Single Institution 6-Year Experience with Intraoperative Parathyroid Hormone Assay in Primary Hyperparathyroidism

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1 /chilat ACTA CHIRURGICA LATVIENSIS 2016 (16/1) ORIGINAL ARTICLE Single Institution 6-Year Experience with Intraoperative Parathyroid Hormone Assay in Primary Hyperparathyroidism Deborah Lina Salewski*, Arturs Ozolins**, Zenons Narbuts** *Riga Stradins University, Riga, Latvia **Pauls Stradins Clinical University Hospital, Department of General Surgery, Latvia SUMMARY Introduction. The operative outcome in patients with primary hyperparathyroidism (PHPT) improved due to progress in surgical techniques and the introduction of the intraoperative PTH assay (IOPTH). However, the optimal timing for taking intraoperative PTH measurements is still controversial, as delayed or adulerated measurements falsify the accuracy of the intraoperative PTH assay. Aim of the study. To evaluate the 6-year experience with IOPTH and to analyse whether elevated really indicate the need for repeated surgery and which factors may influence the IOPTH drop. Material and methods. We conducted a retrospective study of 109 patients, who underwent parathyroidectomy at Pauls Stradins Clinical University Hospital, in Riga, Latvia in the time between 2009 and success was defined as a intraoperative PTH drop of >50% and normal 24 hours after the surgery. Elevated serum were defined as >65pg/ml. Results. The IOPTH assay predicted operative success correctly in 90.2%. However, elevated 24 hours after the operation were found in 9.8% of the patients, even though they had a PTH drop of >50% during the operation. Conclusion. Postoperative elevated are not necessarily an indication for recurrent or persistent hyperparathyroidism. It is important to add the calcium levels into the definition of operative success, as several mechanisms including Vitamin D deficiency and kidney insufficiency may lead to elevated ly. Key words: primary hyperparathyroidism, intraoperative parathyroid hormone assay, hypercalcemia INTRODUCTION PHPT is an endocrine disease of the parathyroid gland characterized by the overproduction of parathyroid hormone (PTH) by one or more of the four existing parathyroid glands. It clinically presents as serum hypercalcemia in the presence of high or inappropriate PTH. The most common cause of sporadic PHPT is a solitary paratyhroid adenoma (2). Parathyroid adenomas occur in approximately 85% of the cases, followed by mutliglandular hyperplasia (15%) and parathyroid carcinoma, which occurs in less than 1% of the cases. (2). PHPT was once thought to be a rare disease, but since the introduction of serum calcium screening tests it is often also diagnosed in asymptomatic patients. Nowadays, PHPT is diagnosed in 1 in every 500 women and in 1 in every 2000 men older than 40 years of age (3). The only cure of PHPT is parathyroidectomy of the hypersecreting gland. It is favoured to preserve the remaining normal functioning glands to obtain a normocalcemic state ly. Surgical methods have changed over the years from bilateral neck exploration with visualization of all four parathyroid glands to the minimally invasive video assisted parathyroidectomy (MIVAP), which reduced the operation time as well as the patients stay in the hospital drastically. To improve the success rate of parathyroidectomies, the IOPTH is used. This tool is used to determine whether the entire hyperfunctioning gland has been removed. The IOPTH is based on a basal PTH sample, which is taken after induction of anesthesia but before incision of the skin. This is then compared to a second PTH sample, which is taken at a specific time after the hyperfunctioning parathyroid gland was excised (4). Several criteria for IOPTH have been developed to set rules which confirm a successful surgery. However, it is controversial which of the criteria predict the best operative success. Most widely accepted and readily used is the Miami criterion (7). It defines operative success as a decrease of the serum PTH level of more than 50% from the highest pre-al value 10 minutes after the hypersecreting gland has been removed (4). Not reaching a PTH drop of 50% suspects persistent hyparathyroidism and is an indication for repeated surgical exploration. AIM OF THE STUDY The aim of this study was to to evaluate the 6-year experience with IOPTH and to analyse whether elevated really indicate the need for expanded or repeated surgery and which factors may influence the IOPTH drop. 16

