Intra-operative parathyroid hormone kinetics and influencing factors with high baseline PTH: a prospective study

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1 Clinical Endocrinology (2013) 78, doi: /cen ORIGINAL ARTICLE Intra-operative parathyroid hormone kinetics and influencing factors with high baseline PTH: a prospective study Dependra N. Singh*,1, Sushil K. Gupta, Gyan Chand*, Anjali Mishra*, Gaurav Agarwal*, Ashok Kumar Verma*, Saroj Kanta Mishra*, Manoj Shukla and Amit Agarwal*,1 *Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences and Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India Summary Background and objective Intra-operative parathyroid hormone (IOPTH) kinetics and therefore the efficacy of IOPTH utilization as a predictor of cure are likely to be affected by baseline IOPTH levels, vitamin D deficiency and parathyroid weight. Patients and methods Consecutive subjects with primary hyperparathyroidism (PHPT, n = 51) undergoing parathyroidectomy with IOPTH monitoring were studied prospectively during the period October 2009 November Samples were collected pre-incision, pre-excision and post-excision (5, 10, 15 min). Iterative analysis of IOPTH kinetics and half-life calculation was carried out in subgroups. Nonparametric testing was used for group statistics. Results Hypovitaminosis D (25(OH)D 3 < 50 nm) was present in 39 (76%), serum PTH > 1000 ng/l in 23 (45%), and giant parathyroid adenoma (weight > 3000 mg) in 23 (45%). The percentage drop at 10 min was significantly higher in large adenomas (weight > 3000 mg). Miami and 5 min criteria showed the highest negative predictive value and maximum accuracy. The average percentage IOPTH drop observed at 5 min postexcision was 798%. Kinetic analysis showed a mean half-life of PTH of 257 ± 027 min (range: ). Conclusion IOPTH monitoring is reliable even in patients with extremely high baseline IOPTH value, with a greater percentage drop at 5 and 10 min post-excision. In patients with high baseline IOPTH, a 50% decay in PTH value at 5 min may be indicative of cure, obviating the need for 10 and 15 min samples. IOPTH kinetics are altered by adenoma weight but not affected by vitamin D status or baseline IOPTH levels. (Received 30 April 2012; returned for revision 25 May 2012; finally revised 27 September 2012; accepted 3 October 2012) Correspondence: Dr Amit Agarwal, Professor, Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow , India. Tel.: ; Fax: +91 (0522) , ; amitsgpgi@rediffmail.com 1 A. A and D. N. S. contributed equally to this manuscript. Introduction Intra-operative parathyroid hormone (IOPTH) monitoring is currently a well-established surgical adjunct to parathyroidectomy and enables a focused approach with small incision and short hospital stay. Many different variations in data interpretation criteria exist, but a fall to below 50% of the baseline value by 10 min after adenoma excision is considered to reflect biochemical cure, and this criterion (Miami criterion 1 ) is widely used. However, the definition of this baseline seems vague, especially as plasma PTH is markedly influenced by surgical manipulation during excision of the affected gland(s). In addition, the recommendation does not account for interindividual variability of PTH half-life and residual concentration. 2 There is limited information about the kinetics of PTH in vivo. IOPTH dynamics and kinetics in patients with high baseline IOPTH and vitamin D deficiency have not been clearly elucidated. 3 6 Vitamin D deficiency provides a stimulus for continued PTH secretion, could cause continued inappropriate PTH elevation intra-operatively and may be responsible for persistently high PTH levels even after removal of an offending adenoma. 7 Similarly, the parathyroid tumour weight may also influence IOPTH decay. 8 The purpose of this study is to see whether hypovitaminosis D, adenoma weight or extremely high PTH levels influence the IOPTH kinetics and therefore the efficacy of IOPTH utilization as a predictor of cure using a number of previously validated criteria. Materials and methods This is a single centre prospective study of 51 consecutive patients with a confirmed diagnosis of primary hyperparathyroidism (PHPT) and subjected to parathyroidectomy with IOPTH monitoring between October 2009 and November All patients with a diagnosis of parathyroid carcinoma were excluded from the study. The study protocol was approved by the Institute Ethics Committee. All patients gave informed consent for surgery and IOPTH monitoring. The diagnosis of PHPT was confirmed by serum calcium (albumin corrected) above 275 mm with high or inappropriately high 935

