ORIGINAL ARTICLE pISSN 2288-6575 • eISSN 2288-6796 http://dx.doi.org/10.4174/astr.2016.91.1.8 Annals of Surgical Treatment and Research Characteristics of patients operated for primary hyperparathyroidism at university hospitals in Türkiye: differences among Türkiye’s geographical regions Turkay Kirdak, Nuh Zafer Canturk1, Nusret Korun, Gokhan Ocakoglu2; Parathyroid Study Group Department of Surgery, Uludag University Faculty of Medicine, Bursa, 1Department of Surgery, Kocaeli University Faculty of Medicine, Kocaeli, 2Department of Biostatistics, Uludag University Faculty of Medicine, Bursa, Türkiye Purpose: The aim of this study was to define the clinical and laboratory characteristics of patients operated on for primary hyperpatathyroidism (PHPT) at university hospitals in Türkiye, and to investigate the differences in the clinical presenta­ tions of the disease between different geographical regions. Methods: Patients operated on for PHPT in the university hospitals of Türkiye were included in the study. The demographic, clinical, and laboratory findings and the operational data of the patients were investigated according to the whole country and to different geographical regions. Comparisons were performed according to whole country and regions. Results: A total of 1,162 cases were included in the study from different regions and 20 university hospitals. The mean age of patients was 52.4 ± 0.38 (mean ± standard error) in the general population of Türkiye. The rates of hypertension, urolithiasis, bone disease and 25­hydroxyvitamin D insufficiency were 35%, 18.6%, 67.6%, and 63%, respectively. The median parathormone (PTH), serum total calcium (Ca+2) and phosphorus value were 220 pg/mL (range, 70–2,500 pg/mL), 11.2 mg/dL (range, 9.5–11.2 mg/dL), and 2.4 mg/dL (range, 1–4.7 mg/dL), respectively. The median size of the adenomas resected was 16 mm (range, 4–70 mm). Significant differences were observed in the clinical and laboratory findings of the patients operated on due to PHPT between different geographical regions of Türkiye (P < 0.05). Conclusion: The clinical and laboratory characteristics of the patients with PHPT in different geographical regions of Türkiye differ. Furthermore, the general findings of the cases in Türkiye give us a hint that the severity of the disease here is somewhere between Eastern and Western countries. [Ann Surg Treat Res 2016;91(1):8-16] Key Words: Primary hyperparathyroidism, Parathyroidectomy, Turkey INTRODUCTION regions [1,3-5]. For example, in a study comparing the female cases with PHPT between New York, United States, and Beijing, Most of the studies on primary hyperpatathyroidism (PHPT) China, clinical findings such as osteoporosis, urolithiasis and and parathyroidectomy are generally of West Europe or North osteitis cystica fibrosa were found to be more frequent, the America origin. Therefore, when the clinical and laboratory parathormone (PTH) and Ca+2 levels were found to be higher, presentations of the disease are defined, the data are generally and 25-hydroxyvitamin D (25(OH)D) level was found to be from North American and Western Europe [1,2]. However, it lower in women living in Beijing. However, in the same study, has been demonstrated in comparative studies that PHPT may asymptomatic PHPT was found to be more common in women have different clinical presentations in different geographical living in New York [1]. Likewise, in another study comparing Received February 16, 2016, Revised April 25, 2016, Copyright ⓒ 2016, the Korean Surgical Society Accepted May 16, 2016 cc Annals of Surgical Treatment and Research is an Open Access Journal. All Corresponding Author: Turkay Kirdak articles are distributed under the terms of the Creative Commons Attribution Non- Department of Surgery, Uludag University Faculty of Medicine, 16059 Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which Gorukle, Bursa, Türkiye permits unrestricted non-commercial use, distribution, and reproduction in any Tel: +90-224-2952022, Fax: +90-224-2952055 medium, provided the original work is properly cited. E-mail: tkirdak@uludag.edu.tr 8 Turkay Kirdak, et al: Primary hyperparathyroidism in Türkiye patients in San Francisco, United States and Bursa, Türkiye completed with a total of 20 university hospitals. matched according to age and gender, osteoporosis was more frequent, the PTH level was higher, the phosphorus level was Determining the regions lower, and the adenoma sizes were larger in patients living The classically predefined 7 regions were considered when in Bursa [3]. However, such studies conducted in a certain investigating the distribution of the disease throughout region of countries may not give enough information for the Türkiye. However, the East Anatolian region