2 MATERIALS AND METHODS The medical records of 109 patients, who underwent a parathyroidectomy at Pauls Stradins Clinical University Hospital, in Riga, Latvia in the time between the years 2009 and 2014, were reviewed retrospectically. The study took into account the patients gender, age, intraoperative PTH values, serum calcium levels, as well as the type of parathyroid pathology, which was classified as single adenoma, multiple adenoma or parathyroid hyperplasia. Only patients with PHPT and complete IOPTH monitoring information were included in the study. Other exclusion criteria were secondary or tertiary hyperparathyroidism, multiple endocrine neoplasia and parathryoid malignancy. The hyperfunctioning parathyroid gland was localized prior to surgery by using neck ultrasonography and scintigraphy. The operation was performed under general anesthesia. The surgeons either performed a conventional bilateral neck exploration with parathyroidectomy, a focused parathyroidectomy or a MIVAP. The were measured at three different moments during the operation. The first measurement was taken preoperatively before the anesthesia. The second measurement was taken before the pathologic gland was mobilized surgically and the third measurement was taken 20 minutes after the parathyroid gland was excised. Serum were determined by using the Architect 2000 machine. The incision was sutured after the gland was excised and the 20 minute PTH measurement was taken. Serum calcium levels were measured twice, once before the operation and once 24 hours after the parathyroidectomy. The criterion for successful surgery was defined as a >50% drop in PTH from within 20 minutes after gland (10). The basal PTH value was always defined as the highest preal measurement of PTH, which can be either the preoperative or pre- mobilizing level. failure was defined as a PTH drop of <50% from the highest basal PTH value within 20 minutes after gland. A fourth venous blood sample was taken from all patients 24 hours ly to exclude persistent hyperparathyroidism. Persistent hyperparathyroidism was suspected when serum calcium levels and PTH levels remained above normal range just after surgery (2). Normal PTH values are defined as PTH values within the range 10-65pg/ml (9). Normal total serum calcium levels were described as mmol/L (9). All four PTH measurements were used to determine the accuracy of operative outcome prediction by the use of the IOPTH assay (table 1.). Positive predicted value, the ability to predict a curative operation, was defined as true cases divided by the sum of true and false cases. The predicted value, the ability to predict operative failure, was defined as true cases divided by the sum of true and false cases (8). Table 1. Prediction outcomes used for analysis (2) Criteria >50% drop in PTH from <50% drop in PTH from cure* (TP) (FN) failure** (FP) (TN) * cure is defined as the presence of normal or decreased PTH values 24h a.fter surgery. ** failure is defined as elevated PTH values 24h after surgery. Normal PTH values are defined as PTH values within the range 10-65pg/ml. All data was collected utilizing Microsoft Excel. Descriptive statistics were used to summarize the patients data by using the SPSS programm for windows. The Pearson s chi-squared test was used to analyze the presence of statistical significance between the PTH drop and the type of parathyroid pathology and to control whether there was a correleation between the PTH drop and the type of gender. A P-value of <0.05 was considered to be statistically relevant. RESULTS 109 patients were included in the study, who underwent parathyroidectomy due to PHPT. Fifteen patients (13.8%) were male and 94 patients were female (86.2%). The age of the studied patients ranged from years, with a mean age of 59 years at the time of operation. Localization of the abnormal gland shown by neck ultrasound and scintigraphy revealed 94 single adenomas (86.2%), two double adenomas (1.8%) and 13 patients with multiglandular disease (11.9%). All 109 patients had elevated PTH values preoperatively, ranging from pg/ml (mean value pg/ ml). 99 patients (90.8%) had elevated serum calcium levels preoperatively, which ranged from 2.6 mmol/l to 3.8mmol/L (mean value 2.9 mmol/l). From the studied 109 patients, 102 (93.6%) patients fulfilled the criterion of having a PTH drop of more than 50% from the baseline to the 20 minute PTH measurement (mean PTH drop 72%). Only 7 patients (6.4%) did not meet the criterion (table 2.1). 17

