Patients with permanent hypoparathyroidism had an increased risk for renal insufficiency, hazard ratio 4.88 (2.00e11.95), and an increased risk for any malignancy, hazard ratio 2.15 (1.08e4.27). Patients with permanent hypoparathyroidism and known cardiovascular disease at the time of thyroidectomy had an increased risk for cardiovascular events during follow-up, hazard ratio 1.88 (1.02e3.47). Conclusion: Patients with permanent hypoparathyroidism after total thyroidectomy have an increased risk of long-term morbidity. These results are a cause of great concern. © 2019 Elsevier Inc. All rights reserved.
Introduction Permanent hypoparathyroidism is the most common serious complication after total thyroidectomy, with an estimated incidence of less than 3% in high volume centers,1-3 but figures of up to 10% have been reported.4 The true impact on long-term morbidity owing to permanent hypoparathyroidism after total thyroidectomy is not known, but case reports and case series suggest that hypoparathyroidism may be associated with severe morbidity.5,6 Previous studies with long-term follow-up in patients with permanent hypoparathyroidism often included patients with nonsurgical hypoparathyroidism,6,7 making results less valid to evaluate morbidity after thyroid surgery.
Presented at the meeting of the American Association of Endocrine Surgeons April 7 to 9, 2019, Los Angeles, CA. * Reprint requests: Professor Anders Bergenfelz, Kamprad Building 4th floor, Barngatan 4, Skåne University Hospital, 221 85 Lund, Sweden. E-mail address: [email protected] (A. Bergenfelz). https://doi.org/10.1016/j.surg.2019.06.056 0039-6060/© 2019 Elsevier Inc. All rights reserved.
Two large Danish studies8,9 included only patients with permanent hypoparathyroidism after surgery for thyroid and parathyroid disease and reported an increased risk of renal insufficiency (hazard ratio [HR] 4.54), renal stones (HR 4.22), seizures, infection, and depression. However, the patients in these studies were matched with controls from the general population, who had not undergone thyroidectomy or parathyroidectomy. This might give biased estimates of the risk of morbidity after permanent hypoparathyroidism because patients undergoing thyroidectomy have a lower risk for mortality than age- and gender-matched controls from the general population.10 Recently, a study from Scotland11 showed an increase risk for renal insufficiency (HR 2.18) in patients with chronic hypoparathyroidism, although this study compared outcomes with matched controls from the general population and included patients with parathyroid surgery. There are several definitions of permanent hypoparathyroidism; a pragmatic and valid definition is the use of medication with active vitamin D or calcium for more than 6 months after thyroidectomy to maintain normocalcaemia.12 By using the definition of medication
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A. Bergenfelz et al. / Surgery xxx (2019) 1e5
with active vitamin D for more than 6 months postoperatively, an incidence of chronic hypoparathyroidism of approximately 5% in Sweden after thyroidectomy for benign disease was previously reported.10 In patients below 18 years of age, the incidence was more than 7%.13 Importantly, adult patients operated owing to benign thyroid disease with permanent hypoparathyroidism had a 2-fold increased risk of death compared to patients without hypoparathyroidism.10 In this study, the risk for morbidity in patients with permanent hypoparathyroidism after total thyroidectomy for benign disease was analyzed. Methods This study was approved by the ethical committee at Lund University (2011/740, 2015/543, 2016/83) and is reported according to STROBE guidelines.14 Patients were registered in the Scandinavian Quality Registry for Thyroid, Parathyroid, and Adrenal Surgery (SQRTPA), which is recognized as the Swedish National