and the Southeast whole country. Of this socio-economic, ethnic or climate- Anatolian region were combined, since the data of patients related differences may be observed in patients of different with PHPT obtained in each region were considered to be geographical regions of a country with a large surface area. This insuffiecient, and named East-Southeast Anatolian region. may lead to the presentation diseases with different clinical Accordingly, the country was then divided into 6 regions. and laboratory findings within the same country. Besides this, centres in the Karadeniz region could not provide Considering this subject, the present information in the sufficient data, and therefore, this region was not included, and literature is insufficient with regard to the clinical, laboratory, Türkiye was investigated as 5 regions (Table 1). and operational data of the patients operated on due to PHPT that reflect the general population of Türkiye. Furthermore, Presentation of data on tables no difference was considered for the clinical presentation of Since this study was retrospective, the total number of cases the disease in different geographical regions of Türkiye, which investigated for each parameter was different. Therefore, for is a quite large country with regard to the surface area and certain parameters investigated, the total number of patients population. The aim of this study was to define the clinical who possessed data for those parameters was expressed in the and laboratory characteristics of patients operated on for tables. PHPT at university hospitals in Türkiye, and to investigate the differences in the clinical presentations of the disorder between different geographical regions. Table 1. Distribution of cases according to regions and uni- versity hospitals in Türkiye METHODS Region/city No. of The study included patients operated on for PHPT at univer- cases (%) sity hospitals in Türkiye between January 2004 and December Marmara region 434 (37.3) 2008. The data were obtained from patient files and electronic İstanbul University, Cerrahpasa Medical 75 Faculty/İstanbul records retrospectively. The number of general surgical İstanbul University Medical Faculty/İstanbul 157 operations between the dates of the study in participating Marmara University/Istanbul 27 hospitals was also recorded. The participating hospitals had Kocaeli University/Kocaeli 75 recorded the data in a standard electronic form, in the Excel Uludag University/Bursa 100 program. The demographic, clinical, laboratory and operational Aegean region 150 (12.9) findings of the whole country and regions of Türkiye were Ege University/Izmir 75 investigated. Additionally, comparisons were performed with Adnan Menderes University/Aydin 35 regard to the general country and different regions. The study Pamukkale University/Denizli 40 Mediterranean region 67 (5.8) was approved by the Ethical Committee of Scientific Researchs Cukurova University/Adana 44 of the hospital in charge. Mersin University/Mersin 23 Central anatolia region 396 (34.1) Determining the centres to provide data to the Erciyes University/ Kayseri 70 study Hacettepe University/Ankara 112 The number of patients operated on due to PHPT in Türkiye Ankara University/Ankara 95 Gazi University/Ankara 75 is limited. The diagnosis and treatment of the disease is Osmangazi University/Eskisehir 19 generally performed by certain reference medical centres. There- Cumhuriyet University/Sivas 25 fore, university hospitals in different regions of the country, East-Southeast anatolian region 115 (9.9) which are believed to be reference centres, were included in Atatü University/Erzurum 53 the study in order to obtain larger patient series. A total of 25 Dicle University/Diyarbakir 8 university hospitals to be included in the study; however, only Gaziantep University/Gaziantep 16 21 universities agreed to participate. One of the 21 hospitals Firat University/Elazig 38 Total 1,162 had insuffient data and was therefore excluded. The study was Annals of Surgical Treatment and Research 9 Annals of Surgical Treatment and Research 2016;91(1):8-16 Statistical analysis were performed. These data indicate that the rate of para- The comparisons were performed between the general data thyroidectomies performed due to PHPT in the university of Türkiye and the data of the regions. Interregional compari- hospitals of Türkiye among all general surgical operations was sons were performed as well. The continuous variables were 0.4%. The distribution in years indicated that the number of expressed as mean ± standard error or median (range), while cases operated due to PHPT in Türkiye increased (Fig. 1). the categorical variables were presented as frequency with related percentage. The