2 936 D. N. Singh et al. serum PTH (Immunoradiometric assay; Diasorin, Stillwater, MN, USA). Serum 25(OH)D 3 estimation was performed at baseline in all patients using a radioimmunoassay (RIA) kit (Diasorin). Hypovitaminosis D was classified as per Lips criteria: insufficiency (50 75 nm), deficiency (25 50 nm) and severe deficiency (<25 nm). For surgical planning, all subjects with confirmed PHPT underwent both anatomical (high-resolution ultrasound neck by linear 12 MHz transducer) and functional ( 99m Tc-sestamibi scans with single photon emission computed tomography) localization studies. Subjects with concordant imaging were subjected to focused parathyroidectomy or unilateral exploration with a 2 25 cm incision, whereas those with discordant imaging underwent bilateral exploration. Irrespective of surgical approach, whole blood was collected in EDTA-containing vacutainer tubes (4 ml; Becton Dickinson India Pvt. Ltd, Haryana, India) from a wide peripheral vein or femoral vein line before skin incision (preoperative baseline concentration), at the time of adenoma excision (pre-excision), and three more samples thereafter at intervals of 5 min (5, 10 and 15 min). We utilized a centralized laboratory for IOPTH estimation using the IM- MULITE and IMMULITE 1000 system Turbo Intact PTH automated analyzer (Diagnostics Products Corp., Los Angeles, CA, USA) based on a solid phase two site chemiluminescent enzyme labelled immunometric assay according to the manufacturer s specifications. The sensitivity of this assay was 40 ng/l with a calibration range up to 2500 ng/l. The interassay coefficient of variation was <96% and the intra-assay variation <12%. Results were usually made available to the surgical team within min, and only thereafter were patients extubated. The primary endpoints were (i) perioperative success of parathyroidectomy as judged by reduction in IOPTH levels (at least 50% within 10 min after adenoma excision) related to the baseline IOPTH (Miami criteria) and (ii) cure of PHPT as defined by persistent eucalcaemia at 6 months after surgery irrespective of postoperative PTH level. The IOPTH data of these patients were retrospectively reanalysed and subjected to the following validated criteria. Criteria 1 (Miami Criteria): More than 50% drop from the highest either pre-incision or pre-excision levels 10 min after the excision of all abnormal parathyroid gland(s). 1 Criteria 2 (Vienna Criteria): More than 50% drop from preincision level only (disregarding pre-excision level) 10 min after parathyroid gland excision. 9 Criteria 3: More than 50% drop from the highest either preincision or pre-excision level 10 min after parathyroid excision with the requirement that IOPTH return to a normal range. 10 Criteria 4: More than 50% drop from the highest pre-incision or pre-excision values 10 min after excision and falling below the pre-incision IOPTH level. 11 Criteria 5: More than 50% drop from the highest either preincision or pre-excision values 5 min after tumour excision. 12,13 Criteria 6: More than 50% drop from pre-excision level only 10 min after gland removal. 14 Criteria 7 (Halle Criteria): IOPTH decay into the low normal range ( 35 ng/l) within 15 min after removal of the hyperfunctioning parathyroid tissue predicts cure. 9 Criteria 8 (Residual Criteria by Libutti et al. 2 ): Residual criterion is calculated as the residual PTH concentration divided by baseline IOPTH (preexcision) and expressed as a percentage. Standard definitions regarding IOPTH test performance including true positive (TP), false positive (FP), true negative (TN) and false negative (FN) were used as published previously. 