Quality Registry within the field. Data on patients operated with total thyroidectomy were extracted from the SQRTPA (January 27, 2016). Data were crosslinked with the Swedish National Prescription Registry for Pharmaceuticals. This registry contains all pharmaceutical prescriptions as of July 1, 2005. The study period was July 1, 2005 to December 31, 2014. Information on all hospital discharge diagnoses was collected from the Swedish National Data Inpatient Registry (going back to January 1, 1964), and date and cause of death were retrieved from the Causes of Death Registry. Definitions The need for medication with active vitamin D for more than 6 months after surgery was defined as permanent hypoparathyroidism. There were 3 pharmaceutical compounds registered for treatment: dihydrotachysterol, Anatomical Therapeutic Chemical Classification System (ATC) A11CC02; alfacalcidol, ATC A11CC03; and calcitriol, ATC A11CC04. These drugs are the only ones approved in Sweden for treatment of renal osteodystrophy, osteomalacia, idiopathic and postoperative hypoparathyroidism, and rickets. They are not approved for treating low levels of 25 OH vitamin D. Patients who were registered as being prescribed and having collected active vitamin D analogues both within the first 180 days and after 180 days after thyroidectomy were defined as having permanent hypoparathyroidism. Patients with follow-up of less than 180 days and with surgery before 1 July 2005 were excluded, as were patients treated with active vitamin D before thyroidectomy. Patients with previous thyroid or parathyroid surgery were also excluded, as were patients undergoing concomitant parathyroid surgery and patients aged <18 years. Lastly, patients with thyroid malignancy were excluded. In SQRTPA, patients are registered with 1 main and up to 3 secondary diagnoses. If any of them contained a malignant diagnosis, the patients were deemed to have been operated owing to malignancy and excluded from analysis. Patients with ICD-10 code C73 (thyroid cancer) as the discharge diagnosis in the National Inpatients Registry or as the underlying cause of death in the Cause of Death Registry were also excluded.
Fig 1. Flowchart according to STROBE guidelines.
Postoperative morbidity was defined using ICD codes in the discharge diagnoses of the National Inpatients Registry for the following diseases: cardiovascular disease (CVD), fracture, nephrolithiasis, renal insufficiency, cardiac arrhythmia, and any malignancy (for definitions see Appendix A, online version). Prevalent morbidity was defined as any hospitalization with the specific discharge diagnosis before the date of thyroidectomy. Incident morbidity was defined as the first (if any) hospitalization with the specific discharge diagnosis after the date of thyroidectomy. Statistics Continuous data are presented as mean (standard deviation [SD]), median and interquartile range (IQR), and categorical data as numbers with percentages. Univariable analysis was performed with c2 test. Multivariable analysis of morbidity in relation to permanent hypoparathyroidism (as defined above) was analyzed by Cox’s regression analysis and presented as HRs and 95% confidence intervals (95% CI). Patients were censored at incident morbidity, death, or end-of-follow-up (December 31, 2014), whichever came first. Patients were analyzed without and with prevalent morbidity. The analysis was adjusted for factors that were deemed to potentially influence morbidity: age at surgery (continuous variable), sex, and for thyrotoxicosis. Statistical tests were 2-sided and significance set at P < .05, and STATA version 13.0 (StataCorp, College Station, TX) was used for statistical analysis.
Analysis Results Patients with benign thyroid disease were subdivided into thyrotoxicosis and other benign disease based on the indication for surgery and histology as registered in SQRTPA.
