PhD THESIS SUMMARY ASPECTS OF THE REGULATORY FACTORS OF CALCIUM AND PHOSPHATE METABOLISM IN SURGICAL AND EMERGENCY PATHOLOGY

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1 PhD THESIS SUMMARY ASPECTS OF THE REGULATORY FACTORS OF CALCIUM AND PHOSPHATE METABOLISM IN SURGICAL AND EMERGENCY PATHOLOGY THESIS PROMOTOR PROF. DR. Dumitru D. BRĂNIȘTEANU PhD STUDENT Cristian VELICESCU Investeşte în oameni! Proiect confinanțat din Fondul Social European prin Programul Operaţional Sectorial Dezvoltarea Resurselor Umane Axa prioritară 1 Educaţia şi formarea în sprijinul creşterii economice şi dezvoltării societăţii bazate pe cunoaştere Domeniul major de intervenţie 1.5 Programe doctorale și post-doctorale în sprijinul cercetării Titlul proiectului: Parteneriat strategic pentru creșterea calității cercetării științifice din universitățile medicale prin acordarea de burse doctorale și postdoctorale - DocMed.net_2.0 Contract nr. POSDRU/159/1.5/S/ Beneficiar: Universitatea de Medicină și Farmacie Iuliu Hațieganu Cluj-Napoca 2017

2 CONTENTS Abbreviation iv Part I. The stage of knowledge CHAPTER I Phosphocalcic metabolism Regulation of phosphocalcic metabolism Parathormon Vitamin D Regulation of calcium homeostasis - collaboration between PTH and vitamin D Other regulation hormones of phosphocalcic and bone metabolism Hipovitamin D - implications of phosphocalcic and bone metabolism Primary hyperparathyroidism Etiology Clinical signs, spectrum of complications of primary hyperparathyroidism Incidence and spectrum of clinical forms of phpth phpth and hipovitamin D Paraclinic diagnosis of phpth Recurrent renal lithiasis and phosphocalcic metabolism 24 CHAPTER II Anatomy of the parathyroid gland Parathyroid surgery in primary parathyroidism The importance of rapid dosing of intraoperative PTH in parathyroid surgery 34 Part II. Personal side CHAPTER III 37 Purpose and motivation of the personal study 3.1. Pre-, intra- and postoperative information in primary hyperparathyroidism qpth in patients operated for primary i

3 hyperparathyroidism Evaluation the volume of the parathyroid adenoma Pre- and postoperative evaluation of FGF Hormonal, matabolic and bone profile at patients with recurrent renal lithiasis 43 CHAPTER IV 45 Study material and investigative methods 4.1. Evaluation of metabolic and hormonal parameters Evaluation of mineral bone density Localization of the preoperative imaging of the parathyroid adenoma Intraoperative measurement of the parathyroid adenoma Protocol of clinical trials The clinical trial regarding rapid intraoperative PTH measurement Multicenter study - volume of parathyroid adenoma Prospective study - evaluating FGF 23 in patients with primary hyperparathyroidism Transversal study - recurrent renal lithiasis The history of clinical and paraclinical diagnosis in our clinic The history of surgical treatment in our clinic 55 CHAPTER V Phosphocalcic metabolism in parathyroid surgery Results 5.1. Rapid intraoperativ measurement of PTH The volume of the parathyroid adenoma FGF 23 in patients with primary hyperparathyroidism Recurrent renal lithiasis Aspects and benefits of doctoral research for surgery Intraoperative aspects of parathyroid adenomas 80 CHAPTER VI 83 Discussions 6.1. Intraoperative evaluations of patients with primary hyperparathyroidism operated by minimally invasive surgery 83 ii

4 Primary hyperparathyroidism Rapid intraoperativ measurement of PTH The volume of the parathyroid adenoma Pre- and postoperative evaluation of FGF 23 in patients diagnosed with primary hyperparathyroidism The calcitropic profile of recurrent renal lithiasis patients News brought by doctoral research 101 CHAPTER VII 105 Conclusions CHAPTER VIII 107 Originality elements CHAPTER IX 109 Perspectives of the doctoral thesis BIBLIOGRAPHY 111 ANEXA 1 - List of scientific papers ANEXA 2 - Informed consent of the patient iii

