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ORIGINAL ARTICLE E n d o c r i n e C a r e Secretory Capacity of the Parathyroid Glands after Total Thyroidectomy in Normocalcemic Subjects Olympia E. Anastasiou, Maria P. Yavropoulou, Theodosis S. Papavramidis, Chrysoula Tzouvara, Konstantina Triantafyllopoulou, Spiros Papavramidis, and John G. Yovos. Department of Endocrinology and Metabolism (O.E.A., M.P.Y., C.T., J.G.Y.) and Third Department of Surgery (T.S.P., K.T., S.P.), American Hellenic Educational Progressive Association (AHEPA) University Hospital, Aristotle University of Thessaloniki, Thessaloniki 54636, Greece Context: Hypocalcemia, transient or permanent, represents a common complication after total thyroidectomy, but data on the secretory capacity of the parathyroid glands in thyroidectomized patients without clinical or biochemical hypocalcemia are limited. Study Design: To address this issue, we studied the parathyroid response to acute hypocalcemia induced by iv infusion of sodium bicarbonate in normocalcemic patients submitted to total thyroidectomy at the early postoperative period and 3 months later. Patients and Methods: Sixty patients who underwent total thyroidectomy for benign thyroid disease and did not develop clinical or biochemical hypocalcemia and hypoparathyroidism postoperatively and 50 healthy volunteers were included in the study. Patients (at 48 h and 3 months after surgery) and controls (after overnight fast) were subjected to a sodium bicarbonate infusion test. Results: In healthy volunteers plasma intact PTH increased significantly at 3 min after infusion (4.42 ⫾ 0.15 ng/ml vs. 11.22 ⫾ 0.5 ng/ml, P ⬍ 0.001) and gradually returned to baseline values. In the thyroidectomized patients, mean PTH levels were also increased after sodium bicarbonate infusion but to a significantly lesser degree compared with healthy controls (1.77 mean fold increase vs. 2.57 mean fold increase, respectively, P ⬍ 0.001). Using as criterion the lowest fold increase of plasma PTH levels at 3 min after infusion observed in healthy volunteers, 38% of the thyroidectomized patients at 48 h after surgery and 6.6% of the patients at 3 months after surgery demonstrated a diminished PTH response to acute hypocalcemia induced by sodium bicarbonate infusion. Conclusion: In thyroidectomized patients, normal postoperative calcium and PTH values do not exclude a reduced secretory response of the parathyroids to hypocalcemic stimuli. (J Clin Endocrinol Metab 97: 2341–2346, 2012) T ransient hypocalcemia is one of the most common complications after total thyroidectomy with a reported incidence of 2–32% of cases (1–3). Underlying mechanisms usually involve removal of the parathyroid glands or disruption of the vascular supply of the remaining tissue (4). Permanent hypoparathyroidism, although not as common, has also been reported in approximately 0.2–10% of cases, depending on the experience of the center (1–3, 5). Untreated hypocalcemia can be a serious complication in the postoperative period, and several studies have focused on pre- and immediate postoperative parameters that could predict the incidence of hypoparathyroidism and subsequent hypocalcemia (6 –16). Preoperative fac- ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2012 by The Endocrine Society doi: 10.1210/jc.2012-1170 Received January 22, 2012. Accepted March 26, 2012. First Published Online April 17, 2012 Abbreviation: SBI, Sodium bicarbonate infusion. J Clin Endocrinol Metab, July 2012, 97(7):2341–2346 jcem.endojournals.org 2341 2342 Anastasiou et al. PTH Secretory Capacity after Thyroidectomy J Clin Endocrinol Metab, July 2012, 97(7):2341–2346 Patients and Methods A prospective study was performed of all patients who underwent total thyroidectomy at the Third Department of Surgery of AHEPA (American Hellenic Educational Progressive Association) University Hospital of Thessaloniki within a period of 20 months (March 2008 to October 2009). A complete clinical and biochemical thyroid workup was performed before surgery. Size and morphology of the thyroid gland was evaluated by thyroid ultrasound and a fine-needle aspiration was performed where appropriate to assess the nature of thyroid nodules. Patient characteristics Only patients with benign thyroid