A flow chart according to STROBE guidelines is presented in Fig 1. The final cohort consisted of 4,828 patients operated with
A. Bergenfelz et al. / Surgery xxx (2019) 1e5
3
Table I Baseline data and prevalent and incident morbidity of the 4,828 patients included in the study. Factor/variable
All, n (%) 4,828 (100)
Men, n (%) 809 (16.8)
Women, n (%) 4,019 (83.2)
Age, y, mean (SD) Type of thyroid disease Thyrotoxicosis Other benign disease Permanent hypoparathyroidism Prevalent morbidity at the time of thyroidectomy Cardiovascular disease Fracture Nephrolithiasis Renal insufficiency Cardiac arrhythmia Malignancy (any) Incident morbidity after thyroidectomy Cardiovascular disease Fracture Nephrolithiasis Renal insufficiency Cardiac arrhythmia Malignancy (any)
46.2 (15.7)
49.8 (16.1)
45.5 (15.6)
2,919 (46.9) 1,909 (30.7) 239 (5.0)
429 (53.0) 380 (47.0) 33 (4.1)
2,490 (62.0) 1,529 (38.0) 206 (5.1)
433 (9.0) 345 (7.2) 66 (1.4) 6 (0.1) 146 (3.0) 209 (4.3)
145 (17.9) 73 (9.0) 21 (2.6) 3 (0.4) 51 (6.3) 40 (4.9)
288 (7.2) 272 (6.8) 45 (1.1) 3 (0.1) 95 (2.4) 169 (4.2)
320 (6.6) 102 (2.1) 16 (0.3) 37 (0.8) 172 (3.6) 144 (3.0)
97 (12.0) 22 (2.7) 8 (1.0) 15 (1.8) 55 (6.8) 35 (4.3)
223 (5.5) 80 (2.0) 8 (0.2) 22 (0.6) 117 (2.9) 109 (2.7)
total thyroidectomy for benign disease. Characteristics of the cohort is shown in Table I. The mean (SD) follow-up was 4.5 (2.4) years. Permanent hypoparathyroidism was diagnosed in 239 (5.0 %) patients. Patients collected the prescribed vitamin D analogue within a median of 4 (IQR 2e9) days. The univariable analysis of the incidence of morbidity and its association with permanent hypoparathyroidism, excluding prevalent morbidity, is shown in Table II. The incidence for renal insufficiency during follow-up in the whole cohort was 36 of 4,822 (0.8%) patients; for patients with permanent hypoparathyroidism, the incidence was 6 of 239 (2.5%) patients and for patients without permanent hypoparathyroidism 30 of 4,583 (0.7%) patients, P < .001. In the whole cohort, the fracture incidence was 87 of 4,483 (1.9%) patients; for patients with permanent hypoparathyroidism the fracture incidence was 1 of 223 (0.5%) patients vs 86 of 4,260 (2.0%) patients without permanent hypoparathyroidism, P ¼ .097. The incidence of any new diagnosis of malignancy in patients with permanent hypoparathyroidism was 9 of 230 (3.9%) vs 95 of 4389 (2.2%) in patients without permanent hypoparathyroidism, P ¼ .081. Multivariable Cox regression analysis was performed adjusted for sex, age, and for thyrotoxicosis (Table III). Analysis was performed for patients without and with prevalent disease at the time of surgery. After excluding prevalent disease, permanent hypoparathyroidism was associated with a significant increased risk for renal insufficiency (HR 4.88 [95 % CI 2.00e11.95]). Permanent hypoparathyroidism was associated with a 2-fold increased risk for any malignancy during follow-up (HR 2.15 [95 % CI 1.08e4.27]). To evaluate the impact of permanent hypoparathyroidism on the risk for incident morbidity in patients with known (prevalent disease) at the time of thyroidectomy, a multivariable analysis was performed including these patients (Table III). Patients operated with permanent hypoparathyroidism and with known CVD at the time of surgery had an increased risk of cardiovascular events during follow-up (HR of 1.88 [1.02e3.47]). Interestingly, patients with permanent hypoparathyroidism operated due to benign thyroid disease and with prevalent malignancy (any malignant diagnosis, excluding ICD code C73) at the time of surgery showed no increased risk for malignancy during follow-up as compared to patients without permanent hypoparathyroidism (HR 0.41 [95 % CI 0.06e3.0]).
