primary hyperparathyroidism ( phpt ) is a disease characterized by hypercalcemia due to autonomous production of parathyroid hormone ( pth ) . phpt is the third most common endocrine disorder in the west after diabetes mellitus and thyroid disorders . overall , about 1% of the adults have phpt in the west , and this figure rises to 2% in people older than 55 years . with the advent of multichannel biochemical screening in the 1970s , the clinical profiles of phpt remarkably differ with regions of the world . in developing countries , such as india , phpt is still uncommonly diagnosed , overtly symptomatic disease with skeletal , muscular , and renal manifestations . in contrast , phpt has become an asymptomatic disease in the west with classic manifestations seen only in 2% cases nowadays . in this study , we describe the clinical characteristics , biochemical profile , and outcome of 78 patients with phpt seen over a period of two decades at a single center from the kashmir valley . all patients who underwent evaluation and surgery for phpt from january 1996 to december 2015 at sher - i - kashmir institute of medical sciences were included in the study . a total of 78 patients were identified during the two decades , of whom 29 patients were studied retrospectively ( 19962012 ) and remaining 49 patients were studied prospectively ( 20122015 ) . the diagnosis of phpt was based on the following : ( i ) persistent elevation of serum calcium above the upper limit of normal range ( 10.5 mg / dl ) ; ( ii ) increased intact pth ( ipth ) ; and ( iii ) histological evidence ( after parathyroid surgery ) of parathyroid adenoma or hyperplasia . evaluation of the patients included the measurement of serum total calcium , inorganic phosphorus , total alkaline phosphatase ( alp ) , ipth , 25-hydroxy vitamin d ( 25-ohd ) , serum albumin , and 24 hour urinary calcium and creatinine . serum total calcium , inorganic phosphorus , total alp , and serum creatinine were measured by automated techniques . the normal laboratory range was 8.510.5 mg / dl for total serum calcium , 2.54.5 mg / dl for serum phosphorus , and 30140 iu / l for serum alp . radiological survey of hands , skull , lumbar spine , pelvis , and any other suspected or known site of fracture was performed . imaging studies for localization of parathyroid adenoma included ultrasonography ( usg ) neck and technetium-99 m ( tc ) sestamibi scan . serum ipth was measured by chemiluminescent immunometric assay and serum 25-ohd was measured by radioimmunoassay . vitamin d deficiency was defined as serum 25-ohd level < 20 ng / ml . in patients in whom a single parathyroid adenoma was localized on tc sestamibi scan , unilateral neck exploration was performed with removal of the adenoma . patients with doubtful lesion or nonlocalized lesions underwent bilateral neck exploration , and all parathyroid glands were examined with the removal of 3 glands . statistical analysis was done on pc windows using statistical package for social sciences ( spss ) , version 11.5.0 , from spss inc . pearson 's chi - square method was used for comparing proportions and percentages , whereas student 's t - test was used for comparing continuous variables . anova was used wherever needed . where the data were not uniformly distributed nonparametric test such as mann smirnov z - test , or kruskal  wallis h - test was used . a p < 0.05 was taken as statistically significant . in patients in whom a single parathyroid adenoma was localized on tc sestamibi scan , unilateral neck exploration was performed with removal of the adenoma . patients with doubtful lesion or nonlocalized lesions underwent bilateral neck exploration , and all parathyroid glands were examined with the removal of 3 glands . statistical analysis was done on pc windows using statistical package for social sciences ( spss ) , version 11.5.0 , from spss inc . pearson 's chi - square method was used for comparing proportions and percentages , whereas student 's t - test was used for comparing continuous variables . anova was used wherever needed . where the data were not uniformly distributed nonparametric test such as mann smirnov z - test , or kruskal  wallis h - test was used . a p < 0.05 was taken as statistically significant . the clinical characteristics of patients are shown in table 1 . an