15 The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of the above criteria were calculated as: sensitivity = (TP/TP + FN), specificity = (TN/TN + FP), PPV = (TP/TP + FP), NPV = (TN/ TN + FN) and overall accuracy as (TP + TN/TP + TN + FP + FN). IOPTH kinetics was assessed in subgroups: Baseline IOPTH [very high (>1000 ng/l), high (> ng/l), low ( 500 ng/l)]. Serum 25(OH)D 3 levels [vitamin D deficient is defined as 25(OH)D 3 <50nM, sufficient 25(OH)D 3 50 nm]. Tumour weight [giant tumour (weight > 3000 mg), large tumour (weight mg) and small tumour (weight < 1000 mg)]. IOPTH half-life and the residual concentrations were calculated by use of Microsoft Excel. We used kinetic analysis as published by Libutti et al. 2 and describe relief of the total suppressed PTH secretion from healthy glands after affected gland excision. Statistical analysis The statistical analyses were carried out using the SPSS 16.0 software program (SPSS Inc, Chicago, IL, USA) employing nonparametric test (Mann Whitney test and Kruskal Wallis Test) for group statistics and correlation was significant when P < 005. Results The demographic and clinical profile of the subjects is given in Table 1. Eight patients (15%) were below 30 years. Crippling bone disease and a history of pancreatitis was present in 27% (n = 14) and 196% (n = 10) of patients, respectively. Biochemical and densitometric profile of PHPT patients is given in Table 1. Severe hypercalcaemia [serum calcium (albumin corrected) >35 mm] was present in 156% (n = 8) of subjects. Vitamin D deficiency [25(OH)D 3 < 50 nm] was present in about 764% patients (n = 39), while severe vitamin D deficiency [25(OH)D 3 < 25 nm] was present in 392% (n = 20) subjects. Of 647% patients (n = 33) had extremely high levels of PTH (>500 ng/l) and out of these 70% (n = 23) had PTH levels more than 1000 ng/l. All subjects underwent surgical exploration for parathyroid adenoma the surgical approaches were as follows: focused parathyroidectomy in 50% (n = 26), bilateral neck exploration in 35% (n = 18), unilateral neck exploration in 98% (n = 5)

3 Intra-operative PTH kinetics 937 Table 1. The demographic, clinical, biochemical and bone density (DXA) data, parathyroid pathology and IOPTH kinetic profile of PHPT patients who underwent parathyroidectomy with IOPTH monitoring 25 (OH)D groups Baseline IOPTH groups Parathyroid weight groups Parameter All patients Deficient (<50 nm) Sufficient ( 50 nm) Very high (>1000 ng/l) High (> ng/l) Low baseline PTH ( 500 ng/l) Giant (>3000 mg) Large ( mg) Small (<1000 mg) Number Age (years) (Mean ± SD) 460 ± ± ± ± ± ± ± ± ± 132 Gender, n (%) Male 17 (33) 13 (33) 4 (33) 7 (30) 3 (30) 7 (39) 11 (48) 2 (17) 4 (25) Female 34 (67) 26 (67) 8 (67) 16 (70) 7 (70) 11 (61) 12 (52) 10 (83) 12 (75) Median duration of symptoms, 36 ± ± ± ± ± ± ± ± ± 118 months ± SE Bone pain, n (%) 36 (70) 26 (66) 10 (83) 18 (78) 7 (70) 11 (61) 17 (74) 7 (58) 12 (75) Crippling bone disease* n (%) 14 (27) 9 (23) 5 (41) 11 (48) 3 (30) 0 (0) 11 (48) 1 (8) 3 (188) Corrected calcium (mm) Mean ± SD 303 ± ± ± ± ± ± ± ± ± 048 S.25 (OH)D3 (nm) Mean ± SE 43 ± ± ± ± ± ± ± ± ±143 S. creatinine (mg/dl) Mean ± SD 97 ± ± ± ± ± ± ± ± ± 71 GFR (MDRD) Mean ± SD 730 ± ± ± ± ± ± ± ± ± 301 (ml/min/173 m 2 ) BMD at distal forearm (T Score) ± SD 39 ± ± ± ± ± ± ± ± ± 12 BMD at hip (T Score) ± SD 23 ± ± ± ± ± ± ± ± ± 14 BMD at Lumber spine (T Score) ± SD 27 ± ± ± ± ± ± ± ± ± 16 Gland weight (mg) ± SE ± ± ± ± ± ± ± ± ± 762 Gland size (cm) ± SD 26 ± ± ± ± ± ± ± ± ± 04 Final residual IOPTH concentration (ng/l) ± SE (P value) % Residual IOPTH (baseline) ± SE (P value) IOPTH half life (minutes) ± SE (P value) 3266 ± ± 734 (057) 279 ± ± 112 (022) 257 ± ± 022 (015) 4004 ± 1511 (057)** 270 ± 74 (022)** 350 ± 090 (015)** 5934 ± 745 (000) 312 ± 40 (073) 236 ± 032 (086) 918 ± 2308 (000) 51 ± 404 (073) 287 ± 102 (086) 1161 ± 406 (000)*** 364 ± 100 (073)*** 266 ± 040 (086)*** 3753 ± 2619 (028) 259 ± 27 (049) 29 ± 048 (026) 1807 ± 1993 (028) 16 ± 305 (049) 232 ± 039 (026) 3660 ± 1292 (028)*** 532 ± 138 (049)*** 216 ± 045 (026)*** *Crippling bone disease is subjects with fractures, bone deformities, osteitis fibrosa cystic. **Calculated by Nonparametric test using (Mann Whitney test). ***Calculated by Nonparametric test using (Kruskal Wallis test). Glomerular filtration rate (GFR) calculated by serum creatinine [measured by isotope dilution mass spectrometry (IDMS)-traceable] using Modification of Diet in Renal Disease (MDRD) study equation, that is, GFR (ml/min/173 m 2 ) = (S cr ) (Age) (0742 if female) 9 (1212 if African American) (conventional units).