comparisons between the groups were Demographic and clinical findings performed using the Kruskal-Wallis or the analysis of variance Nine hundred fifty-seven of the cases (82.4%) operated on due (ANOVA) test, to determine whether the variables followed a to PHPT in the university hospitals of Türkiye were women and normal distribution or not. The Bonferroni test was performed 205 (17.6%) were men. No difference was determined between for multiple comparisons after the ANOVA test. Two-group the regions with regard to gender (P > 0.05). comparisons were performed using the Mann-Whitney test. The mean age was 52.4 ± 0.38 years. The mean ages of the The comparisons of the categorical variables between the women and men were 52.07 ± 0.42 and 54.03 ± 0.38 years, groups were performed using the Fisher-Freeman-Halton test, respectively, which indicated no statistical significance (P = the Pearson chi-square test or the Fisher Exact test. Statistical 0.542). Cases in the East-Southeast Anatolian Region were analyses were also performed using IBM SPSS Statistics ver. 21.0 observed to be younger than the cases in both Türkiye’s general (IBM Co., Armonk, NY, USA), and the level of siginificance was area and Marmara, Aegean and Central Anatolian Regions (P set at α=0.05. < 0.001). The Mediterranean Region included the youngest patients following East-Southeast Anatolian Region, and had RESULTS similar age with the remaining regions (Table 2). The rate of cases operated on due to recurrence or persistent The general surgery clinics of 20 university hospitals from PHPT in the university hospitals of Türkiye was 3.9%. No 5 different regions were included in the study. The total num- difference was detected between the regions (P = 0.377) or ber of cases investigated was 1,228. However, 66 cases were excluded due to various reasons such as high creatinine levels or the operation date being out of the interval accepted in the 400 2004 study. Therefore, the total number of cases included was 1,162. 350 2005 When the distribution of the cases according to the regions 2006300 2007 was investigated, regions with the highest number were the 250 2008 Marmara (n=434, 37.3%) and the Central Anatolian regions (n=396, 34%). The region with the lowest number was the 200 Mediterranean (n=67, 5.8%) (Table 1). However, it should be 150 considered that the cases of East and Southeast Anatolia were 100 combined and the data were included as the East-Southeast 50 Anatolian Region. Thirteen out of 20 centres participating in the study had 0 Turkey Marmara Aegean Mediterranian Central East-south sent the data of general surgical operations performed within anatolia east the dates of the study. According to these data, 169,527 Fig. 1. Distribution of patients with primary hyperp atat hy- general surgical operations and 732 parathyroidectomies roidism according to years and regions in Türkiye. Table 2. Demographic and clinical data of patients undergoing surgery for PHPT at university hospitals in Türkiye Variable Türkiye 1 2 3 4 5 P-valuea) P-valueb) Female/male 957/205 369/65 117/33 51/16 322/74 98/17 0.146 0.054 Age (yr) 52.4 ± 0.38 52.4 ± 0.63 53.9 ± 1.01 50.1 ± 1.50 53.7 ± 0.64 46.8 ± 1.34 <0.001 <0.001 Previous PTx 43/1,116 (3.9) 21/428 (4.9) 4/110 (3.6) 2/67 (3) 15/396 (3.8) 1/115 (0.9) 0.377 0.522 Hypertension 388/1,100 (35.3) 138/399 (34.6) 52/147 (35.4) 26/57 (45.6) 139/391 (35.5) 33/106 (31.1) 0.469 0.614 Urolithiasis 206/1,109 (18.6) 84/420 (20) 29/146 (19.9) 21/47 (44.7) 54/385 (14) 18/111 (16.2) <0.001 <0.001 Values are presented as mean±standard error or number/N (%). PHPT, primary hyperparathyroidism; PTx, parathyroidectomy; N, total cases who have data related that parameter. Regions: 1, Marmara; 2, Aegean; 3, Mediterranean; 4, Central Anatolia; 5, East-Southeast. a)Comparison among regions. b)Comparison between Türkiye and regions. 10 No. of patients 150 167 226 279 340 45 65 101 102 121 14 24 17 40 55 6 9 16 12 24 74 46 72 93 111 11 23 20 32 29 Turkay Kirdak, et al: Primary hyperparathyroidism in Türkiye between Türkiye in general and its regions (P = 0.522) (Table 2). Central Anatolian Region than that of Türkiye’s general region (P In 35% of the cases with PHPT, hypertension was present < 0.001). No significant difference was observed in the Aegean in the general area. This rate varied between 31% and 45% in and East-Southeast Anatolian Regions compared to Türkiye’ different regions. However, no difference was observed between s general region (P = 0.884 and P = 0.862, respectively). the regions or between the general country and regions with Differences were observed in the interregional comparisons regard to hypertension (P > 0.05). with regard to the reduced bone mineralization rates. The Of the cases operated