3 Table 2.1 Overview of the predicted operative outcome used for analysis Criteria >50% drop in PTH from <50% drop in PTH from cure* 92 (84.4%) 5 (4.6%) failure** 10 (9.2%) 2 (1.8%) From the patients who had a PTH drop of more than 50%, 87 patients had a single adenoma (79.8%), 2 patients had a double adenoma (1.8%) and 13 patients had multiglandular disease (11.9%). All seven patients who did not reach a PTH drop of more than 50% were all operated because of a single parathyroid adenoma. According to preoperative imaging techniques, no double adenoma or multiglandular disease was present. The Pearson s chi-squared test showed both that there is no correlation between the type of the pathology and the patients with a PTH drop of <50% (P value 0.05) as well as between the gender of the patients and the PTH drop of <50%. With a P value of 0.09 this result was almost statistically relevant. Predicting operative success by PTH results From the 102 patients who met the IOPTH criteria, 92 patients also had normal PTH values 24 hours after the operation. This gave a true result of 84.4%. Ten patients from this group developed elevated PTH values again 24 hours after the surgery. This gave a false result of 9.2%. Table 2.2 Comparison of 24 hours calcium levels in patients with true and false IOPTH results IOPTH drop >50% Hypocalcemic Normocalcemic Hypercalcemic Sum of patients Normal Elevated 22 (23.9%) 7 (70.0%) 59 (64.1%) 3 (30.0%) 11 (12.0%) 0 (0%) 92 (84.4% TP*) 10(9.2%FP**) *TP, **FP- Taking the previously mentioned results into account, the predicted value was calculated. Since the predicted value is defined as the prediction of successful surgery, one can say that the IOPTH assay predicted operative cure correctly in 90.2% of the cases. Predicting operative failure by PTH results From the seven patients, who did not meet the IOPTH criteria, two patients still had elevated PTH values 24 hours after the operation. This gives a true result of 1.8%. Five patients from this group developed normal PTH values 24 hours after the surgery. This gives a false result of 4.6%. 2.3 Table Comparison of 24 hours calcium levels in patients with true and false IOPTH results IOPTH drop <50% Normal Elevated Hypocalcemic 2 (40.0%) 0 (0%) Normocalcemic 3 (60.0%) 2 (100.0%) Hypercalcemic 0 (0%) 0 (0%) Sum of patients 5 (4.6% FN*) 2 (1.8%TN **) *FN-, TN**- Taking the previously mentioned results into account, the predicted value was calculated. Since the predicted value is defined as the prediction of operative failure, it can be concluded that the IOPTH assay predicted an operative failure correctly in 28.6% of the cases. DISCUSSION The IOPTH assay predicted the operative sucess in 90.2% of the operations correctly according to our criteria of operative cure and operative failure. This result is compareable with other studies, which also had an operative sucess rate of 90%. Yen et al documented a prediction of an operative cure in even 98.2% of their patients (282 out of 287 patients) by the use of IOPTH criteria (8). Calo et al even achieved a correctly predicted operative cure in 99.8% (10). The difference of the results can be explained by the definition of operative cure and operative failure. Most studies define operative cure as a successful IOPTH drop of >50% or normal and normocalcemic serum levels within 6 months after the surgery (8). Since our study did not include the long-term follow up of the patients, we adapted the definitions according to our available data. 18

4 Some authors suggest that the PTH level depends on the weight of the excised pathologic gland and suggest that patients with severly elevated preoperative PTH values will more likely not achieve an IOPTH drop of >50% during surgery(11). This study analyzed the statistical significance between the PTH drop of less than 50% and gender as well as type of pathology and came to the conclusion that there is no correlation. The reason why traditional bilateral neck exploration was replaced by unilateral minimally invasive methods lies in the improvement in perioperative localization studies of the pathologic gland. Currently, patients are examined by scinticgraphy, neck ultrasound and possibily magnetic resonance before surgery, which allows a detailed depiction of all parathyroid glands (12). That is why during surgery the focus is only on the pathologic gland, which was identified beforehand. Additionally, the IOPTH assay is used as an adjunct to preoperative imaging to confirm that the hyperfunctioning gland was successfully removed (12). Minimally invasive methods bring several advantages including shorter operation time, decreased risk of hypocalcemia and less recurrent nerve injury (10). Furthermore the smaller incisions during surgery do not only heal faster with a smaller risk of wound infection, but also give a cosmetically better appearance ly. However, minimally invasive methods may also falsify the IOPTH results. The surgeons need to perform the of the parathyroid gland through incisions that are not larger than 1-2 centimeters (10). This leads to unintended squeezing of the gland during surgical preparation, which in turn influences the PTH concentration (10). Touching or squeezing the parathyroid gland may unnecessarily result in a massive release of PTH into the circulation. That is why there is an increased risk of inaccurate IOPTH measurements when the gland is touched before clamping its blood supply (10). Calo et al compared the IOPTH