4 938 D. N. Singh et al. % IOPTH remaining Baseline Very high (>1000 ng/l) n = 23 High (> ng/l) n = 10 Low ( 500 ng/l) n = 18 Post-excision 5 min Post-excision 10 min Post-excision 15 min Fig. 1 IOPTH Kinetic analysis (percentage decay of IOPTH value) in different groups based on IOPTH baseline value P value at 5-, 10- and 15 min postexcision are 044, 088 and 087 respectively [P value calculated by non-parametric test using (Kruskal Wallis test)]. % IOPTH remaining Baseline s.25 (OH)D3 <50 nmol/l (n = 39) s.25 (OH)D3 50 nmol/l (n = 12) 5 min postexcision 10 min postexcision 15 min postexcision Fig. 2 IOPTH Kinetic analysis (percentage decay of IOPTH value) in different groups based on S.25(OH)D3 levels P value at 5-,10- and 15 min postexcision are 050,084 and 038 respectively [P value calculated by non-parametric test using (Mann 0057hitney test)]. % IOPTH remaining and mediastinal exploration in 4% (n = 2). 92% (n = 47) had a single adenoma, 4% (n = 2) had double adenomas and 4% (n = 2) had hyperplasia. The median weight of resected adenomas was 2800 mg (IQ: ). Of 45% patients (n = 23) had parathyroid tumour weight more than 3000 mg (range mg). Figures 1, 2 and 3 show the impact of baseline IOPTH levels, serum 25(OH)D 3 levels and tumour weight on IOPTH kinetics. The baseline IOPTH was higher than 1000 ng/l in 23 (45%) patients. Baseline IOPTH levels had no impact on percentage drop at 5, 10 and 15 min (Fig. 1). Similarly, vitamin D deficient subjects had similar percentage drops at 5, 10 and 15 min as compared to the sufficient group (Fig. 2). However, subjects with higher adenoma weight (>3000 mg) had a significantly higher percentage drop in IOPTH at 10 min (Fig. 3). The sensitivity, specificity, PPV, NPV and overall accuracy of previously validated IOPTH criteria are shown in Table 2. Criteria 1 (Miami) and criteria 5 were found to be most sensitive (100%) with the highest negative predictive value (100%) and maximum accuracy (98%) of IOPTH monitoring while criteria 6 and 7 (Halle criteria) had highest positive predictive value (100%). Half-life and IOPTH Kinetics The mean half-life for PTH was 257 min (range: min). Iterative analysis was used to calculate the half-life of PTH and showed a similar mean half-life of PTH in the vitamin D sufficient group (vitamin D sufficient: 338 ± 083 vs vitamin D deficient 238 ± 023 min, P = 022) and in patients with parathyroid adenomas (Table 1). Regression analysis found a significant linear relationship between half-life of PTH and serum 25(OH)D 3 level [Y = 0014X (R 2 Linear = 0092, r = 0304, P = 0030)]. A histogram of the half-life calculated by the kinetic algorithm is shown in Fig. 4. As can be seen in Fig. 4, the patient distribution for PTH half-life follows a skewed distribution, with a subset of patients having a relatively long half-life. We did not observe the half-life variability in different baseline IOPTH groups. The percentage drop at 5, 10 and 15 min also had a significant negative linear relationship with serum creatinine (P value 001, 001 and 0003, respectively). The half-life of IOPTH was higher in patients with high serum creatinine compared with those having normal value (284 ± 328 vs 257 ± 154 min, P = 024). The follow-up period ranged from 6 to 30 months. During follow up, two patients were found to have persistent hyperparathyroidism and were re-operated, after which they became eucalcaemic, one patient had a missed double adenoma and the other had 4 gland hyperplasia. All patients were eucalcaemic at minimum of 6 months follow-up. Discussion Giant >3000 mg (n = 23) Large mg (n = 12) Small <1000 mg (n = 16) Baseline Post-excision 5 min Post-excision 10 min Post-excision 15 min Fig. 3 IOPTH Kinetic analysis (percentage decay of IOPTH value) in different groups based on pathological parathyroid weight P value at 5-,10- and 15 min postexcision are 023, 002 and 008 respectively [P value calculated by non-parametric test using (Kruskal Wallis test)]. Primary hyperparathyroidism (PHPT) is caused by a single adenoma in 80% of cases, multiglandular hyperplasia in 10 15%,