5 ABBREVIATIONS PTH Parathormon FGF23 Fibroblast growth factor PLC Fosfolipaza C RANK Receptor Activator of Nuclear Factor Kb OPG Osteoprotegerina TNF-a Tumoral necrosis factor-a P Phosphor Ca Calcium CaSR Ca sensing receptors VDR Vitamina D receptor DBP Vitamin D binding protein RXR Acid retinoic ADHR Autosomal dominant hypophosphatemic rickets TIO Tumor Induced Osteomalacia IL Interleukina phpth Primary hyperparathyroidism shpth Secondary hyperparathyroidism CT Computertomography RMN Magnetic resonance DXA Dual absorbance IH Idiopathic hypercalcuria qpth Intraoperator parathormon MIP Minimally invasive parathyroidectomy thpth Tertiary hyperparathyroidism NR Recurrent nephrolithiasis OC Osteocalcina BMD Bone mineral density AP Phosphatase alcaline ONS Open neck surgery iv

6 Introduction Aims and motivation of our study The diagnosis and therapy of primary hyperparathyroidism evoluated lately due to the improvement of presurgical diagnosis allowing minimal surgical intervention (1). Parathyroid adenoma remains the main cause of primary hyperparathyroidism (phpth) but multiple glandular disease remains an important diagnosis challenge and should be accurately surgically approached. Presurgical imagistic investigation is very important for localizing the parathyroid lesion(s) and guiding the surgical team for choosing between minimally invasive parathyroidectomy and open neck surgery (2). Presurgical localization of diseased parathyroid tissue has, nevertheless, a sensibility deficiency even when several localization techniques are used. It is, therefore, possible to misdiagnose the presence of supplementary parathyroid adenomas (3). The excision of a parathyroid adenoma can be confirmed intrasurgically by extemporeal histological investigation, but this confirmation is not sufficient especially when minimally invasive parathyroidectomy is performed in the context of multiple glandular disease where hyperfunctional parathyroid tissue not presurgically identified coexists (4). Once found and excised, the parathyroid adenoma can be also easily weighed and measured, its volume being approximated by using the formula of a rotating ellipsoid (5). A parathyroid adenoma of large dimensions may imagistically and possibly also functionally mask the presence of a second, initially undiagnosed smaller adenoma that may cause subsequent relapse of phpth (6). We found ourselves quite frequently patients operated for phpth by minimally invasive parathyroidectomy who suffered a relapse at a short time interval after surgical intervention. This observation motivated us to proceed to the design of the main part of our clinical studies the importance of some elements of 1

7 intrasurgical diagnosis (quick evaluation of intraoperatory PTH, qpth, and intraoperatory evaluation of the volume of parathyroid adenomas) for confirming the sugical success and eventually for bringing up new guidance elements for further therapeutic strategy. Inraoperatory quick evaluation of PTH (qpth) was first used in the University Emergency Hospital St. Spiridon when just before our doctoral project started (October 2013). Our application for the project POSDRU/159/1.5/ via the University of Medicine and Pharmacy "Gr.T.Popa" Iași allowed the acquisition of needed technology and kits for intrasurgical evaluation of parathyroid hormone (qpth). Our decision for open neck surgery instead of minimally invasive parathyroidectomy could be taken function of presurgical biochemical markers, imagistic investigations, but also the dimensions of parathyroid adenoma. It is known that parathyroid adenomas generating phpth greatly vary with respect to their dimensions (5). The volume of parathyroid adenoma can be evaluated by measuring three of its diameters with the help of a micrometer, by using the formula of a rotating ellipsoid (5). We wanted to find out whether a parathyroid adenoma of larger dimensions could be accompanied by a more abundant PTH secretion and/or a more severe metabolic impact, with more important complications. This particular aspect is not clearly proven, but if true, intrasurgical measurement of parathyroid adenoma may reach prognostic importance, influencing further therapeutic strategy. The intraoperatory evaluation of the volume of parathyroid adenoma was further used for correlations with calcemic parameters, with special attention on the impact of D hypovitaminosis upon the parathyroid adenoma. The immediate further aims of this study should be to evaluate the degrees of severity of parathyroid disease expressed as the spectrum of complications of phpth, which may me modulated by all these parameters, including the volume of the parathyroid adenoma. We 2