overwhelming majority ( 67/78 ; 85.7% ) of the patients were females giving a male : female ratio of 1:6 . the mean age of patients was 44.72  12.46 with a median of 45 years and a range of 1670 years . nephrolithiasis and/or nephrocalcinosis [ figure 1 ] was the most common presentation , seen in 50 ( 64.10% ) patients followed by bone pain in 26 ( 44.1% ) , abdominal pain in 24 ( 39% ) , constipation in 16 ( 26% ) , and myopathy in 11 ( 14.10% ) . skeletal involvement ( osteopenia , sub - periosteal resorption , pathological fractures , salt and pepper appearance of skull , brown tumors ) was present in 31 ( 39.74% ) patients ; 8 ( 10.25% ) had fractures [ figure 2 ] . about one - fourth ( 19 ; 24.38% ) of our patients had both renal and skeletal manifestations . clinical characteristics of 78 patients with primary hyperparathyroidism ( a ) radiograph of abdomen showing extensive bilateral nephrolithiasis ; ( b ) striking improvement after successful parathyroid surgery radiograph showing advanced bone disease . ( a ) fracture of femur ; ( b ) brown tumor of tibia out of fifty patients with nephrolithiasis , 15 ( 30% ) had a past history of at least one surgery for renal stones prior to the diagnosis of phpt , and another four patients had received extracorporeal shock wave lithotripsy at least once prior to diagnosis of phpt . the mean serum calcium level was 12.5  1.7 mg / dl , ( median12 , range 10.719 ) . the mean serum ipth level was 377.6  386.1 pg / ml ( median 224.5 , range 701900 ) . hypophosphatemia ( serum inorganic phosphorus < 2.5 mg / dl ) was documented in 54 ( 69.23% ) patients . the mean serum inorganic phosphorus level was 2.2  0.6 mg / dl ( median 2.2 ) . hypercalciuria ( 24 h urinary calcium 4 mg / kg ) was present in 41 ( 52.56% ) patients . the mean serum alp was 255.1  336.8 iu / l ( median 154 ) . biochemical variables of 78 patients with primary hyperparathyroidism serum 25-ohd was available for 54 patients . the mean 25-ohd level was 37.2  58.1 ng / ml ( median 22.8 , range 4.3312 ) . we did not find any correlation between vitamin d status and biochemical parameters ( serum calcium and ipth ) or adenoma weight . two females ; aged 25 and 23 years had phpt and microprolactinoma , whereas a 58-year - old female patient had phpt and acromegaly . two of our patients had associated adrenal incidentalomas causing sub - clinical cushing 's syndrome in one of them . a 27-year - old female patient presented in postpartum period with nephrogenic diabetes insipidus as the sole manifestation of phpt , which settled immediately after parathyroid surgery . all our patients underwent usg neck and tc-99 m sestamibi scan for localization of parathyroid adenoma . in our series , the sensitivity of usg and tc-99 m sestamibi scan for the localization of adenoma was 89.8% and 95.3% , respectively . at the time of surgery , single adenoma was involved in 69 ( 88.46% ) double adenomas in 6 ( 8.57% ) and more than 2 gland involvement in 3 ( 4.28% ) patients . among the 69 patients with single adenoma , right inferior gland was involved most often ( 40 ; 57.97% ) , followed by left inferior ( 22 ; 31.88% ) and right superior ( 7 ; 0.14% ) ; none of the patients had involvement of left superior gland . on histopathology , adenoma was found in 75 ( 94.44% ) , hyperplasia in 3 ( 3.79% ) patients . the mean parathyroid gland weight was 2.05  3.03 g ( median 1.05 ; range 0.113.8 ) . using pearson 's correlation coefficient , the mean postoperative serum ipth level was 61.8  43.8 pg / ml ( range : 10.7154 ) . postoperative hungry bone syndrome ( hbs ) was observed in 8 ( 10.12% ) patients . this was managed with oral calcium and calcitriol in five patients , whereas three patients needed parenteral calcium gluconate infusion . permanent hypoparathyroidism was observed in a single patient , and postoperative pancreatitis was documented in one patient . no patient sustained permanent vocal cord paralysis , wound infection , or sepsis . the surgical success ( cure ) for phpt is defined by the maintenance of eucalcemia at the arbitrarily accepted interval of 6 months after surgery . based on this definition , the overall cure rate in our series was 96.15% ( 75 out of our 78 patients achieved cure ) . one of these patients had men-1 ( phpt and acromegaly ) ; she underwent the removal of