disease were included in the study. Exclusion criteria were participation in other clinical trials within 3 months from the initial recruitment period, known parathyroid disease, other diseases or medications known to affect bone metabolism and calcium homeostasis (i.e. bisphosphonates, calcimimetics, glucocorticoids), vitamin D deficiency (assessed as 25-hydroxyvitamin D levels ⱕ 20 ng/ml), and abnormal liver or FIG. 1. Flow chart of the patients recruited for the study. renal function. All patients were euthyroid for at least 2 months before surgery. Patients who developed postoperative hytors include an advanced age, the preexistence of second- pocalcemia (serum calcium ⱕ 8.00 mg/dl) and hypoparathyroidary hyperparathyroidism due to vitamin D deficiency, and ism (PTH ⱕ 0.6 pmol/liter) were excluded from the study and hyperthyroidism (6, 7). Low PTH in the early postoper- were supplemented with calcium and vitamin D. In patients with ative period is considered the most reliable marker, with a borderline calcium (between 8.10 and 8.50 mg/dl) or PTH levels (between 1.0 and 2.0 pmol/liter), we evaluated the response to cutoff point of 85–90%, in identifying those patients at Trousseau and Chovsteck signs for latent hypocalcemia. Rehigh risk of hypocalcemia after thyroidectomy (8 –10). sponse was assessed by two independent endocrinologists and Besides the overt postoperative hypoparathyroidism, patients who did not show any clinical signs of hypocalcemia cases of latent hypoparathyroidism after cervical sur- were subjected to sodium bicarbonate infusion test the second gery or radiotherapy that develop severe hypocalcemia day after surgery and were included in the final analysis. Patients during treatment with agents that alter calcium homeo- with postsurgical histological findings of thyroid carcinoma were also excluded from the study. stasis, such as bisphosphonates, have also been deFifty healthy volunteers matched for age and body mass index scribed (17–19). However, data are scarce regarding the were recruited from the personnel of AHEPA University Hospisecretory capacity of the parathyroid glands in thyroid- tal. Informed consent was obtained from all the participants ectomized patients without postoperative clinical or enrolled and the research protocol was approved by the Ethics Committee of the Aristotle University of Thessaloniki. The study biochemical hypocalcemia. To address this issue we evaluated the secretory re- was registered with www.clinicaltrials.gov with registration number NCT 00793689. sponse of PTH to hypocalcemic stimulus induced by an iv One hundred twenty-seven patients underwent total thyroidinfusion of sodium bicarbonate in normocalcemic patients ectomy over the study period and from those, 70 were considered in the early postoperative period and 3 months after total eligible for the study according to the inclusion criteria used (Fig. thyroidectomy. A sodium bicarbonate infusion (SBI) test 1). Seven patients also excluded from the analysis due to posthas been recently introduced in clinical practice for the operative clinical and/or biochemical hypocalcemia, and three quick evaluation of parathyroid response to acute hy- patients were excluded due to postsurgical histological findings of thyroid carcinoma (two patients with papillary and one papocalcemia (20, 21), as a simple and more safe and effectient with follicular thyroid carcinoma) (Fig. 1). None of the tive test, compared with EDTA and sodium citrate infu- patients developed permanent hypoparathyroidism. From the 60 sion tests that have been previously used to differentiate patients who were included in the final analysis, 44 had euthybetween parathyroid adenomas and hyperplasia (22–24). roid nodular or multinodular goiters, six patients had Grave’s J Clin Endocrinol Metab, July 2012, 97(7):2341–2346 disease, and 10 patients had hyperfunctioning adenoma or toxic multinodular goiters. jcem.endojournals.org 2343 to be significant. The statistical software packages SPSS version 20.0 for OsX (SPSS Inc., Chicago, IL) and GraphPad Prism 4 (GraphPad Software, Inc., La Jolla, CA) were used. Research protocol Blood samples were collected preoperatively and 4 h, 48 h, and 3 months postoperatively. Circulating levels of calcium, albumin, magnesium, phosphate, 