Discussion In this population-based study of almost 5,000 patients undergoing thyroidectomy for benign disease, permanent hypoparathyroidism after thyroidectomy showed an almost 5-fold increased risk of renal insufficiency (HR 4.88, (2.00e11.95) and a doubled risk of a diagnosis of any malignancy (HR 2.15 (1.08e4.27) in the multivariable analysis of patients without prevalent disease. In patients with permanent hypoparathyroidism and with known CVD at the time of surgery (ie, prevalent disease), the multivariable analysis showed an approximately 2-fold increased risk for cardiovascular events (HR 1.88 [1.02e3.47]) during followup. In the context of the overall rate of permanent hypoparathyroidism after total thyroidectomy, 5% in the current series, and the previously shown increased risk for mortality in patients with permanent hypoparathyroidism operated for benign disease,10 the results clearly demonstrate the severity of the problem. The finding that permanent hypoparathyroidism increases the risk of renal insufficiency agrees with previous investigations, as demonstrated by Mitchell et al6 in a small case series and Underbjerg et al and Vadiveloo et al in population-based case-control studies.8,11 The observation that permanent hypoparathyroidism is associated with an increased risk of malignancy has not, to our knowledge, been reported. Patients with benign disease, which excluded all patients with ICD-code C73 (thyroid cancer) either before or after the date of surgery, had an increased risk for a diagnosis of any malignancy during follow-up. The reason for this finding remains obscure, whether by chance, causal relationship with hypoparathyroidism, medical treatment, or an increased surveillance leading to detection bias. However, in the context of renal insufficiency an increased risk for digestive cancer in pre-dialytic patients has recently been reported.15 An increased risk for cardiovascular events during follow-up in patients with permanent hypoparathyroidism with known CVD at the time of surgery has not been reported and should be considered when monitoring vitamin D therapy for patients with hypoparathyroidism with known CVD. It is not known whether low calcium or PTH levels or medical treatment for hypoparathyroidism, or a combination of those, are the cause of the increased risk for morbidity demonstrated in the
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A. Bergenfelz et al. / Surgery xxx (2019) 1e5 Table II Univariable analysis of the risk for morbidity in patients with or without permanent hypoparathyroidism after total thyroidectomy for benign disease. Patients with known (prevalent morbidity) at the time for thyroidectomy were excluded for this analysis. Numbers of total (percentages) are shown. Variable
Number/total morbidity (%)
CVD Fracture Nephrolithiasis Renal insufficiency Cardiac arrhythmia Malignancy (any) *
129/4,395 (2.9) 87/4,483 (1.9) 14/4,762 (0.3) 36/4,822 (0.8) 158/4,682 (3.4) 104/4,619 (2.2)
Benign thyroid disease N ¼ 4,828 Permanent hypoparathyroidism
No permanent hypoparathyroidism
P value*
8/219 1/223 1/238 6/239 8/232 9/230
121/4,176 (2.9) 86/4,260 (2.0) 13/4,524 (0.3) 30/4,583 (0.7) 150/4,450 (3.4) 95/4,389 (2.2)
.519 .097 .712 .001 .949 .081
(3.7) (0.5) (0.4) (2.5) (3.5) (3.9)
c2 test.
Table III Multivariable Cox’s regression of the risk for incident morbidity after permanent hypoparathyroidism, presented separately for patients with and without prevalent morbidity Morbidity
Benign thyroid disease without prevalent morbidity* (N ¼ 4,828) HR (95 % CI)
Benign thyroid disease with prevalent morbidity* (n is different for different morbidities) HR (95 % CI)
Cardiovascular disease Fracture Renal insufficiency Nephrolithiasis Cardiac arrhythmia Malignancy (any)
1.52 0.29 4.88 1.71 1.02 2.15
1.88 (1.02e3.47) 0.88 (0.11e7.00)
* y
(0.74e3.12) (0.04e2.10) (2.00e11.95 (0.22e13.11) (0.50e2.08) (1.08e4.27)
y y y
0.41 (0.06e3.05)
Adjusted for age, sex, and thyrotoxicosis. Numbers were too small to analyze.