due to PHPT in the university hospitals Mediterranean and Marmara Regions had the highest rate of of Türkiye, 18.6% had a history of urolithiasis. The incidence of abnormal DXA findings. This rate was higher in the Marmara urolithiasis was significantly different between the regions (P Region than Aegean, Central Anatolian and East-Southeast < 0.001). The highest incidence belonged to the Mediterranean Regions (P = 0.003, P < 0.001, and P = 0.010, respectively). Region (44.7%), and the lowest incidence belonged to the The lowest rate of abnormal bone density was observed in Central Anatolian Region (14%). The incidence of urolithiasis the Central Anatolian Region (39.5%). The differences were was higher in the Mediterranean Region compared to Marmara, observed between the Central Anatolian Region and the Aegean, Central Anatolia and East-Southeast Anatolia Regions Marmara, Mediterranean and East-Southeast Anatolian Regions (P < 0.001, P = 0.001, P < 0.001, and P < 0.001, respectively). (P < 0.001, P < 0.001, and P = 0.002, respectively). The highest The incidence in the Central Anatolian region was lower than rates of osteoporosis were observed in the Aegean (76.8%) and that of the Marmara Region (P = 0.025). No other difference the Central Anatolian (68.5%) Regions. was observed between the regions. Compared to the general The rate of patients with a history of bone fracture among country, the incidence of urolithiasis was lower in the Central those operated on due to PHPT in Türkiye was found to be 6%. Anatolian region and higher in the Mediterranean Region (P = When Türkiye’s general region and the regions were compared, 0.043, P < 0.001, respectively) (Table 2). only the Central Anatolian Region had a higher bone fracture rate (11.6%) (P = 0.036). The interregional comparisons revealed Bone findings significant differences in the frequency of patients with a The bone density findings of 688 out of 1,162 patients were history of bone fracture (P = 0.004). The rate of patients with present. In patients operated on due to PHPT in Türkiye, a history of bone fracture was higher in the Central Anatolian the rates of detection of abnormal findings (osteopenia or Region than the Marmara (P = 0.019), Aegean (P = 0.039) and osteoporosis) in femur, vertebrae or radius with dual-energy the East-Southeast Anatolian (P = 0.019) Regions, higher in the X-ray absorbtiometry (DXA) were 67.6%, and 54% had osteo- Mediterranean Region than the Aegean Region (P = 0.050), and porosis (Table 3). The incidence of osteopororis in the regions higher in the Mediterranean Region than the East-Southeast except the Marmara Region was higher than the incidence of Anatolian Region (P = 0.021) (Table 3). osteopenia. When the abnormal DXA findings of these cases The rate of bone cyst among patients operated on due to were investigated, differences were observed between both PHPT in Türkiye was found to be 1.5%. The interregional the regions and the general country. The rates of patients with comparisons revealed a higher rate of bone cyst in the Central reduced bone mineralization in the Marmara and Mediter- Anatolian Region than the Marmara Region (P < 0.001). No ranean Regions were higher than that of Türkiye’s gene ral (P < difference was observed between the remaining regions (Table 3). 0.001 and P = 0.037, respectively). This rate was lower in the Table 3. Bone findings in patients undergoing surgery for PHPT at university hospitals in Türkiye Region Variable Türkiye P-valuea) P-valueb) 1 2 3 4 5 DXA Abnormal 465/688 (67.6) 269/328 (82) 69/101 (68.3) 20/22 (90.9) 73/185 (39.5) 34/52 (65.4) <0.001 <0.001 Osteopenia 214 (46.0) 144 (53.5) 16 (23.2) 8 (40.0) 23 (31.5) 23 (67.6) <0.001 <0.001 Osteoporosis 251 (54.0) 125 (46.5) 53 (76.8) 12 (60.0) 50 (68.5) 11 (32.4) Fracture 62/971 (6.0) 19/386 (4.7) 5/141 (3.4) 5/38 (11.6) 31/301 (9.3) 2/105 (6.0) 0.004 0.010 Bone cyst 14/943 (1.5) 1/422 (0.2) 1/132 (0.8) 0/41 (0) 10/243 (4.0) 2/105 (1.9) 0.003 0.009 Values are presented as number/N (%). PHPT, primary hyperparathyroidism; DXA, dual-energy X-ray absorptiometry; N, total cases who have data related that parameter. Regions: 1, Marmara; 2, Aegean; 3, Mediterranean; 4, Central Anatolia; 5, East-Southeast. a)Comparison among regions. b)Comparison between Türkiye and regions. Annals of Surgical Treatment and Research 11 Annals of Surgical Treatment and Research 2016;91(1):8-16 Parathormone The median PTH value in patients operated on in the univer- sity hospitals of Türkiye was found to be 220 pg/mL (range, 70– 2,500 pg/mL). The regions with the highest and lowest median PTH values were the East-Southeast Anatolian Region (375 pg/ mL) and the Mediterranean Region (180 pg/mL), respectively (Table 4). Differences were observed in