8 finally took into consideration the way through which the volume of parathyroid adenoma may help us in choosing the type of surgical intervention minimally invasive parathyroidectomy or its conversion to open neck surgery, for preventing postsurgical persistance of the disease due to incomplete resection of diseased parathyroid tissue. Materials and methods 1. Clinical study regarding the quick intrasurgical measurement of PTH We wanted to monitor the outcome of minimally invasive parathyroidectomy after presurgical localization of parathyroid adenomas and the advantages of quick intrasurgical measurement of PTH. We organized therefore a retrospective clinical study starting from a prospective database belonging to the university surgical department. The study included a total number of 53 patients diagnosed during three years with phpth caused by a presurgically localized presumtive solitary parathyroid adenoma. All patients were submitted to MIP, with intrasurigal histolgical confirmation after evaluation of criogenized histological sections of the anatomopathological excized anatomopathological adenoma. A number of 40 patients, 32 women and 8 men, with ages between years at the moment of surgical intervention, formed the control group (C). These patients were operated by minimally invasive parathyroidectomy without measurement of qpth. A second group, qpth, formed of 13 patients between 18 and 64 years of age, 10 women and 3 men, were operated with intrasurgical measurement of qpth and calcium in blood extracted from the internal jugular vein form the same side as the excised parathyroid adenoma, ten minutes after its excision. qpth values were interpreted function of the adapted Miami criteria of cure. Patients were considered, therefore, of being cured when qpth levels decreased with more than 50 % when compared to presurgical PTH values or re-entered into the normal range. When 3

9 the above mentioned criterion was not reached, wwe proceeded to the convertion of minimally invasive parathyroidectomy to open neck surgery and bilateral exploration of all parathyroid glands. 2. Multicentric study the volume of parathyroid adenoma We wanted to evaluate the correlations between the intraoperatory assessed volume of the parathyroid adenoma and the presurgical metabolic and hormonal profile of patients diagnosed with phpth, as well as the correlation between of the volume of the parathyroid adenoma and the risk of postsurgical relapse. We performed a transversal multicentric study followed by a prospective follow-up. The study included patients diagnosed with phpth in the surgical departments of two university centers (Iași, the IIIrd and IVth Clinics of Surgery, university Hospitl St Spiridon, and Cluj, Ivth Clinic of Surgery, University Hospital CF Cluj) for a period of 16 months (between January 2014 April 2015). We included a total number of 52 patients, 43 women and 9 men, with ages between 16 and 77 years. Thirty-three of these patients (28 women and 5 men) were recruited from the University center of Iași, whereas 19 patients (15 women and 4 men) were recruited from the University center of Cluj. We evaluated presurgical serum levels of PTH, calcium and phosphate at all patients, as well as the 25OHD 3 levels only at patients from Iași. All patients were submitted to minimally invasive parathyroidectomy, with intrasurgical histological confirmation after performing criogenized sections of the anatomopathological isolated tissue. The volume of parathyroid adenoma was intrasurgically evaluated immediately after excision, by measuring three diameters of the excised adenoma and then approximating the volume by using the mathematical formula of a rotataing ellipsoid object, V = L x l x i xπ/6. 3. Prospective study evaluation of FGF23 at patients with primary hyperparathyroidism We wanted to evaluate the presurgical level of FGF23 at patients with phpth, and to correlate the data obtained with various hormonal and metabolic parameters (PTH, 25OHD 3, Ca, 4