25-hydroxyvitamin D, and intact PTH were assessed. A sodium bicarbonate infusion test was performed 48 h after surgery for the evaluation of the secretory capacity of the parathyroids, as has been previously described (20). In brief, after an overnight fast, 35 ml/m2 of body surface of 8.4% sodium bicarbonate solution was infused in about 2 min into the antecubital vein, and blood samples for the measurement of PTH and calcium levels were drawn at 0, 3, 5, 10, 30, and 60 min after the infusion from the antecubital vein of the other arm. The acute infusion of sodium bicarbonate causes a transient increase in blood pH and a subsequent decrease in ionized calcium due to transport of calcium ions from the extracellular to intracellular space. In turn, release of PTH from the parathyroids is potently stimulated. Patients were then followed for the next 3 months and at the end of the third month, a second sodium bicarbonate infusion test was performed. Fifty healthy individuals were also subjected to sodium bicarbonate infusion test after an overnight fast. The reproducibility of the SBI test was evaluated in a separate group of four healthy volunteers (two males and two females aged between 46 and 50 yr), who were subjected to sodium bicarbonate infusion three consecutive times. Each infusion was performed 2 d apart from the previous infusion. The average intraassay coefficient of variation of fold increase in PTH levels at 3 min after SBI was 2.8% (range between 0.4 and 4.7%). The test was well tolerated from all the participants, and no serious complications were recorded except for a transient paresthesia of the digits, metallic taste, and mild discomfort in the infusion arm. Results Demographic characteristics and baseline values of all participants are depicted in Table 1. There were no significant differences in the baseline PTH, total and corrected calcium, and 25-hydroxyvitamin D levels between the control group and the patients submitted to total thyroidectomy (Table 1). Plasma PTH levels were significantly decreased from the baseline values at 4 and 48 h after total thyroidectomy (4.9 ⫾ 0.2 vs. 3.26 ⫾ 0.25 and 3.6 ⫾ 0.3, pmol/liter, respectively P ⬍ 0.001) and were restored at 3 months postoperatively (Fig. 2A). Similarly, serum calcium levels significantly decreased after surgery but remained within normal limits at all time points measured (Fig. 2B). Sodium bicarbonate infusion test In the healthy volunteers, plasma PTH levels were immediately increased at 3 min after the infusion (4.42 ⫾ 0.15 vs. 11.22 ⫾ 0.5 ng/ml, P ⬍ 0.001) and then rapidly returned to baseline values (Fig. 3). At 48 h postoperatively, thyroidectomized patients also increased mean PTH levels at 3 min after sodium bicarbonate infusion but TABLE 1. Demographic characteristics and baseline values of patient and control group Assays Serum levels of total calcium, albumin, phosphate, and magnesium, were routinely measured in the Department of Biochemistry of AHEPA University Hospital. Plasma 25-hydroxyvitamin D levels (nanograms per milliliter) were measured by a RIA (RIA; DiaSorin, Sallugia, Italy), according to the manufacturer’s instructions. The minimum detectable concentration is 1.5 ng/ml, and the within-run and total run assay coefficients of variation are between 8.6 –12.5 and 1–9.4%, respectively. Plasma PTH levels (picomoles per liter) were measured by an electrochemiluminescence immunoassay (ECLIA, Cobas; Roche, West Sussex, UK), according to the manufacturer’s instructions. The minimum detectable concentration is 0.127 pmol/liter, and the within-run and total run assay coefficients of variation are between 0.6 –2.8 and 1.6 –3.4%, respectively. No cross-reactions were detected with osteocalcin, PTH fragment 1–37, PTH-related protein, bone-specific alkaline phosphatase, or -CrossLaps. Statistical analysis All data are presented as mean values ⫾ SEM or mean ⫾ SD, when indicated. A Student’s t test or ANOVA for repeated measures was used as applicable, and Pearson analysis was performed for correlations between measured parameters. Categorical data were analyzed using Pearson 2 test. For all values, P ⬍ 0.01 was considered n Age (yr) BMI (kg/cm2) Men (%) iPTH (pmol/liter) (RR. 1.6 – 6.9) Total calcium (mg/dl) (RR. 8.2–10.6) Corrected