the median PTH values between both Türkiye’s general area and the regions, and between the regions (<0.001) (Tables 4, 5). The normal labo- ratory value of PTH was accepted as 35–68 pg/mL. Calcium The median serum total Ca+2 levels of the patients operated in the university hospitals of Türkiye was 11.2 mg/dL (range, 9.5–15.1 mg/mL). The Ca+2 value observed in all of the regions was 11 mg/dL or more. The region with the highest median Ca+2 value was the Mediterranean region (12.1 mg/dL). Differences were observed between both the Mediterranean Region and the other regions, and the Mediterranean Region and Türkiye’ s general region (P < 0.05) (Tables 4, 5). The median values of the remaining regions were closer to Türkiye’s general region. The median values of Ca+2 in the 24-hour urine of the patients ope rated on due to PHPT in the university hospitals of Türkiye was 345 mg/24 hr (range, 40–1,385 mg/24 hr). No difference was observed between the regions (P > 0.05). The normal laboratory values for the total serum Ca+2 and urinary Ca+2 were accepted as 8.4–10.2 mg/dL and 100–300 mg/24 hr, respectively. Phosphorus The median serum phosphorus value in patients operated on due to PHPT in Türkiye was 2.4 mg/dL (range, 1–4.7 mg/dL). The regions with the lowest and highest median phosphorus values were the East-Southeast Anatolian and the Aegean Regions, respectively. Inter-regional differences were observed in the median phosphorus values (P < 0.05). The normal laboratory values of phosphorus was accepted as 2.3–4.7 mg/dL. 25-hydroxyvitamin D The median value of 25(OH)D among patients operated on due to PHPT in Türkiye was 15 ng/mL (range, 3–98 ng/mL). The regions with the lowest median 25(OH)D level were the Mar- mara with 11 ng/mL (range, 4–98 ng/mL) and the East-Southeast Anatolian with 11 ng/mL (range, 3–24 ng/mL), whereas the region with the highest median 25(OH)D level was the Aegean Region with 31 ng/mL (range, 8–59 ng/mL) (Table 4). 25(OH)D deficiency was observed in 63% of the patients operated on due to PHPT in Türkiye’s general region. The incidence of 25(OH)D deficiency was higher in the Marmara and the East-Southeast Anatolian Regions compared to Türkiye’s general region (P = 0.023 and P = 0.043, respectively). The inci dence of 25(OH)D deficiency was significantly lower in the Aegean, Mediterranean 12 Table 4. Laboratory findings in patients undergoing parathyroidectomy for PHPT at university hospitals in Türkiye Region Variable Türkiye P-valuea) P-valueb) 1 2 3 4 5 PTH 220 (70–2,500)/1,162 236 (70–2,500)/434 225 (70–2,500)/150 180 (70–1,631)/67 192 (72–2,500)/396 375 (72–2,229)/115 <0.001 <0.001 Ca+2 11.2 (9.5–15.1)/1,162 11 (9.6–15.1)/434 11.1 (9.5–15.5)/150 12.1 (9.6–17.6)/67 11.2 (9.5–16.8)396 11.2 (9.4–13.5)/115 <0.001 <0.001 P 2.4 (1–4.7)/991 2.3 (1.1–4.6)/327 2.6 (1.5–4.4)/127 2.4 (1.5–4.4)/64 2.5 (1–4.7)/372 2 (1.1–4.1)/101 <0.001 <0.001 Ur.Ca+2 345 (40–1,385)/493 342 (49–980)/306 332 (40–1,385)/55 358 (43–772)/18 353 (41–1,300)/91 380 (150–754)/23 0.754 0.863 ALP 116 (10–299)/807 110 (47–1,682)/192 105 (33–2,772)/128 229 (48–1,567)/42 104 (22–2,128)/340 201 (10–2,990)/105 <0.001 <0.001 Vit D 15 (3–98)/331 11 (4–98)/201 31 (8–59)/11 29.5 (10–86)/22 21.4 (5–97)/75 11 (3–24)/22 <0.001 0.003 Low Vit D 207/331 (63) 145/201 (72) 3/11 (27) 6/22 (27) 34/75 (45) 19/22 (86) <0.001 <0.001 High ALP 297/807 (37) 67/192 (35) 43/128 (34) 30/42 (71) 86/340 (25) 71/105 (68) <0.001 <0.001 Values are presented as median (range)/N or number/N (%). PHPT, primary hyperparathyroidism; N, total cases who have data on that parameter. Regions: 1, Marmara; 2, Aegean; 3, Mediterranean; 4, Central Anatolia; 5, East-Southeast. PTH, parathormon (35–68 pg/mL); Ca+2, calcium (8.4–10.2 mg/dL); P, phosphorus (2.3–4.7 mg/dL); ALP, 25–100 U/L; Low Vit D, 25–(OH) Vitamin D ≤ 20 ng/mL); Ur.Ca+2, Urine Ca+2(100–300 mg/24 hr). a)Comparison among regions. b)Comparison between Türkiye and regions. Turkay Kirdak, et al: Primary hyperparathyroidism in Türkiye Table 5. P-values of comparisons for laboratory data among regions in Türkiye Regions Vit D Urine Ca+2 PTH Ca+2 P ALP 1–2 0.001 0.431 0.705 0.434 0.001 0.927 1–3 <0.001 0.487 0.008 <0.001 0.243 <0.001 1–4 <0.001 0.556 0.002 0.861 0.008 0.172 1–5 0.278 0.298 <0.001 0.196 0.002 <0.001 2–3 0.749 0.903 0.054 <0.001 0.162 <0.001 2–4 0.032 0.721 0.103 0.401 0.228 0.276 2–5 <0.001 0.831 <0.001 0.610 <0.001 <0.001 3–4 0.011 0.689 0.376 <0.001 0.604 <0.001 3–5 <0.001 0.979 <0.001 <0.001 0.002 0.490 4–5 <0.001 0.624 <0.001 0.171 <0.001 <0.001 PTH, parathormone; Ca+2, calcium; Vit, vitamin; P, phosphorus. Regions: 1, Marmara; 2, Aegean; 3, Mediterranean; 4, Central Anatolia; 5, East-Southeast. Table 6. Operative findings in patients undergoing parathyroidectomy for PHPT at