10 P) as well as with the volume of the excised parathyroid adenoma. The study included an initial number of 42 patients diagnosed with phpth in the Clinic of Endocrinology of Iași. After enrolling the patients who signed an informed consent, we collected a blood sample for the evaluation of FGF23, PTH, 25OHD 3, calcium and phosphate. Patients were subsequently submitted to surgery (minimally invasive parathyroidectomy) and the previously mentioned parameters were reevaluated in 38 patients at the first day after surgery. Thirteen patients continued to be followed for one year, coming for control at three months, six months and one year from surgical intervention. 4. Cross sectional study relapsing kidney lithiasis We wanted to evaluate the particularities of the metabolic and calcitropic hormonal profile, as well of bone metabolism at young male patients with idiopathic hypercalciuria and relapsing nephrolithiasis. We performed a cross-sectional study including 30 young volunteers with ages between 24 and 50 years, having in their history at least three episodes of nephritic colic (the RN group). We compared the patients from this group with an age- and body weight- matched control group of healthy volunteers (CTR). Results 1. Quick intraoperatory measurement of PTH Presurgical 99mTc-Sestamibi scintigraphy and cervical ultrasound localized a solitary parathyroid adenoma in all 53 cases submitted to surgery. The parathyroid adenoma was histologically confirmed in all patients included in the study group. Six of the forty patients from the control group (C) where minimally invasive parathyroidectomy without intrasurgical evaluation of qpth, had high PTH (above 55pg/ml, figure 5.1a) and serum calcium levels (above 10,5mg/dl, figure 5.1b). The two parameters had persistently elevated values at one month, three months and six months after surgery at six of the 40 patients, suggesting the persistence of phpth despite histological description of an excised parathyroid adenoma. (figure 5.1). 5

11 Figure 5.1.a. The evolution of serum PTH at 40 patients operated by minimally invasive parathyroidectomy with presurgical localization of the parathyroid adenoma the first day after surgery and at 1, 3 and 6 months after surgery. All six patients were recalled for supplementary investigations and a second surgical intervention due to the coexistence of other parathyroid adenomas. Serum calcium, but not PTH was still increased after surgery at other three patients, but came back to normal values after one month. We also noticed mild postsurgical hypocalcemia at other six patients, but calcium again normalized during follow-up (figure 5.1). Figura 5.1.b The evolution of serum calcium at 40 patients operated by minimally invasive parathyroidectomy with presurgical localization of the parathyroid adenoma the first day after surgery and at 1, 3 and 6 months after surgery. In the case of the 13 patients operated by minimally invasive parathyroidectomy where intrasurgical qpth and calcium were evaluated from blood extracted from the ipsilateral internal jugular vein, we observed a quick (ten minutes after excision) and significant decrease of PTH levels (at values lower than 50 % compared to the presurgical levels, suggesting cure by using the adapted Miami criteria) at only eleven patients. Nine of the patients showed even a decrease of qpth within the normal range. The fast intrasurgical decrease of qpth was followed by a decrease of circulating calcium levels. qpth did not, however, decrease significantly at two patients from the study group. These 6

12 two patients also had high intraoperatory calcium levels and were therefore rapidly considered uncured, even during the surgical intervention, while still being under general anesthesia. The rate of surgical failures was therefore comparable between the two groups - C and qpth. The quick diagnosis of failure allowed switching to open neck surgery and cure the two patients during the same surgical session. The parathyroid adenoma was presurgically located at the inferior pole of the right thyroid lobe in one of the two cases, and in the inferior pole of the left thyroid lobe in the other case. Enlarging the intervention to open neck surgery and exploring all remnnt parathyroid glands allowed the discovery of a second parathyroid adenoma not detected prior to surgery, at the inferior pole of the controlateral lobe in the first case and at the superior pole of the ipsilateral thyroid lobe in the second case. 2. The volume of parathyroid adenomas Figure 5.5. (a) The correlations between serum calcium (left) or PTH (right) and the volume of the excised parathyroid adenoma in the University center of Iași * p < 0.05, ** p < Figura 5.5. (b) The correlations between serum calcium (left) or PTH (right) and the volume of the excised parathyroid adenoma in the University center of Cluj * p < 0.05, ** p < We noticed a significant correlation between the volume of parthyroid adenoma and presurgical circulating PTH levels both in the groups of Iași and Cluj, either separately, or in the pooled patients from both university centers (figures 5.5 a,b,c, right). The 7