decline in 188 patients after 10 and 20 minutes and found out that a PTH drop of >50% within 10 minutes compared to the highest pre-exision value occured in 156/188 patients (83%) (10). In further 12 patients, a PTH drop of >50% was obtained after 20 min (6.4%) (10). This is consistent with the findings in our study, in which 102 patients (93.6%) had a PTH drop of >50% after 20 minutes. However, 24 hours after surgery additional 5 patients achieved normal. On the one hand, this finding confirms the assumption that operative mobilization through small incisions may lead to PTH peaks, which do not decrease exponential and may lead to false results. On the other hand, it shows the importance of the PTH measurement after 20 minutes. In contrast to many other IOPTH criteria, that prefer the post al measurement after five to ten minutes, the doctors at Pauls Stradins Clinical University Hospital decided according to their own experience to take the post al PTH measurement after 20 minutes. The previoulsy mentioned results of the Calo et al study confirm their approach. Furthermore, one may explain the normalization of 24 hours after the operation in some patients, even though these patients did not have a PTH drop of more than 50% during the operation. The group of false results consisted of five patients (4.6%) in our study. Accodring to the squeezing of the gland theory, one may assume that even though they only reached normal PTH values 24 hours after surgery, the parathyroidectomy must have been successful. Another explanation for not reaching the PTH drop of >50% during the operation is the timing of the measurements during the operation. The nurses take the PTH sample on the surgeons command, which can lead to a delay and change in measurements. Some studies also suspect a prolonged half-life of the parathyroid hormone, which may lead to false results (10). Only two patients were considered as true operative failures, which leads to the conclusion that IOPTH predicted operative failure correctly in only 28.6% of the cases. This result is consistent with the Yen et al study, which also had a predicted value of 23.3% by the use of intraoperative PTH assay (8). Besides focusing on the accuracy of the IOPTH assay, this study payed attention to PTH elevation. PTH elevation after successful surgery is a major concern of physicians, since it may indicate persistent hyperparathyroidism. In this study, a PTH drop of more than 50% with elevated PTH values occured in 9.2%. This patient group was classified as false results. The scientific work by Yen et al came to the conclusion that PTH values do not predict operative failure well (8). They evaluated 315 curative parathyroidectomies and reported that the could be elevated in the beginning and remain elevated, normalize or fluctuate overtime, regardless of whether they met their IOPTH criteria or not (8). To predict operative failure as accurate as possible one needs to add the calcium levels into the definition. Out of our ten patients who had a PTH drop of more than 50%, but revealed elevated PTH level, ten patients had hypocalcemic serum levels 24 hours after surgery. Only a smaller part of patients, 3 out of 10, developed normocalcemic levels. None of the mentioned patients with elevated PTH values ly still had hypercalcemic serum levels. Normocalcemic elevated serum after successful surgery According to Goldfarb et al, the incidence of normocalcemic PTH elevation after successful surgery, varies from 8-43% (13). Our study did not include the long term follow up of the patients, but according to the PTH measurements 24 hours after the operation one may assume that the incidence of normoclacemic PTH elevation in our study is 30%. Some authors argue that PTH elevation is a physiologic adaptive response to decreased serum calcium levels (13). The decreased calcium levels may stimulate the parathyroid cells to secrete more PTH to 19

5 increase the calcium absorption in the intestine as well as the renal reabsorption of calcium. Other authors suggest that Vitamin D deficiency may be a potential cause of PTH elevation. Wang TS et al compared the pre- and Vitamin D levels in 768 patients, out of which 114 patients had persistently elevated after successful operation. Their study confirmed their assumption that patients with persistently elevated PTH had lower vitamin D levels than those with normal (14). Furthermore, they found out that the PTH abnormality may be prevented easily by Vitamin D supplementation (14). Carsello and colleagues studies findings are consistent with Wang TS findings and thereby support the idea of aggressive vitamin D supplementation in patients with low Vitamin D levels (15). Unfortunately, our study data did not include Vitamin D data of the studied patients. Carmen C.Solorzano and colleagues reported that