5 Intra-operative PTH kinetics 939 Table 2. The sensitivity, specificity, PPV, NPV and overall accuracy of previously validated IOPTH criteria IOPTH criteria Sensitivity (TP/TP + FN) Specificity (TN/TN + FP) % PPV (TP/TP + FP) % NPV (TN/TN + FN) % Overall accuracy (TP + TN/TP + TN + FP + FN) % Criteria 1 (Miami criteria) Criteria 2 (Vienna criteria) Criteria Criteria Criteria 5 (5 min criteria) Criteria Criteria 7 (Halle criteria) Criteria 8 (Residual Criteria by Libutti et al.) PPV, positive predictive value; NPV, negative predictive value; TR, true positive; TN, true negative; FP, false negative; FP, false negative. double adenomas in 2 3% and parathyroid carcinoma in <5% cases. 16 The only definitive treatment is surgical excision of hypersecreting glands. Minimally invasive surgery or focused parathyroidectomy with or without intra-operative parathyroid hormone monitoring is now becoming the standard of care for PHPT patients. Although the rapid PTH assay has been validated 13,17 22 and a 50% decrease in level of PTH measured 10 min after removal of the offending/hypersecreting parathyroid adenoma has been considered indicative of cure, 1 the PTH half-life can vary over a wide range from patient to patient. Further, IOPTH dynamics can be influenced by various factors such as preoperative PTH levels, vitamin D status and adenoma weight etc. 3 8,23,24 Although the reliability of IOPTH monitoring in patients with mild PHPT has been studied, 5 there are no reports of reliability of IOPTH testing in patients with extremely high baseline PTH levels. Thus, we sought to determine the reliability of IOPTH monitoring in patients with extremely high baseline IOPTH levels, vitamin D deficiency and large adenomas. We also studied the effect of these variables on IOPTH elimination kinetics and constructed a kinetic analysis of our IOPTH data. We also sought to determine whether the 50% decay in IOPTH value at 10 min is reliable or necessary in patients with extremely high baseline IOPTH. Baseline IOPTH and IOPTH Kinetics Fig. 4 Histogram of IOPTH elimination kinetics calculated by iterative analysis the mean IOPTH baseline values (ng/l) for the patients in each category are shown in parentheses above each bar. The optimal interpretation of IOPTH data continues to be defined. It has been proposed that IOPTH monitoring may be difficult to interpret in patients with low or extremely high levels of baseline IOPTH. The interpretation of IOPTH monitoring in mild PHPT has been found to be difficult in one series 4 while it has been found to be useful in another. 5 In our study, out of 51 patients, 49 (96%) had baseline IOPTH more than 100 ng/l. When we did subgroup analysis of our patients (baseline IOPTH >1000, and <500 ng/l), we found no significant difference in percentage drop at 5, 10 and 15 min. Also, when we studied the elimination kinetics in these subgroups, we did not find any substantial variation in PTH half-life. This is in contrast to Libutti et al. 2 who demonstrated that patients with high baseline IOPTH had a shorter half-life and conversely that patients with relatively low baseline levels had a longer half-life. However, it should be noted that the mean baseline IOPTH in their series was only 180 ng/l. The average drop in IOPTH level at 5 min post-excision was 798% in our series, in contrast to 51% in a series by Miller et al. 4 and 75% in a series by Untch et al. 7 Vitamin D deficiency and IOPTH Kinetics There are few reports of vitamin D deficiency influencing the IOPTH kinetics. 6,7,23 In the study by Untch et al., 7 the author found that IOPTH decreases more quickly in patients with vitamin D deficiency at 5 min post-resection. The present study found no difference between these groups in rate of IOPTH decay. However, when we did regression analysis between halflife of IOPTH calculated by iterative analysis and serum 25(OH) D 3 level, a significant positive relationship was found (P = 003). Patients with low vitamin D levels were found to a have shorter half-life and vice-versa.