present study. Most guidelines for treatment recommend aiming for serum calcium levels in the low normal or just below normal range.16,17 However, in 1 study, 9.4 % of patients experienced hypercalcemic and 15.6 % hypocalcemic episodes, respectively.18 Treatment frequently fails to reach target values for serum calcium, serum phosphorus, calcium-phosphate product, and, especially, for urinary calcium excretion.6,19 Recently, an association between high levels of phosphate and mortality was shown, as was an increased risk for mortality and renal disease with high calciumphosphate product.20 Mortality, cardiovascular disease, and renal disease increased with the number of hypercalcemic episodes in this case-control study.20 Some weaknesses of the present study are acknowledged. Morbidity was evaluated based on ICD discharge codes, and longterm biochemical values, including PTH, calcium, and creatinine, were not analyzed. This could probably lead to an under- or overestimation of risk for several of the analyzed variables. For instance, decreased estimated glomerular filtration rates (< 60 mL/min/1.73 m2) consistent with chronic kidney disease grade 3 or higher has been found in between 12.2% and 41% of patients treated for chronic hypoparathyroidism.6,18-20 Therefore, the impact of treatment for permanent hypoparathyroidism on renal insufficiency is most likely underestimated in the present study. Most patients with renal stones are now treated in the ambulatory setting. Previous studies have shown that nephrolithiasis or nephrocalcinosis occurred in 10.5% to 31% of patients and was often asymptomatic.6,18,19 Therefore, the present study may underestimate the impact of this complication. In the present study, we did not analyze the impact of the 3 pharmaceutical compounds registered for treatment of hypoparathyroidism. A previous study found that calcitriol, compared with calcifediol, showed a higher level of creatinine, and renal failure was twice as common in the calcitriol group.18
This study has several strengths. The cohort was homogenous and included only patients who had been operated with total thyroidectomy. The crosslinking of data enables a robust analysis of the incidence of the studied complications and risk assessment for morbidities that otherwise would be problematic owing to risk for loss to follow-up. In conclusion, this study shows a high incidence of permanent hypoparathyroidism after total thyroidectomy associated with an increased morbidity. Strategies to reduce the risk for postoperative hypoparathyroidism, for instance by reducing the extent of surgery or to develop new intraoperative techniques, are needed.
Funding/Support This study was supported by Research Grant from Region Skåne, Sweden, 2018-2020. Participating clinics in the Scandinavian Quality Registry for Thyroid, Parathyroid, and Adrenal Surgery (SQRTPA).
Conflict of interest/Disclosure The authors have no conflict of interest to disclose.
Supplementary materials Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.1016/j.surg.2019. 06.056.
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References 1. 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;101:307e320. 2. Asari R, Passler C, Kaczirek K, Scheuba C, Niederle B. Hypoparathyroidism after total thyroidectomy: a prospective study. Arch Surg. 2008;143:132e137. € m W, Bergenfelz A. Prediction of 3. Almquist M, Hallgrimsson P, Nordenstro permanent hypoparathyroidism after total thyroidectomy. World J Surg. 2014;38:2613e2620. 4. Chadwick DR. Hypocalcaemia and permanent hypoparathyroidism after total/ bilateral thyroidectomy in the BAETS Registry. Gland Surg. 2017;6:S69eS74. 5. Agarwal R, Lahiri D, Biswas A, Mukhopadhyay J, Maity P, Roy MK. A rare cause of seizures, Parkinsonian, and cerebellar signs: Brain calcinosis secondary to thyroidectomy. N Am J Med Sci. 2014;10:540e542. 6. Mitchell DM, Regan S, Cooley MR, et al. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab. 2012;97:4507e4514. 7. Marcucci G, Cianferotti L, Parri S, et al. HypoparaNet: A database of chronic hypoparathyroidism based on expert medical surgical centers in Italy. Calcif Tissue Int. 2018;103:151e163. 8. 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;28:2277e2285. 9. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Postsurgical hypoparathyroidism-risk of fractures, psychiatric diseases, cancer, cataract, and infections. J Bone Miner Res. 2014;29:2504e2510. €m E, Bergenfelz A. Mortality in patients 10. Almquist M, Ivarsson K, Nordenstro with permanent hypoparathyroidism after total thyroidectomy. Br J Surg. 2018;105:1313e1318.