university hospitals in Türkiye Region Variable Türkiye P-valuea) P-valueb) 1 2 3 4 5 Adenom Single 1,028/1,146 (90) 377/431 (87) 136/146 (93) 59/66 (89) 353/388 (91) 103/115 (90) >0.05 >0.05 Multiple 103/1,146 (9) 51/431 (12) 10/146 (7) 7/66 (11) 23/388 (6) 12/115 (10) >0.05 >0.05 Hyperplasia 15/1,146 (1) 3/431 (1) 0/146 (0) 0/66 (0) 12/388 (3) 0/115 (0) >0.05 >0.05 Dimention (mm) 16 (4–70)/928 16.5 (4–70)/394 20 (6–60)/118 15 (7–65)/61 15 (5–65)/249 20 (7–40)/106 <0.001 <0.001 Thyroidectomyc) 342/958 (36) 88/277 (32 ) 49/108 (45) 22/67 (33) 134/391 (34) 49/115 (43) >0.05 >0.05 Values are presented as number/N (%) or median (range)/N. PHPT, primary hyperparathyroidism; N, total cases who have data on that parameter. Regions: 1, Marmara; 2, Aegean; 3, Mediterranean; 4, Central Anatolia; 5, East-Southeast. a)Comparison among regions. b)Comparison between Türkiye and regions. c)Thyroidectomy means concurrent thyroidectomy. and Central Anatolian Regions compared to Türkiye’s general observed between the Central Anatolian and the Mediterranean region (P = 0.026, P = 0.002, and P = 0.006, respectively). A Regions (P = 0.205) (Table 4). blood level of 25(OH)D ≤ 20 ng/mL was accepted as 25(OH)D deficiency in this study. Alkaline phosphatase The number of patients with 25(OH)D deficiency was The median level of ALP among patients operated due to significantly different between the regions (P < 0.001). 25(OH) PHPT in the university hospitals of Türkiye was determined D deficieny was observed in the Aegean and the Mediterranean to be 116 U/L (range, 10–299 U/L). Regions with the highest Regions with the lowest rate (Table 4). The East-Southeast median ALP levels were the Mediterranean (229 U/L; range, Anatolian (86%) and the Marmara (72%) Regions were the 48–1,567 U/L) and the East-Southeast Anatolian (201 U/L; range, regions with highest rates of 25(OH)D deficiency. 25(OH)D 10–2,990 U/L) Regions. The ALP levels observed in these 2 deficiency was higher in the Marmara Region compared to the regions were significantly higher compared to the remaining Aegean, Mediterranean and Central Anatolian Regions (P = regions (P < 0.05). The ALP levels were found to be higher than 0.004, P < 0.001, and P < 0.001, respectively). No difference the normal level in 37% of the patients operated in Türkiye’s was observed between the Marmara and the East-Southeast general region. The number of cases with an ALP level higher Anatolian Regions (P = 0.237). The incidence of 25(OH)D than normal was highest in the East-Southeast Anatolian (68%) deficiency was higher in the East-Southeast Anatolian Regions and the Mediterranean (71%) Regions (Tables 4, 5). The normal compared to the Aegean, Mediterranean and the Central laboratory values of ALP was accepted as 25–100 U/L. Anatolian Regions (P = 0.001, P < 0.001, and P = 0.002, respectively). No difference was observed between the Aegean Operative findings Region and the Mediterranean and Central Anatolian Regions The rates of single adenoma, multiple adenoma and hyper- (P = 0.338 and P = 1.000, respectively). No difference was plasia in patients operated on due to PHPT in the university Annals of Surgical Treatment and Research 13 Annals of Surgical Treatment and Research 2016;91(1):8-16 hospitals of Türkiye were 90%, 9%, and 1%, respectively. No differed between 14% and 44%. The region with the highest difference was observed between the regions (P > 0.05) incidence of kidney stone was the Mediterranean Region. (Table 6). The median adenoma size in the longest axis was Mollerup et al. [19] have reported that kidney stone was more 16 mm (range, 4–70 mm). Regions with the largest adenoma common among young patients. The Mediterranean Region size were the Aegean (20 mm; range, 6–60 mm) and the East- included the second youngest patient group after the East- Southeast Anatolian (20 mm; range, 7–40 mm) Regions. The Southeast Anatolian Region, although not significantly different median adenoma sizes observed in these 2 regions were from the other regions. However, although the ages of patients higher than those of the Mediterranean and Central Anatolian in Türkiye were younger compared to the Western countries, Regions (P < 0.001). No statistical difference was observed and those in the East-Southeast Anatolian Region were younger between Türkiye’s general area and the regions (P > 0.05). than the other regions, no significant difference was observed Concomitamt thyroidectomy was performed for 36% of the with regard to the rates of urolithiasis. The differences observed patients undergoing the PHPT operation for different reasons. in the urolithiasis rates between the regions/countries may No difference was observed between the regions with regard to be related to the different etiological