6 940 D. N. Singh et al. Parathyroid weight and IOPTH Kinetics Moretz et al. 8 found a significant correlation between parathyroid adenoma weight and the percentage decrease of IOPTH levels at 10 min compared to baseline (P < 004). We also observed a significantly higher percentage drop in IOPTH at 10 min post-excision in large pathological glands, as observed by others. 8 However, regression analysis in our study group showed a non-significant positive linear relationship between percentage drop at 5, 10 and 15 min post-excision and parathyroid weight with P value of 0250, 0285 and 0248, respectively. Our results are in contrast to the study by Gannagé-Yared et al. 24 who, on multivariate analysis, found age, weight of adenoma and GFR (glomerular filtration rate) as independent negative predictors of the IOPTH fall (P = 001, P = 0018 and P < 0001, respectively). Commonly applied criteria of IOPTH monitoring Various published criteria for IOPTH monitoring including iteration analysis of IOPTH kinetic data 1,2,9 15,24 28 reported variable success rates in predicting cure. When analysing our IOPTH data by various criteria, criterion 1 (Miami) was found to be most sensitive. Criteria 6 and 7 (Halle criteria) had the highest specificity and positive predictive value. The Miami criterion was found to have the highest negative predictive value and also the maximum accuracy of IOPTH monitoring. On applying criterion 2 (Vienna criteria), the false negatives were high and could have lead to unnecessary exploration. In 5 of 51 patients, the pre-excision IOPTH value was more than preincision IOPTH value, probably reflecting the effect of gland handling. 9,27 Using IOPTH criterion 3 (normal limit criterion), the number of false negatives would have increased in our study in contrast to a Mayo Clinic experience published recently with only 36% false-negative results in PHPT patents having mean (SD) baseline IOPTH 278(422) ng/l. 28 Although criterion 3 had a high positive predictive value, the negative predictive value was very low. Similar results were also reported by Chiu B et al. 25 The results of criterion 5 (5 min criterion) were identical to criterion 1(Miami criterion). These 5 min criteria can be well utilized in our country, reducing the number of IOPTH samples from 5 to 3 and therefore cost by about 40% with almost identical long-term results of cure. Libutti et al. 2 suggested a kinetic analysis based on first-order decay of the PTH level. This article is especially important, as it was the first to address the contribution of background or residual PTH secretion by other healthy remaining parathyroid glands. We analysed the IOPTH criteria using iteration base kinetic analysis 2 and calculated the residual PTH after applying the percentage of baseline residual criterion (Criterion 8). We found that false negatives increased from 0 to 568% with identical false positives. Thus, iterative calculation-based IOPTH analysis is not useful in our cases as it significantly increased the false negatives and would have lead to unnecessary explorations. In all of our cured patients, a more than 50% drop was observed at 5 min post-excision. Thus, if the operation would have been terminated at this point of time, all patients would have been cured. Thus, we propose that in patients with high baseline IOPTH values, the decay of PTH is faster; perhaps due to the large adenoma causing profound suppression of PTH secretion by the remaining normal glands. During parathyroidectomy, manipulation of hyper functioning parathyroid tissue can results in increased PTH release and may contribute to false-negative IOPTH monitoring. Conversely, surgical dissection may cause a decrease in PTH levels. We believe that performing both pre-incision and pre-excision PTH measurement will circumvent this problem. Also, during 4-gland exploration, the remaining 3 glands are explored only after the adenoma removal and IOPTH measurement. Five patients had baseline PTH value at the upper limit of the calibration range, that is, 2500 ng/l. However, the percentage drop in these patients would not have been affected by the exact value. Dilution methods to determine the exact value was not performed for logistic reasons. Half-lives and IOPTH Kinetics We calculated the half-lives for each patient assuming that PTH follows first-order elimination kinetics as described by Libutti et al. 2 and found a large variation, with a mean (± SE) half-life of 257 ± 027 min (range: min). A longer half-life of PTH was found in the Vitamin D sufficient group and in patients with a giant pathological parathyroid gland. The IOPTH half-life was found to have significant linear relationship with percentage drop at 5 min (P = 00001), 10 min (P = 0001) and 15 min (P = 0001).This finding was consistent with those observed by Libutti et al. 2 and Gauger et al. 15 We also analysed the impact of renal impairment on IOPTH kinetics since the incidence of renal impairment is likely to be high in symptomatic PHPT. The percentage drops at 5, 10 and 15 min had a significant negative linear relationship with serum creatinine (P value 001, 001 and 0003, respectively). The half-life of PTH was higher in patients with high serum creatinine (>140 lm) compared with those having normal value (284 ± 328 vs 257 ± 154 min, P = 024). Strengths of this study include its prospective nature, the inclusion of subjects with moderate to severely symptomatic PHPT, and large subgroups with vitamin D deficiency and large parathyroid adenomas. Limitations of the study are its small sample size and the small number of minimally symptomatic PHPT patients commonly seen in Western populations. Some negative results may have been related to the study being underpowered. Conclusion IOPTH monitoring is reliable even in patients with extremely high baseline IOPTH values, with greater percentage drops at 5 and 10 min post-excision. In patients with a high baseline IOPTH, a 50% decay in PTH value at 5 min may be indicative of cure in majority of patients, obviating the need for 10 and 15 min samples. IOPTH kinetics is altered by adenoma weight but not affected by vitamin D status or baseline IOPTH levels.