calcium Phosphate (mg/dl) (RR. 2.7– 4.5) Magnesium (mg/dl) (RR. 1.58 –2.55) 25-Hydroxyvitamin D (ng/ml) Urea (mg/dl) (RR. 10 –50) Creatinine (mg/dl) (RR. 0.4 –1.10) Control group 50 47.58 ⫾ 14.2 27.1 ⫾ 3.9 10 4.5 ⫾ 1.2 Patients’ groupa P value 60 NA 48.3 ⫾ 11.5 0.763 27.6 ⫾ 5.5 0.124 10 NA 4.9 ⫾ 1.3 0.059 9.8 ⫾ 0.6 9.4 ⫾ 0.5 0.336 9.5 ⫾ 0.34 3.4 ⫾ 0.55 9.3 ⫾ 0.27 3.5 ⫾ 0.8 0.445 0.450 2.1 ⫾ 0.25 2.1 ⫾ 0.36 0.991 36.56 ⫾ 4.4 38.31 ⫾ 6.5 0.170 20.23 ⫾ 1.4 25.6 ⫾ 1.5 0.446 1.1 ⫾ 0.1 0.714 0.9 ⫾ 0.06 BMI, Body mass index; iPTH, intact PTH; NA, Not applicable; RR, reference range. Values are presented as mean ⫾ SD. a Preoperative values. 2344 Anastasiou et al. PTH Secretory Capacity after Thyroidectomy J Clin Endocrinol Metab, July 2012, 97(7):2341–2346 standardized for evaluation of parathyroid gland function in large clinical trials, we arbitrarily used as a cutoff value the lowest fold increase of plasma PTH levels at 3 min after the infusion observed in the healthy volunteers (1.5-fold increase). According to this criterion, 38% of the patients (n ⫽ 24) demonstrated a diminished PTH response at 48 h after surgery, suggestive of a partial subclinical postoperative hypoparathyroidism (Fig. 4). These patients showed a significant decrease in calcium and PTH levels at 4 and 48 h after thyroidectomy (Fig. 2). However, when they were compared with patients who had increased PTH levels at 3 min after sodium bicarbonate infusion more than 1.5-fold (n ⫽ 36), there was no significant difference in the absolute decline of calcium levels at 4 or 48 h postoperatively (0.78 ⫾ 0.1 vs. 0.66 ⫾ 0.1 mg/dl at 4 h and 0.84 ⫾ 0.09 vs. 0.73 ⫾ 0.08 mg/dl at 48 h, respectively, P ⬎ 0.05). FIG. 2. Changes in serum calcium (A) and plasma PTH (B) levels after total thyroidectomy. Values are presented as mean ⫾ SEM. **, P ⬍ 0.001 post-op (postoperatively). PTH response at 3 min after the SBI test was significantly correlated only to a significantly lesser degree compared with controls with PTH levels at 4 h postoperatively (r ⫽ 0.408, P ⫽ (mean fold increase 1.77 ⫾ 0.07 vs. 2.57 ⫾ 0.1, respec- 0.002) (Fig. 5) but not with serum calcium at 4 or 48 h. tively, P ⬍ 0.001). At 3 months after surgery, an SBI test During the follow-up period, none of the patients rewas repeated in the thyroidectomized patients. Mean quired calcium or vitamin D supplementation. At 3 plasma PTH levels were significantly increased at 3 min after the infusion (5.2 ⫾ 0.22 vs. 12.1 ⫾ 0.68 ng/ml, respectively, P ⬍ 0.001, mean fold increase 2.36 ⫾ 0.1). Because the sodium bicarbonate test has not yet been FIG. 3. Plasma PTH levels after sodium bicarbonate infusion. Values are presented as mean ⫾ SEM. FIG. 4. PTH response at 3 min after sodium bicarbonate infusion in patients and controls. Transverse lines indicate mean ⫾ SD. CMR, Control Minimum Response. J Clin Endocrinol Metab, July 2012, 97(7):2341–2346 FIG. 5. Relationship between plasma PTH at 4 h after surgery and PTH response at 3 min after the sodium bicarbonate infusion 48 h after surgery. Patients are classified according to PTH fold increase at 3 min after sodium bicarbonate infusion. months after surgery, the great majority of patients significantly increased PTH levels 3 min after the infusion (⬎1.5-fold increase), but 6.6% (n ⫽ 4) persisted in showing a diminished response (Fig. 4). All patients who showed a diminished response in PTH secretory capacity at 3 months had also shown a reduced response at 48 h after surgery. In addition, we found no association between the underlying thyroid disease and the occurrence of a deficient PTH response to the SBI test. Discussion Decreased secretory capacity of the parathyroid glands after total thyroidectomy is an underrecognized condition due to lack of clinical symptoms. In our study we have shown that within thyroidectomized patients who are normocalcemic and with normal PTH levels postoperatively, PTH response to hypocalcemic stimulus can still be impaired. This diminished response of the parathyroid glands to acute hypocalcemia is mostly evident during the early postoperative period (48 h after thyroidectomy) and attenuates during time, and although in a small percentage of patients, it persists even at 3 month after surgery. A sodium bicarbonate infusion test was