factors in kidney stone concomitant thyroidectomy (P > 0.05). formation or ineffective radiological evaluation of the kidneys in asymptomatic patients [20-22]. DISCUSSION The bony findings in patients with PHPT may differ between countries/regions. For example, the bone mineral density in The age of patients with PHPT is greater in Western Coun- caucasian women with PHPT living in the USA were found to tries (USA, 60–62; Germany, 59; Italy, 59; Denmark, 65) than be higher than those living in Italy [4]. Bone diseases among Eastern countries (China, 37; India, 38) [1,6-11]. In this study, patients with PHPT have been reported to vary between 5% the median age of patients with PHPT was 52. This indicates and 8% in the USA [17]. The rate of osteoporosis was 100% in that the age of the patients with PHPT in Türkiye is somewhere China and 50% in Taiwan [1,23]. Bone cyst has been reported in between Eastern and Western countries. When the regions each case in India [11]. In this study, bone diseases (osteopenia were investigated, the median age of the patients in the East- or osteoporosis) were detected in 67% of the cases with PHPT. Southeast Anatolian Region was significantly younger than However, when the regions of Türkiye were investigated sepa- those of the remaining regions, except for the Mediterranean rately, it was observed that the rates of bone disease were Region. Griebeler et al. [6] reported that the median age of the homogeneous. Furthermore, the rates of bone diseases in the cases in Rochester, America with PHPT was 55 between 1985 Mediterranean (90%) and the Marmara (82%) Regions were and 1997, which significantly increased by time reaching 60 much higher than the mean of Türkiye. According to these data, between 1998 and 2010. Similarly, in studies conducted in it may be concluded that the rate of bone diseases in Türkiye China and Hong Kong, the mean age of the patients with PHPT is somewhere between the eastern and western countries, but had increased in time compared to the previous times [12,13]. rather similar to the eastern countries in some regions. Another characteristic concerning age was that the patients It has been believed that 25(OH)D deficiency has an impor- living in regions with a severe form of the disease were younger tant role in different severities of PHPT observed among the [1,11]. However, it was reported in age and sex matched studies world. In regions where 25(OH)D deficiency is endemic, a that the clinical and laboratory findings of the disease may be severe form of the disease is observed, whereas mostly the different [3,4]. There are not many studies investigating the asymptomatic form is observed in western counties [24]. It factors affecting the difference in age of patients in different has been reported that 25(OH)D deficiency is an important countries or regions of a country. factor defining in particular the bone disease in patients with With the use of autoanalysers in the 1970s, a significant PHPT [9,10,24,25]. Furthermore, a negative correlation is pre- increase was reported in both the incidence of the cases with sent between 25(OH)D levels and the adenoma weight, and PHPT and the rate of the asymptomatic cases related to the a positive correlation with PTH, Ca++ and ALP levels [7,19,24- frequent measurement of routine Ca++ [14,15]. This change is 26]. In this study, the East-Southeast Anatolian Region and the specifically significant in Western countries including North Marmara Region were the regions with more frequent patients America and North Europe. In the remaining regions of the with 25(OH)D deficiency and with more severe PHPT. However, world, the number of classic symptomatic PHPT cases is still the rate of patients with subnormal 25(OH)D levels has been high despite a partial change [12,16]. For example, the rates of reported as 63% in Türkiye, 93% in France, 81% in Denmark, kidney stone among patients with PHPT are 3%–20% in USA, 33% in Italy, and 86% in China [10,12,26]. When these rates are 11% in Germany, 42% in China, and 50% in India [1,8,17,18]. investigated, it is obvious that it is not possible to explain the In this study, the kidney stone rate in Türkiye was found to more severe form of the disease observed in eastern countries, be 18%. Interregional comparisons have shown that this rate and the asymptomatic form observed in western countries with 14 Turkay Kirdak, et al: Primary hyperparathyroidism in Türkiye 25(OH)D deficiency only. Additionally, Mishra et al. [11] claimed consumption), climatic conditions, and the duration of living that 25(OH)D levels were normal despite the severe form of the in the region in question. Furthermore, due to the fact that this disease in patients with PHPT in India, and thus, additional