7 Intra-operative PTH kinetics 941 Acknowledgement Study was supported by ICMR financial assistance for MCh prospective project (Ref No: 3/2/010/PG-thesis-MPD6 Dated: ). Conflict of interest We have no conflict of interest. References 1 Carneiro, D.M., Solorzano, C.C., Nader, M.C. et al. (2003) Comparison of intraoperative PTH assay (QPTH) criteria in guiding parathyroidectomy: which criterion is the most accurate? Surgery, 134, ; discussion Libutti, S.K., Alexander, H.R., Bartlett, D.L. et al. (1999) Kinetic analysis of the rapid intraoperative parathyroid hormone assay in patients during operation for hyperparathyroidism. Surgery, 126, ; discussion Kandil, E., Alabbas, H., Tufaro, A.P. et al. (2010) The impact of baseline intact parathyroid hormone levels on severity of primary hyperparathyroidism and outcomes in patients undergoing surgery. Archives of Otolaryngology Head and Neck Surgery, 136, Miller, B.S., England, B.G., Nehs, M. et al. (2006) Interpretation of intraoperative parathyroid hormone monitoring in patients with baseline parathyroid hormone levels of <100 pg/ml. Surgery, 140, ; discussion Alhefdhi, A., Pinchot, S.N., Davis, R. et al. (2011) The necessity and reliability of intraoperative parathyroid hormone (PTH) testing in patients with mild hyperparathyroidism and PTH levels in the normal range. World Journal of Surgery, 35, Adler, J.T., Sippel, R.S. & Chen, H. (2010) 25-hydroxyvitamin D status does not affect intraoperative parathyroid hormone dynamics in patients with primary hyperparathyroidism. Annals of Surgical Oncology, 17, Untch, B.R., Barfield, M.E., Dar, M. et al. (2007) Impact of 25-hydroxyvitamin D deficiency on perioperative parathyroid hormone kinetics and results in patients with primary hyperparathyroidism. Surgery, 142, Moretz, W.H. 3rd, Watts, T.L., Virgin, F.W. Jr et al. (2007) Correlation of intraoperative parathyroid hormone levels with parathyroid gland size. Laryngoscope, 117, Riss, P., Kaczirek, K., Heinz, G. et al. (2007) A defined baseline in PTH monitoring increases surgical success in patients with multiple gland disease. Surgery, 142, Yang, G.P., Levine, S. & Weigel, R.J. (2001) A spike in parathyroid hormone during neck exploration may cause a false-negative intraoperative assay result. Archives of Surgery, 136, Irvin, G.L. 3rd, Molinari, A.S., Figueroa, C. et al. (1999) Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay. Annals of Surgery, 229, ; discussion Udelsman, R., Donovan, P.I. & Sokoll, L.J. (2000) One hundred consecutive minimally invasive parathyroid explorations. Annals of Surgery, 232, Irvin, G.L. 3rd & Deriso, G.T. 3rd (1994) A new, practical intraoperative parathyroid hormone assay. American Journal of Surgery, 168, Weber, C.J. & Ritchie, J.C. (1999) Retrospective analysis of sequential changes in serum intact parathyroid hormone levels during conventional parathyroid exploration. 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