all four parathyroid glands . the second patient was a young male in whom preoperatively left inferior adenoma was localized but had a persistent disease ; however , he achieved cure after second surgery . out of 75 patients who achieved cure , long - term follow - up ( more than one year , range 19 years ) was available for 41 patients . during this follow - up period , none had recurrence of phpt . at the time of surgery , single adenoma was involved in 69 ( 88.46% ) double adenomas in 6 ( 8.57% ) and more than 2 gland involvement in 3 ( 4.28% ) patients . among the 69 patients with single adenoma , right inferior gland was involved most often ( 40 ; 57.97% ) , followed by left inferior ( 22 ; 31.88% ) and right superior ( 7 ; 0.14% ) ; none of the patients had involvement of left superior gland . on histopathology , adenoma was found in 75 ( 94.44% ) , hyperplasia in 3 ( 3.79% ) patients . the mean parathyroid gland weight was 2.05  3.03 g ( median 1.05 ; range 0.113.8 ) . using pearson 's correlation coefficient , the mean postoperative serum ipth level was 61.8  43.8 pg / ml ( range : 10.7154 ) . postoperative hungry bone syndrome ( hbs ) was observed in 8 ( 10.12% ) patients . this was managed with oral calcium and calcitriol in five patients , whereas three patients needed parenteral calcium gluconate infusion . permanent hypoparathyroidism was observed in a single patient , and postoperative pancreatitis was documented in one patient . no patient sustained permanent vocal cord paralysis , wound infection , or sepsis . the surgical success ( cure ) for phpt is defined by the maintenance of eucalcemia at the arbitrarily accepted interval of 6 months after surgery . based on this definition , the overall cure rate in our series was 96.15% ( 75 out of our 78 patients achieved cure ) . one of these patients had men-1 ( phpt and acromegaly ) ; she underwent the removal of all four parathyroid glands . the second patient was a young male in whom preoperatively left inferior adenoma was localized but had a persistent disease ; however , he achieved cure after second surgery . out of 75 patients who achieved cure , long - term follow - up ( more than one year , range 19 years ) was available for 41 patients . during this follow - up period , the traditional age of presentation of phpt in india is in the 4 decade . in our study , our results reflect a shift in the presentation of phpt from fourth to fifth decade in india . however , our patients continue to be much younger than patients from the developed countries . comparison of present study with other indian studies renal stone disease ( 50:64.10% patients ) was the most common presentation in our series . the prevalence of renal stones has fallen from 57% to < 5% in the west due to the detection of more and more asymptomatic cases . thirty percent of our patients with renal stones had a past history of at least one surgery for renal stones and another four patients ( 8% ) had received lithotripsy prior to diagnosis of phpt . surprisingly , in none of these patients serum calcium estimation had been advised during previous evaluation . this significant delay in the diagnosis of phpt reflects the lack of awareness among urologists , nephrologists , and general practitioners regarding phpt . mishra et al . in 2001 in a study of 29 patients reported osteitis fibrosa cystica in all of them and fractures in 57% of the patients . in a study of 52 patients reported bone disease in 67% and fractures in 48% patients . a systematic review of phpt in india has reported fractures in 40% and brown tumors in 42% patients . a recent indian study reported fractures in 25.8% of phpt patients and brown tumors in none . in our study , fractures were present only in 10.25% and brown tumors in 6.41% patients . this is the lowest prevalence of fractures in a cohort of phpt patients from india . our results reflect a changing trend in the presentation of phpt in india wherein the overt skeletal disease in the form of fractures and brown tumors is on the decline . the remarkably low prevalence of fractures in our series probably is due to earlier diagnosis of phpt for last few years ( more than half of our subjects were enrolled from 2013 onwards ) . the improvement in vitamin d nutrition is reflected by the mean serum 25-ohd of 37.2 ng / ml in our