their patients with normocalcemic PTH elevation also had significantly higher creatinine levels if compared with those who had normal (16). We did not measure the creatinine levels in our study, but this finding may support the theory of some authors that renal insufficiency may be one of the causes of elevated. The pathophysiological explanation of this phenomenon is based on the fact that patients with impaired renal function are known to have imparied peripheral sensitivity to the calcemic action of PTH and resistance to serum PTH stimulation (13). Other possible explanations for elevated include higher preoperative calcium levels, advanced age, osteoporosis and ethnicity. All patients with elevated in Solorzanos study were of older age, with a mean age of 62, which is comparable to the mean age of our patient group that had elevated postoperativly (mean age 63.8 years) (16). Dhillon et al followed up 21 patients with high. Their result was that none of the patients with elevated developed hypercalcemia during an average follow up period of 9 months, indicating that high do not immediatly indicate operative failure (15). They came to the conclusion that elevated serum in patients with normal serum calcium levels may be transient and resolve within 3 months (15). Hypocalcemic elevated serum after successful surgery Seven out of ten patients had hypocalcemic serum levels in the presence of elevated 24 hours after surgery. Usually it takes about 24 to 48 hours to regain normal calcium levels after parathyroidectomy (17). But according to Kwang-Min et al hypocalcemia develops in around 10 to 30% of the cases (17). This is known do be due to the time required for normal parathyroid glands to recover their sensitivity to calcium after surgery, which takes several days (17). Alabdulkarim and colleagues analyzed the behaviour of calcium after paratyhroidectomy in patients with PHPT and found out that it took the majority of patients (72.9%) an average of 12 to 48 hours to achieve calcium levels within normal reference ranges (18). Since we only measured calcium levels once 24 hours after surgery, one may assume that there will be a decline in calcium during the next couple of days. PHPT is known to affect the mineral density of bones. Several studies have revealed that bone loss is most severe at cortical sites (1). The hungry bone syndrome is a complication after parathyroidectomy, which occurs when there is no further increased production of PTH and serum calcium and phosphates quickly migrate to the bone for remineralization (17). This means that there is an increase in bone mineral density after the hyperfunctioning parathyroid gland is removed, which in turn leads to hypocalcemia. The missing PTH stimulus also affects the renal tubuli that stops reabsorbing calcium, which also facilitates hypocalcemia (4). Symptoms of the hungry bone syndrome include muscle spasms and tetani (17). Treatment focuses on replenishing the serum calcium level usually by adequate mineral supplementation. According to Marx et al hungry bones should be anticipated preoperatively by very high PTH, sometimes low 25OHD, decreased bone mass, bone cysts (osteitis fibrosa cystica), and high alkaline phosphatase (20). In a study about predicitve factors for early hypocalcemia, Steen and colleagues found out that a drop of >80% in IOPTH 10 minutes after of the pathologic gland was a conscientious predictor of hypocalcemia (21). Furthermore, they stated that having normal or minimally elevated preoperative serum calcium levels is also significant in the prediction of decreased calclium levels. However, in this study none of the patients who had hypocalcemic serum levels at 24 hours after the surgery had an IOPTH drop of >80% (mean PTH drop 64.8%). The preoperative calcium levels of the hypocalcemic patients ranged from pg/ml, showing that most of them had only slightly elevated calcium levels. The findings in our study thus cannot really confirm Stehen and colleagues theory of hypocalcemia predictors. CONCLUSION Pauls Stradins University Clinical Hospital had similar good experiences with the IOPTH assay as reported in other studies. Although modified IOPTH measurement times were used, the success rate remained approximately the same, identifying that no specific criterion for operative success is needed. Furthermore elevated in the presence of normal serum calcium levels did not necessarily indicate recurrent or persistent hyperparathyroidism. A longer follow up period would be needed to find out how many patients with elevated finally achieved normal PTH values. 20