study was retrospective, it has not been possible to evaluate the pathogenetic factors may be present in the formation of the regional differences due to insufficiency of data. In order not to severe disease. Likewise, although the number of patients with be speculative, no comment has been made regarding regional 25(OH)D deficiency in the Mediterranean Region of Türkiye differences.. was quite low, this region had the highest rates of urolithiasis, In conclusion, the clinical and laboratory characteristics of the bone diseases, blood Ca+2 and ALP levels. Therefore, it should be patients operated due to PHPT in different classically defined considered that Vitamin D is not the only factor indicating the geographical regions of Türkiye differ. Furthermore, the general severity of PHPT, delays in access to detection and treatment findings of the cases in Türkiye give us a hint that the severity of the disease, and factors such as ethnicity, genetics, and race of the disease here is somehwere between Eastern and Western may play a defining role in the severity of the disease as well countries. This study indicates that the clinical presentation of [2,6,27-29]. PHPT may vary even in different regions of the same country. The median PTH and Ca+2 levels in patients with PHPT Therefore, it should be considered when planning such studies in Türkiye were found to be 220 pg/mL and 11.2 mg/dL, comparing the differences between regions/countries. respectively. The median Ca+2 in USA was reported to be 10.8 mg/dL [6]. The median PTH and Ca+2 levels were 134 pg/ CONFLICTS OF INTEREST mL and 11.4 mg/dL in France, 102 pg/mL and 11 mg/dL in Denmark, and 141 pg/mL and 11.1 mg/dL in Italy, respectively No potential conflict of interest relevant to this article was [9,10,26]. The PTH levels were 20 and 17 fold the normal value reported. in China and India, respectively [1,11]. In another study from Korea, mean PTH and Ca+2 levels were reported as 263 pg/mL ACKNOWLEDGEMENTS and 11.6 mg/dL, respectively [30]. According to these data, no significant difference is observed between the blood Ca+2 levels The Parathyroid Study Group members include the following of the patients with PHPT in Türkiye and Europe and America; collaborators. however, the PTH levels were higher than those in western Yesim Erbil (Istanbul University Medical Faculty / Istanbul), countries. Iskender Sayek (Hacettepe University / Ankara), Semih Baskan The limitations of this study were: it was retrospective, there (Ankara University / Ankara), Osman Kurukahvecioglu and was a lot of data loss, lower possibilities of interlaboratory Ferit Taneri (Gazi University / Ankara), Serkan Teksoz and differences, and the data of the study were old. Due to the Yusuf Bukey (Istanbul University, Cerrahpasa Medical Faculty / difficulty of data collection, recent data could not be added. Istanbul), Gokhan Icoz and Ozer Makay (Ege University / Izmir), However, the data of patients operated on due to PHPT in Turgay Sımsek (Kocaeli University/Kocaeli), Erdogan Sozuer Türkiye’s general and separate regions is not available in the (Erciyes University / Kayseri), Mufide Nuran Akcay (Atatürk literature. We believe that we have contributed to literature in University / Erzurum), Orhan Demircan (Cukurova University this regard. / Adana), Akın Ozden (Pamukkale University / Denizli), Erhan In this study, the general characteristics of patients with Aygen (Fırat University/ Elazig), Serdar Ozbas (Adnan Menderes PHPT have been determined, and it has been demonstrated that University / Aydın), Bahadır M. Gulluoglu (Marmara University / the demographic, clinical and laboratory data of cases living in Istanbul), Ayhan Koyuncu (Cumhuriyet University / Sivas), Koray different regions of the same country may not be homogenous. A. Ocal (Mersin University / Mersin), Enver Ihtiyar (Osmangazi As it is known, the patients’ clinical characteristics are under University / Eskisehir), Gokturk Maralcan (Gaziantep University / the influence of multiple factors such as ethnic, genetic and Gaziantep), Yusuf Yagmur (Dicle University / Diyarbakir). socio-economic statuses, nutritional habits (for example, milk REFERENCES 1. Bilezikian JP, Meng X, Shi Y, Silverberg SJ. Int J Fertil Womens Med 2000;45:158-65. prev alence of primary hyper para thy roid - Primary hyperparathyroidism in women: 2. Yeh MW, Ituarte PH, Zhou HC, Nishimoto ism in a racially mixed population. J Clin a tale of two cities--New York and Beijing. S, Liu IL, Harari A, et al. Incid ence and Endocrinol Metab 2013;98:1122-9. Annals of Surgical Treatment and Research 15 Annals of Surgical Treatment and Research 2016;91(1):8-16 3. Kirdak T, Duh QY, Kebebew E, Clark OH. 12. 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