13 correlation was more important in the group from Cluj (p < 0,001) compared to the group from Iași (p < 0,05). We did not find a significant correlation between the volume of the excised parathyroid adenoma and the serum calcium levels (figures 5.5 a,b,c, left). Figure 5.5. (c) The correlations between serum calcium (left) or PTH (right) and the volume of the excised parathyroid adenoma at pooled patients from both university centers * p < 0.05, ** p < We did not observe a significant correlation between PTH and presurgical serum calcium levels at patients from Iași, Cluj or in the pooled patient group from both centers. Presurgical level of 25OHD 3 ws evaluated only at patients from Iași. These patients frequently had a low or even very low level of 25OHD 3, in the range of insufficiency, deficiency and even severe vitamin D deficiency. Vitamin D level was negatively correlated with the volume of parathyroid adenomas excised from the patients of Iași. Dynamic follow-up of 13 patients We further followed in dynamics at 13 patients the levels of FGF23, calcium, phosphate, 25OHD 3 and PTH. Blood sampling was initiated in the first day after surgery, together with all the other patients, and continued at different time points at 3 months, 6 months and one year after surgery. It is important to mention that all patients with D hypovitaminosis were substituted with vitamin D supplements in variable dosages, function of the severity of hypovitaminosis, already starting from the moment of presurgical diagnosis of vitamin D deficiency. Twelve out the 13 patients experienced an increase of PTH levels three months after surgery and persisted to be slightly increased at 6 months and one year, but with a trend towards normalization. Serum calcium level decreased immediately after surgery and was maintained within the normal 8

14 range until the end of te follow-up period at the 13 patients, despite of a slightly increased PTH level. Serum phosphate did not increase significantly in the postoperatory period, but started to increase at 3 months, reaching levels in the normal range that were preserved for the whole follow-up period. 25OHD 3 levels were already higher after surgery due to vitamin D repletaion already initiated before surgery due to D hypovitaminosis. 25OHD 3 further increased at 3 and 6 months, reaching normal range at one year at the majority of our patients. FGF23 levels remained unmodified for the whole follow-up period (figure 5.17). Our results of the one year follow up of thirteen patients can be summarized as follows: we observed a significant negative correlation between PTH and FGF23, as well as 25OHD 3. We observed rapid postsurgical decrease of serum PTH and calcium without being accompanied by significant postsurgical modifications of phosphate and FGF23 levels. Finally, we observed an increase in PTH levels three months after surgery, without modifications in serum calcium that remained within the normal range. Phosphate levels increased significantly only after 3 months, reaching normal levels. We did not notice any modifications of FGF23 levels, whereas 25OHD 3 increased significantly at 3 months, due to the repletion initiated in the moment of D hypovitaminosis. Figure The evolution in dynamics of FGF23 level after surgery, at 3 6 months and one year after parathyroidectomy at 13 patients. 9

15 Discussions 1. Rapid intrasurgical measurement of qpth The forty patients reunited in the control group (C) were diagnosed before surgery with phpth caused by a solitary parathyroid adenoma. The localization of the parathyroid adenoma was performed by imaging with 99m Tc-sestaMIBI scintigraphy together with ultrasound investigation of the inferior cervical region. Six of these 40 pacienți (15 %) had persistently increased postoperatory PTH and calcium levels, being considered not cured after MIP. The incidence of multiglandular disease misdiagnosed before surgery was higher than that described in the literature (7), reaching 15 %. This difference may be caused by certain particularities of our patients, including a decreased level of 25OHD 3, that was also described in the general Romanian poulation (7). Intraoperatory evaluation of qpth raises two performance problems: evaluation speed and information accuracy. In other words, the correct definition of cure or therapeutic failure should come as fast as possible, determining a quick therapeutic decision - either a finalization of minimally invasive parathyroidectomy in case of cure, or the conversion of minimally invasive parathyroidectomy toward open neck surgery, with exploration of the cervical region and identification of other diseased parathyroid glands with their excision when persistent high levels of qpth are found. Our protocol including qpth measurement allowed the fast diagnosis of cure at eleven of the 13 patients, whereas the persistently increased qpth lead to the conversion of minimally invasive parathyroidectomy to open neck surgery, which allowed the identification and excision of supplementary parathyroid adenomas, thereby allowing the cure of the two patients in the same operating moment and increasing the cure rate to 100 % of cases (8). We observed, nevertheless, a clear decrease of qpth levels to less than 50 % of presurgical values at the 11 patients subsequently proven to be cured and a complete long term normalization of PTH at nine patients. The short time lapse until we obtained qpth also allowed the conversion of 10