6 However it is important to take the patients comorbidities into account when using the IOPTH assay. In some cases elevated can be easily prevented by preoperative Vitamin D supplementation. Conflict of interest: None REFERENCES 1. Khan, A. and J. Bilezikian, Primary hyperparathyroidism: pathophysiology and impact on bone. CMAJ, (2): p M. C. Neves, M.N.O., 2 M. Rosano,1 M. Abrahão,1 O. Cervantes,1 M. Lazaretti-Castro,2 J. G. H. Vieira,2 I. S. Kunii,2 and R. O. Santos1. A 10-Year Experience in Intraoperative Parathyroid Hormone Measurements for Primary Hyperparathyroidism: A Prospective Study of 91 Previous Unexplored Patients ); Available from: A K Chan, Q.Y.D., M H Katz, A E Siperstein, and O H Clark. Clinical manifestations of primary hyperparathyroidism before and after parathyroidectomy. A case-control study ); Available from: nih.gov/pmc/articles/pmc / 4. Pasquale2, G.G.a.L.D. Hungry Bone Syndrome after Parathyroidectomy for Primary Hyperthyroidism ); Available from: omicsonline.org/open-access/hungry-bonesyndrome-after-parathyroidectomy-for-primaryhyperthyroidism php?aid= A. N. Morks, M.D., T. M. VAN Ginhoven, M.D., PH.D., J. M. Pekelharing, M.D., PH.D., E. J. J. Duschek, M.D., PH.D., P. C. Smit, M.D., PH.D. P. W. DE Graaf, M.D., PH.D.. Intra-operative parathyroid hormone measurements experience of a nonacademic hospital. August ); Available from: sajs/article/viewfile/70494/ Vignali E1, P.A., Materazzi G, Steffe S, Berti P, Cianferotti L, Cetani F, Ambrogini E, Miccoli P, Pinchera A, Marcocci C. A quick intraoperative parathyroid hormone assay in the surgical management of patients with primary hyperparathyroidism: a study of 206 consecutive cases. June ); Available from: Marlon A Guerrero, O.H.C. A Comprehensive Review of Intraoperative Parathyroid Hormone Monitoring ); Available from: aspx?id=509&type=free&typ=top&in=~/ ejournals/images/jplogo.gif&iid=49&ispdf=no 8. Tina W. F. Yen, M., Stuart D. Wilson, MD, Elizabeth A. Krzywda, ANP, MSN, and Sonia L. Sugg, MD and W. Milwaukee. The role of parathyroid hormone measurements after surgery for primary hyperparathyroidism. Oktober ); Available from: com/upload/docs/services/cancer/publications/ yen-parathyroid-hormone-measurements-afterhyperparathyroidism.pdf 9. Mitarbeiter, G.H.u., Innere Medizin Vol : Herold 10. Pietro Giorgio Calò, c.a.g.p., 1 Giulia Loi,1 Fabio Medas,1 Lucia Barca,2 Matteo Atzeni,1 and Angelo Nicolosi1. Intraoperative parathyroid hormone assay during focused parathyroidectomy: the importance of 20 minutes measurement ); Available from: nih.gov/pmc/articles/pmc / 11. Mittendorf EA1, M.C. Persistent parathyroid hormone elevation following curative parathyroidectomy for primary hyperparathyroidism. March ); Available from: nih.gov/pubmed/ Faisal Zawawi, c.a., 4 Alex M Mlynarek,1 Arielle Cantor,2 Rickul Varshney,1 Martin J Black,1 Michael P Hier,1 Louise Rochon,3 and Richard J Payne1. Intraoperative parathyroid hormone level in parathryoidectomy: which patients benefit from it? ); Available from: PMC /#!po= Goldfarb M1, G.S., Irvin GL 3rd, Lew JI. Normocalcemic parathormone elevation after successful parathyroidectomy: long-term analysis of parathormone variations over 10 years ); Available from: nih.gov/pubmed/ Wang TS, O.S., Heller KS., Persistently elevated parathyroid hormone levels after parathyroid surgery. Surgery (6): p Kimvir S. Dhillona, P.C., Christine Darwina, Andre Van Herlea, Inder J. Chopraa,. Elevated serum parathyroid hormone concentration in eucalcemic patients after parathyroidectomy for primary hyperparathyroidism and its relationship to vitamin D profile ); Available from: pii/s Carmen C. Solorzano, M.W.M., MD; John I. Lew, MD; Steven E. Rodgers, MD, PhD; Raquel Montano, BS; Denise M. Carneiro-Pla, MD; George L. Irvin III, MD. Long-term Outcome of Patients With Elevated Parathyroid Hormone Levels After Successful Parathyroidectomy for Sporadic Primary Hyperparathyroidism ); Available from: aspx?articleid=

7 17. Kwang-Min Kim, J.-B.P., Keum-Seok Bae, and Seong-Joon Kangcorresponding author. Hungry bone syndrome after parathyroidectomy of a minimally invasive parathyroid carcinoma ); Available from: nih.gov/pmc/articles/pmc /#!po= Nassif, Y.A.a.E. Delayed Serum Calcium Biochemical Response to Successful Parathyroidectomy in Primary Hyperparathyroidism ); Available from: articles/pmc /# ffn_sectitle 19. J.E. Witteveen1, S.v.T., 2, J.A. Romijn1,3, N.A.T. Hamdy1. Hungry bone syndrome: still a challenge in the post-operative management of primary hyperparathyroidism ); Available from: early/2012/11/14/eje full.pdf 20. Stephen J. Marx MD, L.S.W.M., PhD, William F. Simonds MD, Michael T. Collins MD. Management of hypocalcemia after parathyroidectomy ); Available from: nih.gov/.../hypopara.doc 21. Shawn Steen, M., corresponding author Brandon Rabeler, MD, Tammy Fisher, RN, and David Arnold, MD. Predictive factors for early hypocalcemia after surgery for primary hyperparathyroidism ); Available from: PMC /#!po= Address: Deborah Lina Salewski Riga Stradins University Dzirciema iela 16, Riga LV deborah.salewski@gmail.com 22