introduced by Iwasaki and colleagues (20, 21) as a safer, easier, and reliable test for the evaluation of the secretory capacity of parathyroid glands compared with previous tests with EDTA and sodium citrate infusion (22–24). In the study by Iwasaki et al. (20), the infusion of sodium bicarbonate in eight healthy volunteers demonstrated an average of 4.3- jcem.endojournals.org 2345 fold increase in plasma PTH levels at 3 min after the start of the infusion, whereas patients diagnosed with hypoparathyroidism have shown diminished or no response. In our study the mean PTH increase in healthy subjects was lower (2.5-fold increase). We do not have an explanation for this discrepancy between results, but differences in age of the population or the size of the sample could mostly contribute. Postoperative hypoparathyroidism can be caused by injury, devascularization, stretching, compression, or ischemia and unintentional excision of parathyroid glands. The relatively quick recovery of the parathyroid glands shows that in case of injury or devascularization, they can regain their function and in the case of inadvertent excision of one or more parathyroid glands, the remaining tissue can, over time, compensate the functional postoperative deficit through the development of hyperplasia. Spontaneous delayed recovery of the parathyroid function after 2 yr of total thyroidectomy has also been described (25), and thus, a longer follow-up of these patients is needed. In addition, even in the absence of occult hypocalcemia, cases of latent hypoparathyroidsm have been described in patients with a history of previous surgery in the cervical region (26). The identification of such cases can be useful in preventing incidents of acute hypocalcemia after drug administration, such as bisphosphonates, that interfere with calcium homeostasis and can alter the compensatory mechanisms of the parathyroid glands. This is the first study evaluating the secretory capacity of the parathyroid glands after total thyroidectomy in patients with normal calcium and PTH levels. Despite the limitations that this study has, mainly due to the use of a PTH provocation test that has not yet been standardized in large clinical trials and the relatively short follow-up period of our patients, it has clearly shown that parathyroid response can be impaired after total thyroidectomy, even in normocalcemic subjects. In addition, low, but within normal range, plasma PTH levels at 4 h after surgery appear to be a valuable predicting tool for the functional status of parathyroid glands and should not be neglected. Significant decrease of PTH values at the early postoperative period (3 h after surgery) has been reported, even in patients with normal calcium levels (27). However, in this study (27), researchers did not look for a potential parathyroid dysfunction in hypocalcemic stimuli in these patients. The use of an SBI test in everyday clinical practice is probably limited, but it could be of value in cases with significant decrease of PTH levels in the early postoperative period, even without the development of hypocalcemia. The possibility of an asymptomatic impaired parathyroid function in patients with a previous history of total 2346 Anastasiou et al. PTH Secretory Capacity after Thyroidectomy thyroidectomy should be taken into consideration when prescribing medications that could potentially impair the parathyroid gland compensatory mechanisms and result in an unexplained hypocalcemia. J Clin Endocrinol Metab, July 2012, 97(7):2341–2346 11. 12. Acknowledgments Address all correspondence and requests for reprints to: Maria P. Yavropoulou, M.D., Ph.D., Department of Endocrinology and Metabolism, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 Stilponos Kyriakidi Street, 54636 Thessaloniki, Greece. E-mail: [email protected]. Disclosure Summary: The authors have nothing to disclose. 13. 14. 15. 16. References 1. Agarwal G, Aggarwal V 2008 Is total thyroidectomy the surgical procedure of choice for benign multinodular goiter? An evidencebased review. World J Surg 32:1313–1324 2. Moalem J, Suh I, Duh QY 2008 Treatment and prevention of recurrence of multinodular goiter: an evidence-based review of the literature. 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