16 minimally invasive parathyroidectomy to open neck surgery at the two patients with persistently increased qpth. Both patients had a second parathyroid adenoma that could be excised in the same surgical session, thereby increasing success rate to 100 %. We can conclude that both diagnosis sensitivity and specificity for therapeutic cure in the relatively small group in which we completed diagnostic investigations by adding the evaluation of qpth, reached 100 %. Patients with phpth need a complex approach, including presurgical localization of the parathyroid lesion and minimally invasive parathyroidectomy with patient cure in an important number of cases. Using intrasurgical qpth measurement we could maximize therapeutic success in the same surgical session to 100 % of the operated cases, thereby recommending routine utilization of qpth in a complex protocol. (figure 5.30) Figura Proposal for protocol for pre- and intra-operative investigation of patients with primary hyperparathyroidism. We conclude that quick evaluation of PTH during surgery from an unique blood sample taken from the internal jugular vein should be carefully taken into consideration, because it is technically easy to be performed and seems to give a precise and fast confirmation of cure or surgical failure. The rapidity of this technique allows the modification of therapeutic strategy during the same surgical session, thereby optimizing patient cure in selected cases. 2. The volume of parathyroid adenomas It is known that in certain cases the secretory product may sometimes by strictly proportional with the volume of the secreting tumor (such as, for instance, in the case of prolactinomas) (9) 11

17 whereas in the case of other tumors (GH secreting adenomas, pheochromocytomas, carcinoid tumors) this correlation is less evident or even absent (9). The aim of our multicentric cross sectional study was to evaluate the relationship between the volume of the parathyroid adenoma evaluated during surgery and various presurgical hormonal (PTH, 25OHD 3 and FGF23) and humoral (calcium and phosphate) parameters. Similar to other authors (10), our study confirmed the presence of a significant correlation between the volume of excised parathyroid adenoma and presurgical PTH both in the patient group from Iași and Cluj, as well as in the pooled group of patients. Surprisingly, although previous studies finding a correlation between the dimensions of parathyroid adenomas and PTH levels also found a comparable correlation of the volume of parathyroid adenomas with the presurgical level of calcium, we did not find a significant correlation between presurgical calcium levels and the volume of parathyroid adenoma. This lack of correlation could be explained by an increased incidence of D hypovitaminosis in our patients. D hypovitaminosis was confirmed at the majority of patients from Iași, where presurgical 25OHD 3 was evaluated. From the total of 33 patients included in the study, only four had a 25OHD 3 level within the limit of sufficiency. The better correlation between PTH levels and adenoma volume found in the group of patients from Cluj does not have an immediate explanation. The difference in the amplitude of correlation may reside from differences in vitamin D levels, fact impossible to be verified since 25OHD 3 was not evaluated in the group of Cluj. Possibly locally activated vitamin D (inside the parathyroid cell) may directly inhibit the expression of the PTH gene. Vitamin D deficiency may hamper the parathyroid gland of this negative feedback and may favor the development of larger parathyroid adenomas in phpth (11). The relationship between the volume of the parathyroid adenoma and the severity of disease complications remains largely unknown and may represent the subject of future investigations. Our cross sectional multicentric study proved the 12

18 existence of a direct correlation of the volume of the parathyroid adenoma with presurgical level of PTH both in the group of patients from Iași and Cluj as well as in the pooled patients from both university centers, but no correlation with presurgical levels of serum calcium. We could also conclude that D hypovitaminosis may attenuate the correlation between PTH and serum calcium to non-significant levels. D hypovitaminosis may in the same time have an important interference in the relationship between presurgical calcium and the dimensions of the parathyroid adenoma, which was absent in our patients, by contrast with the data obtained by other authors. The discovery of a contradiction between a hormonal profile including high PTH and D hypovitaminosis and a low volume of the parathyroid adenoma may provide, together with the lack of intrasurgical normalization of qpth a supplementary indication for the conversion of minimally invasive parathyroidectomy to open neck surgery, with exploration of all parathyroid glands. Conclusions Our investigative projects started from the clinical experience in the field of phosphocalcic and bone metabolism, and especially the experience connected to the cases of phpth of the Clinic of Endocrinology from the St. Spiridon hospital on one hand, and the surgical experience in the field of parathyroidectomy from the same hospital on the other hand. The projects were finalized with the conceiving of this PhD thesis. Not too long ago, parathyroid surgery implied open neck surgery, with exploration of all parathyroid glands. The development of modern visualization techniques of the parathyroid glands, especially sesta-mibi scintigraphy and cervical ultrasound, allowed a good presurgical localization of parathyroid adenomas, facilitating minimally invasive interventions for targeted excision of parathyroid adenomas. The surgical department of the St. Spiridon hospital was among the first Romanian centers where minimally invasive parathyroidectomy was used. In a multicentric study involving 13