patients . the frequency of specific radiological manifestations of phpt in the united states declined from 23% in the 1960s to a remarkably low 2% in the 1990s . the difference in the severity of skeletal disease in phpt between western and eastern populations is determined by calcium and vitamin d nutrition , but additional factors also play a role . previous data from india report that 1213% patients with phpt have pancreatitis . in our series , the mechanisms of phpt induced pancreatitis include hypercalcemia - induced activation of trypsinogen to trypsin , ductal obstruction due to pancreatic calculi , and finally genetic risk factors . all our patients had hypercalcemia and their mean serum calcium level was 12.5 mg / dl , which is remarkably similar to that reported by other indian studies . a previous indian study has reported hypophosphatemia in 65% patients with phpt , but another indian study has reported a normal mean serum phosphorus in phpt patients . the mean serum ipth level in our patients was 377.6 pg / ml , which is lower than that reported by previous indian studies . elevated alp has been consistently reported by other indian series due to high prevalence of bone disease in phpt patients . the mean parathyroid weight ( 2.05  3.03 g ) in our study is markedly lower than that reported by other indian studies [ table 3 ] . we found a strong correlation of parathyroid gland weight with serum calcium and ipth , as has been reported previously . the mean serum 25-ohd ( 37.2  58.1 ng / ml ) in our study was higher than that reported by previous indian studies ; however , vitamin d deficiency was present in 38% of our patients . an inverse correlation between serum 25-ohd concentration and parathyroid gland weight has been reported previously . we did not find any correlation between vitamin d status and biochemical parameters ( serum calcium and ipth ) or adenoma weight . the likely reason is the possibility of prior vitamin d treatment and uncertainty about its timing and amount , which could have confounded the 25-ohd measurements at the time of presentation . in addition , vitamin d may not be the only significant factor in the development of bone disease in phpt patients , other factors could be playing a significant role . the preoperative localization of an abnormal parathyroid gland can reduce operative time , postoperative morbidity , and the need for repeat surgery . the imaging methods for localization include high - resolution usg , tc sestamibi scan , computerized tomography , and magnetic resonance imaging . the sensitivity of usg to localize the adenoma has been reported as 6577% , whereas the sensitivity of tc sestamibi scan has been reported as 86.9100% . in our series , the sensitivity of usg and tc sestamibi scan for localization of adenoma was 89.8% and 95.3% , respectively . with a sensitivity of 89.8% , we conclude that usg is an effective localization modality as it is inexpensive and is widely available . mishra et al . , in a study of 29 patients reported a cure rate of 100% . previous indian studies have reported postoperative hbs in a large proportion of patients from 24% to 82% . in our study , our results are in agreement with a recent indian study in which postoperative hbs was seen in only four patients ( 8% ) out of fifty . our policy to treat all patients with preoperative serum 25-ohd level < 30 ng / ml with vitamin d is in all probability , responsible for much lower prevalence of postoperative hbs in our series . consistent with the data about recurrent phpt on long - term follow - up revealing recurrence rates of zero to 41.6% , none of the 41 patients in our series on whom follow - up was available for 19 years , had recurrence of phpt . the strengths of our study include its large size and largely prospective nature with about two - thirds ( 62% ) of the subjects evaluated prospectively . lack of data on bone mineral density and for many patients , on vitamin d status are the limitations of the study . in conclusion , our study reflects a changing trend in the clinical profile of phpt in india . there is a shift in the age of presentation of phpt from fourth to fifth decade . renal stone disease is emerging , the most common presentation , whereas overt skeletal disease in the form of fractures and brown tumors is on the decline .