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11. Vadiveloo T, Donnan PT, Leese CJ, Abraham KJ, Leese GP. Increased mortality and morbidity in patients with chronic hypoparathyroidism: A populationbased study. Clin Endocrinol. 2019;90:285e292. ~ oz-Nova JL, S 12. Lorente-Poch L, Sancho JJ, Mun anchez-Vel azquez P, Sitges-Serra A. Defining the syndromes of parathyroid failure after total thyroidectomy. Gland Surg. 2015;1:82e90. €m E, Bergenfelz A, Almquist M. Permanent hypoparathyroidism 13. Nordenstro after total thyroidectomy in children: Results from a national registry. World J Surg. 2018;42:2858e2863. 14. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, the STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007;335:806e808. 15. Oh HJ, Lee HA, Moon CM, Ryu DR. Incidence risk of various types of digestive cancers in patients with pre-dialytic chronic kidney disease: A nationwide population-based cohort study. PLoS One. 2018;13:e0207756. 16. Bollerslev J, Rejnmark L, Marcocci C, et al. and the European Society of Endocrinology. European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol. 2015;173:G1eG20. 17. Bilezikian JP, Brandi ML, Cusano NE, et al. Management of hypoparathyroidism: Present and future. J Clin Endocrinol Metab. 2016;101:2313e2324. 18. Lorente-Poch L, Sancho JJ, Carballo L, Sitges-Serra A. Clinical profile and longterm follow-up of 32 patients with postoperative permanent hypoparathyroidism. Gland Surg. 2017;6:S3eS10. 19. Meola A, Vignali E, Matrone A, Cetani F, Marcocci C. Efficacy and safety of longterm management of patients with chronic post-surgical hypoparathyroidism. J Endocrinol Invest. 2018;41:1221e1226. 20. Underbjerg L, Sikjaer T, Rejnmark L. Long-Term complications in patients with hypoparathyroidism evaluated by biochemical findings: A case-control study. J Bone Miner Res. 2018;33:822e831.
Discussion Dr Scott Wilhelm (Cleveland, OH): A lot of your patients had benign disease. I think almost 50% had hyperthyroidism, and of them 90% were due to Graves' disease. Do you think that had a very large impact in your study? We certainly know the higher rate of finding parathyroids in total thyroidectomy specimens after Graves' disease. Also, do you think there is a relationship with the bone hunger problems we see in these patients affecting the use of vitamin D? That makes me wonder if your definition of hypoparathyroidism is correct here. Dr Anders Bergenfelz: There is no impact, actually, of the rate of thyrotoxicosis within the study group, although it was included in the adjusted multivariable model. As a matter of fact, we have done some other analyses on these data, and the risk for mortality and for morbidity is actually increased in the multinodular disease patients that had operation due to compressive symptoms. Also, most of the patients having operation for Graves' disease are young patients, perhaps between 20 and 35. Dr Barry Inabnet (New York, NY): Your data emphasizes the importance of large registries and the ability to cross link them and map the data to other registries to allow for some meaningful observations. There is one additional point that you should include, and that's the experience of the surgeon. So, in your data, were you able to drill down to a level to better understand practice patterns and the volume of the surgeons and perhaps address that potential issue of low-volume surgeons contributing to this problem? Thank you. Dr Anders Bergenfelz: That's a very good question, and of course there are differences between surgeons and between institutions. But as far as I can see from our initial data, the differences, at least between institutions, are not as big as you may think.
Dr Jennifer Rosen (Washington, DC): I found it interesting that you excluded patients who had vitamin D supplementation before surgery because, in fact, it's our practice and many people's practice to actively check and replace the vitamin D before surgery. Why did you exclude those patients, and would you consider looking at them? Because I tell my patients that's one of the modifiable risk factors. Dr Anders Bergenfelz: But they were not excluded. Those who were excluded were those treated with specific medications, and the treatment with these compounds is fairly restricted. So those who had supplementation because they had, let's say, borderline 25-hydroxy vitamin D levels were not excluded. Dr Jennifer Rosen: Why not, therefore, look at the outcomes in those patients who were replaced? And maybe we should be replacing patients more actively with those compounds to prevent these complications. Dr Anders Bergenfelz: I really doubt that this is the reason for these figures because all of those patients were treated immediately after surgery. And even if there is a slight correlation between low or borderline 25-hydroxy vitamin D levels and slightly low calcium levels, in the long run, this doesn’t imply they were being treated with the effective drugs that are very restricted. Dr Jennifer Rosen (Washington, DC): So careful surgical technique still outweighs drug replacement before surgery? Dr Anders Bergenfelz: Well, I guess so. But the problem is that if you ask colleagues, everyone tells you they are very careful. They do high capsular dissection and so on and so forth, and still we have these kind of results.