19 patients from Iași and Cluj, we evaluated the volume of parathyroid adenomas, by measuring three diameters and using the formula of a rotating ellipsoid. Contrary to other authors, we noticed that the volume of parathyroid adenoma was positively correlated to PTH, but not presurgical calcium levels at patients from both centers and at pooled patients from both centers as well. We concluded therefore that PTH and 25OHD 3, but not serum calcium are correlated to the volume of parathyroid adenoma in conditions of D hypovitaminosis. We proposed that the association of a low level of 25OHD 3 with an increased PTH level is prognostic for a larger volume of the excised parathyroid adenomas. The contrast between a hormonal profile prognostic for a large parathyroid adenoma and the small dimensions of an excised parathyroid adenoma measured during surgery may suggest the existence of undiagnosed multiple glandular disease and, together with the lack of qpth normalization, may certify the need for the conversion of minimally invasive parathyroidectomy to open neck surgery. We tried to define the importance of FGF23 in phpth. We evaluated therefore FGF23 before surgery and immediately after surgical intervention. FGF23 levels were within the normal range at all patients and did not modify significantly after surgery. We consider therefore that in conditions of autonomous PTH hypersecretion, the role of FGF23 is greatly taken over by PTH. The role of FGF23 may therefore be much less important in phpth, contrary to the conclusions reached by other authors. Summarizing all data obtained from our research regarding phpth, we proposed a presurgical and intrasurgical investigation protocol of the affected patients (figure 5.30.). The obtained data are also tempting us to propose a therapeutic strategy including the repletion of vitamin D reserves and the usage of antiresorbtive drugs such as bisphosphonates for being able to prevent both osteoporosis and the risk of relapses of kidney nephrolithiasis. The doctoral thesis contains 73 figures, 6 tables and 196 bibligraphic references. 14

20 Bibliografie 1. Diaconescu M. R. Patologia chirurgicală a glandelor paratiroide, Ed. Performantica, Iaşi, 2009, 21-22, 26-27, 77-78, 84-85, 88, , 127, Pallan S, Rahman MO, Khan A. Diagnosis and management of primary hyperparathyroidism. BMJ 2012; 344: e Kandil E, Alabbas HH, Bansal A, Islam T, Tufaro AP, Tufano RP. Intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and double adenoma. Acta Otolaryngol Head Neck Surg. 2009; 135(12): Henry JF, Defechereux T, Gramatica L, de Boissezon C (1999) Minimally invasive videoscopic parathyroidectomy by lateral approach. Langenbecks Arch Surg 384: Hamidi S, Aslani A, Nakhjavani M et al (2006) Are biochemical values predictive of adenoma s weight in primary hyperparathyroidism? ANZ J Surg 76(10): F. Kamani & A. Najafi & S. S. Mohammadi & S. Tavassoli & S. P. Shojaei (2011) Correlation of Biochemical Markers of Primary Hyperparathyroidism with Single Adenoma Weight and Volume Indian J Surg (March April 2013) 75(2): Riss P, Kaczirek K, Heinz G, Bieglmayer C, Niederle B. A defined baseline in PTH monitoring increases surgical success in patients with multiple gland disease. Surgery. 2007; 142(3): Barczynski M, et al. Intraoperative parathyroid hormone assay improves outcomes of minimally invasive parathyroidectomy mainly in patients with a presumed solitary parathyroid adenoma and missing concordance of preoperative imaging. Clin Endocrinol (Oxf) 2007;66(6): Williams JG, Wheeler MH, Aston JP et al (1992) The relationship between adenoma weight and intact (1 84) parathyroid hormone level in primary hyperparathyroidism. Am J Surg 163: Arrabal-Polo MA, Arrabal-Martin M, de Haro-Munoz et al. Mineral density and bone remodeling markers in patients with calcium lithiasis. BJU International 2011; 108: Katz AD, Hopp D (1982) Parathyroidectomy. Review of 338 consecutive cases for histology, location, and reoperation. Am J Surg 144: