ASSOCIATIONS OF SERUM IONIZED CALCIUM, PHOSPHATE, AND PTH LEVELS WITH TECHNETIUM-99 SESTAMIBI PARATHYROID SPECT/CT SCAN IN PRIMARY

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1 ENDOCRINE PRACTICE Rapid Electronic Article in Press Rapid Electronic Articles in Press are preprinted manuscripts that have been reviewed and accepted for publication, but have yet to be edited, typeset and finalized. This version of the manuscript will be replaced with the final, published version after it has been published in the print edition of the journal. The final, published version may differ from this proof. Original Article EP ASSOCIATIONS OF SERUM IONIZED CALCIUM, PHOSPHATE, AND PTH LEVELS WITH TECHNETIUM-99 SESTAMIBI PARATHYROID SPECT/CT SCAN IN PRIMARY HYPERPARATHYROIDISM. Thanh D. Hoang 1 ; Ami G. Jani 1 ; Vinh Q. Mai 1 ; Francois O. Tuamokumo 2 ; Mohamed K.M. Shakir 1 From: 1 Department of Endocrinology, Walter Reed National Military Medical Center, Bethesda, MD, United States, 20889; 2 Department of Research Programs, Walter Reed National Military Medical Center, Bethesda, MD, United States, Running title: Correlation of biomarkers with parathyroid scan Corresponding Author & reprint request: Dr. Thanh D. Hoang Division of Endocrinology, Walter Reed National Military Medical Center, 8901 Wisconsin Ave, Bethesda, MD thanh.d.hoang.mil@mail.mil

2 *No grant supports the writing of this paper. * Disclosure summary: The views expressed in this poster are those of the authors and do not necessarily reflect the official policy or position of the Department of the Army, Department of the Navy, Department of Defense, nor the U.S. Government. I certify that all individuals who qualify as authors have been listed; each has participated in the conception and design of this work, the analysis of data, the writing of the document, and the approval of the submission of this version; that the document represents valid work; that if we used information derived from another source, we obtained all necessary approvals to use it and made appropriate acknowledgements in the document; and that each takes public responsibility for it. Authors acknowledge that research protocol NNMC received applicable Institutional Review Board review and approval. Key words: Hyperparathyroidism, PTH, ionized calcium, serum phosphate, parathyroid scan

3 ABSTRACT Objective: To evaluate the relationship between various biochemical parameters in patients with PHPT with positive and negative technetium-99 sestamibi parathyroid scans SPECT/CT (Tc scan). Method: Retrospective analysis. Development of a logistic probability model. There were 218 patients with PHPT evaluated. Main outcome measures were serum total calcium, ionized calcium, intact PTH, albumin, alkaline phosphatase, phosphate, 25-hydroxy vitamin D, 1,25- dihydroxy vitamin D, 24-hour urine calcium levels and parathyroid adenoma weight. Results: Individually, using cut-off levels of 6.0 mg/dl for ionized calcium, 3.0 mg/dl for phosphate, and 90 pg/ml for intact PTH, we found that 91.3% (p=0.005), 70.7% (p=0.004) and 87.90% (p=0.023) of the patients had a positive Tc scan with their corresponding strengths of associations in the parentheses. Similar significant association was sustained in multivariate setting for serum ionized calcium (p = 0.015), phosphate (p=0.016) and intact PTH (p=0.028). A logistic probability model was designed to predict the probability of being positive for Tc scan given a set of covariates. Conclusion: There is a significant association between the levels of serum ionized calcium, phosphate, intact PTH, and the positivity of Tc scan. Further studies with larger patient populations are needed.

4 Abbreviations: BMD = Bone mineral density; BMI = body mass index; CT = computed tomography; CV = coefficient variation; DXA = dual-energy x-ray absorptiometry; GE = General Electric; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; MRI = magnetic resonance imaging; MET-PET-CT = C-11 methionine-positron emission tomographycomputed tomography scan; NIH = National Institutes of Health; PPV = positive predictive value; SPECT= single-photon emission computed tomography; Tc scan = technetium-99 sestamibi parathyroid scan. INTRODUCTION Primary hyperparathyroidism (PHPT) is a relatively common disorder of the inappropriate secretion of parathyroid hormone (PTH) from one or more of the parathyroid glands that leads to hypercalcemia. PHPT is often discovered incidentally; the majority of cases arise from a single parathyroid adenoma whereas 15% arise from hyperplastic glands (1). Most of the patients with PHPT are asymptomatic, but many may present with nephrolithiasis, decreased bone mass, or nonspecific symptoms such as weakness, fatigue, neuromuscular dysfunction, cardiovascular effects, and neuropsychiatric problems that may improve after parathyroidectomy. Prior to the advent of the technetium-99 sestamibi parathyroid scan (Tc scan), patients with PHPT underwent surgical bilateral neck exploration to assess all four parathyroid glands, which can be a long and tedious surgical procedure. The Tc scan was introduced in the early

5 1990s and has become a popular preoperative test to localize the parathyroid adenoma with the reported sensitivity of % and the positive predictive value of % (2, 3). Presently there are no well-established biochemical markers to predict the probability of a positive Tc scan in patients with PHPT. The objective of the study was to evaluate the relationship between various biochemical parameters in patients with positive and negative Tc scans. METHODS This study is a retrospective analysis of patients who were diagnosed with PHPT and seen at Walter Reed National Military Medical Center (previously National Naval Medical Center), Bethesda, MD, USA over a 14-year period. 265 patients with primary hyperparathyroidism were evaluated from We could not collect sufficient data on 47 patients. Out of these 47 excluded patients, 15 had recurrent disease. The diagnostic criteria for primary hyperparathyroidism are (a) elevated serum PTH level with elevated serum calcium level; (b) inappropriately normal PTH level with elevated serum calcium level; (c) elevated PTH level with normal calcium level; (d) calcium/cr clearance ratio >0.02. The intraoperative serum PTH was started in 2000 and this was performed in all patients who underwent surgery. A drop of > 50% PTH level intraoperatively suggested a successful removal of parathyroid adenoma. Exclusion criteria included persistent or recurrent disease after a prior neck exploration. Patients were divided into two groups: positive Tc scan (those with localized parathyroid adenoma) and negative Tc scan group (those with no localized parathyroid adenoma). During the study period, all imaging studies were performed with a Siemens singleheaded gamma camera (Trionix Biad, Twinsburg, OH) between The sensitivity and

6 specificity for this camera were 71% and 79%, respectively. Since 2006, Symbia T6 SPECT/CT (Siemens Medical Solutions, Hoffman Estates, IL) was used for parathyroid scanning with the sensitivity of 87% and specificity of 99%. Since 2016, we added GE Optima 640 SPECT/CT (GE Healthcare, Waukesha, WI) with the sensitivity of 82% and specificity of 78%. However, it is to be noted that the sensitivity for Tc scan with all these cameras is much lower with multiple parathyroid adenomas and hypercellular glands. Out of 218 patients, 30 patients were scanned with the Siemens camera and the remaining 188 patients were studied with the GE Optima and Symbia T6 SPECT/CT. The blood samples were drawn in a fasting state between a.m. in the morning because of the diurnal variation of serum PTH and calcium (4). Additionally, consumption of high phosphate containing foods may affect serum phosphate level (5). Laboratory data were analyzed by Quest Laboratory, including serum total calcium (corrected for albumin), ionized calcium, intact PTH, albumin, alkaline phosphatase, phosphate, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, magnesium, and 24-hour urine calcium levels. Parathyroid adenoma weight and histology were performed by the Pathology Department of Walter Reed National Military Medical Center. The intra-assay coefficient variation (C.V.) for ionized calcium was 2.02% and the inter-assay C.V. was 5.05%. The intra-assay C.V. for serum total calcium was 2.70% and inter-assay C.V. was 2.80%. Similar values for PTH were 2.82% and 4.81%, respectively. Serum intact PTH levels were determined by immunoradiometric assay (Quest Laboratory, San Juan Capistrano, CA). All patients underwent preoperative diagnostic imaging of the parathyroid glands by utilizing Tc scan with or without neck ultrasonography. In some patients, computed tomography (CT) and magnetic resonance imaging (MRI) of the parathyroid glands were also performed at the discretion of the treating physicians. Scintigraphy was performed with the use of a gamma

7 camera after injection of 15 to 20 mci of 99mTc-Sestamibi. The preoperative Tc scan was considered positive if the report revealed an adenoma localization. When ultrasonography of the neck was performed, it was done with an HDI-5000 ultrasound machine (ATL, Seattle, WA). CT scanning and MRI were performed by using a GE Highspeed CT scanner (General Electric, Milwaukee, WI) and a GE Horizon MRI scanner (General Electric, Milwaukee, WI), respectively. BMD measurement was performed with the use of either a Hologic QDR 2000 (Hologic, Waltham, MA) or a Norland XR-26 Mark II (Norland, Fort Atkinson, WI) dual-energy x-ray absorptiometry bone densitometer (DXA). Parathyroid surgery was performed based on criteria for parathyroidectomy (NIH criteria published in 2004) and patient preference in both Tc scan positive and Tc scan negative groups (6). DATA ANALYSIS Statistical analysis was performed to determine if there are any differences or associations between each of the aforementioned variables and Tc scan (positive/negative), using either the Wilcoxon rank sum test for the numerical variables or the Fisher s exact for the categorical variables. Several cut-off points for ionized calcium, phosphate and intact PTH levels were tested for associations with Tc scan positivity. Three variables, serum ionized calcium (cut-off point 6.0 mg/dl), phosphate (cut-off point 3.0 mg/dl), and intact parathyroid levels (cut-off point 90 pg/ml) that showed significant associations with Tc scan positivity at their cut-off points were used in a binary logistic regression model to determine if their significances were sustained in the multivariate setting. Subsequently, a multivariate logistic regression model was fitted to the data using these variables for predictive interest. The following logistic probability model was used

8 , where is the probability of being positive for Tc scan for a given set of covariates. The estimated parameters of the model are: Thus, for an individual whose serum phosphate level is less than 3.0 mg/dl (that is, x1 = 1), serum intact parathyroid level is higher than 90 pg/ml (that is, x2 = 1), and serum ionized calcium is greater than 6.0 mg/dl (that is, x3 = 1), there is a 93.2% chance (probability) of observing a positive scan. RESULTS There were 218 patients with PHPT in the study whose age ranged from 22 to 91 years with a 1.95:1 female-to-male ratio (Table 1), 138 patients with positive Tc scans (63.8% female, 36.2 % male); and 80 patients with negative Tc scans (30% male, 70 % female). Out of those patients who underwent parathyroid surgery, 113 had adenoma, 16 had hypercellular gland, one with parathyroid cancer, and one with multiglandular disease. Those with positive Tc scans were found to have higher parathyroid adenoma weight (mean = 569 mg) compared to those with negative Tc scan (mean =140 mg). The average values for serum total calcium, ionized calcium, phosphate and PTH levels were ± 0.54 mg/dl, 6.13 ± 0.42 mg/dl, 2.58 ± 0.58 mg/dl, and ± pg/ml, respectively, for the positive Tc scan group and ± 0.75 mg/dl, 5.99 ± 0.57 mg/dl, 2.82 ± 0.68 mg/dl, and ± pg/ml, respectively, for the negative Tc scan group (Table 2). Of all the biomarkers evaluated, only three (serum ionized calcium, phosphate, and intact PTH levels) were found to significantly correlate with parathyroid

9 scan positivity. The cut-off levels for ionized serum calcium were arbitrarily determined with the range from lowest to highest values ( mg/dl) with a good sensitivity (Table 3). For serum phosphate, the cut-off level was also arbitrarily chosen with the range from mg/dl. Values of 2.5 and 3.0 mg/dl were significant when correlating with positive Tc scan. Serum phosphate levels of 2.0 and 1.5 mg/dl did not show any significant correlation and we cannot explain the lack of correlation. It is possible the relatively small number of patients with these serum phosphate levels may be responsible for this discrepancy. Other biomarkers such as alkaline phosphatase, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, 24-hour urinary calcium, magnesium, and albumin were not significant. There were 7 patients with normocalcemic hyperparathyroidism. Out of these 7 patients, 3 underwent surgery (pathology confirmed parathyroid adenoma in all of them). The surgery was performed in the 3 patients because of patient preference and other criteria. In this study, 206 patients had neck ultrasound performed. All of these patients have normal thyroid function tests and 35 patients had benign thyroid nodules. In this group, neck ultrasound revealed parathyroid adenoma in 88 patients and did not localize parathyroid adenoma in 118 patients. The maximum cut-off point for serum ionized calcium at which an association was established was 6.7 mg/dl, with a corresponding p-value of At a cut-off point of 6.8 mg/dl, the p-value became 0.335, indicating no association. Using a cut-off level of 6.6 mg/dl for serum ionized calcium, 91% of the patients had a positive Tc scan (Table 3). For serum phosphate levels, the minimum cut-off point at which an association was established was 2.5 mg/dl, with a p-value of (Table 3). There is about two times more probability for positive Tc scan for an individual whose serum phosphate is at 2.5 mg/dl. For serum intact PTH levels,

10 at a cut-off point of 90 pg/ml, an association (p-value = 0.023) between serum intact PTH level and Tc scan positivity was observed (Table 3). There is approximately 7 times the likelihood of detecting a positive Tc scan for an individual whose serum intact PTH level is at least 90 pg/l or greater compared to an individual with PTH less than 90 pg/ml. These three variables, serum ionized calcium (cut-off point 6.0 mg/dl), phosphate (cut-off point 3.0 mg/dl), and intact PTH level (cut-off point 90 pg/ml) that showed significant associations at their cut-off points with Tc scan positivity also showed sustained significance in multivariate setting using the binary logistic regression model (Table 4). Age and gender did not affect the true positive rates of the Tc scan. In the positive Tc scan group (138 patients) (Figure 1): Of the 103 patients who had surgery, 91 patients were confirmed to have a single adenoma and 12 with hypercellular gland. There were 39 patients with nephrolithiasis. Dual-energy X-ray absorptiometry (DXA) showed normal findings in 42 patients, osteopenia in 59 patients, osteoporosis in 31 patients. Six patients did not have DXA scan performed. Thyroid ultrasound was positive for parathyroid adenoma in 65 patients, negative for 67 patients and not done in 6 patients with positive parathyroid scan. In the negative Tc scan group (80 patients) (Figure 1): Out of 28 patients who underwent parathyroidectomy, there were 22 patients with a parathyroid adenoma, 4 with hypercellular gland, 1 with a parathyroid carcinoma, and 1 with multiglandular disease. There were 17 patients with history of nephrolithiasis. DXA showed 23 patients with normal scan, 28 with osteopenia, 25 with osteoporosis; and 4 patients did not have DEXA scan

11 performed. Thyroid ultrasound was positive for parathyroid adenoma in 23 patients, negative in 51 patients, and not done in 6 patients. Obese vs non-obese patients with primary hyperparathyroidism: There were 129 non-obese patients (59.17%) (BMI <30 kg/m 2 ) and 89 obese patients (40.83%) (BMI>30 kg/m 2 ). For the non-obese patients, 77 had positive Tc scan (59.7%) and 52 with negative Tc scan (40.3%). For the obese patients, there were 61 patients with positive Tc scan (68.5%) and 28 with negative Tc scan (31.5%). For the non-obese patients who underwent surgery, there were 66 parathyroid adenomas, 1 parathyroid cancer, and 9 hypercellular gland. For the obese patients who underwent surgery, there were 54 parathyroid adenomas and 4 hypercellular parathyroid cases (7,8). DISCUSSION Our retrospective study demonstrates that the serum ionized calcium, intact PTH, and phosphate levels may be useful to predict the likelihood of localization on Tc scan. Other biomarkers such as alkaline phosphatase, 25-hydroxy vitamin D, 1, 25-dihydroxy vitamin D, 24- hour urinary calcium, magnesium, and parathyroid adenoma weight were not predictive in determining likelihood of detection of parathyroid adenoma on scintigraphy. Age and gender also had no effect on predicting localization. Preoperatively, the patient with parathyroid cancer presented with the same features like a parathyroid adenoma and because of this, we wanted to include it in the analysis. The parathyroid cancer was diagnosed postoperatively by histology. In this patient, serum PTH and serum calcium were moderately elevated, similar to that seen in a parathyroid adenoma.

12 There are limited number of studies that have correlated serum calcium levels with the parathyroid localization on Tc scans (9,10). One study reported a strong correlation of greater than 95% with Tc scan positivity when serum total calcium level is greater than 11.3 mg/dl (9). Another study reported decreased localization when serum total calcium level was less than mg/dl (10). However, correlation of serum ionized calcium levels with Tc scan was not reported in these studies. It was found that serum total calcium frequently does not correlate with serum ionized calcium in classifying calcium status and measurement of serum ionized calcium is recommended to accurately evaluate the calcium states (11). Our study found that lower serum total calcium levels correlate with decreased sensitivity on Tc scan and that serum ionized calcium level is a useful predictor of Tc scan positivity. In our study, a serum ionized calcium level of 6.6 mg/dl predicted a 91% probability of a positive Tc scan (p=0.005). We also observed that there is approximately five times the chance of positive Tc scan in patients whose serum ionized calcium level is above 6.0 mg/dl relative to those below 6.0 mg/dl. Interestingly, serum total corrected calcium levels were elevated in Tc scan positive patients (11.27 ± 0.54) compared to Tc scan negative patients (11.10 ± 0.75), but it was not statistically significant. Unlike other previous studies in which PTH levels did not correlate with diagnostic sensitivity (9,12), we found a relationship between serum intact PTH levels and positive Tc scans. We observed that there was about two times (the odds ratio) the chance of detecting a positive Tc scan in an individual whose serum intact PTH level is above 90 pg/ml relative to an individual with intact PTH below 90 pg/ml. Mean serum intact PTH levels in both positive and negative scans were ± pg/ml and ± pg/ml, respectively (p=0.032). Interestingly, correlation between serum intact PTH level and localization of parathyroid adenoma on Tc scan has been mixed and the reason for this mixed correlation is not clear (12-

13 15). It was apparent that high PTH levels (mean of 508 pg/ml) reported high sensitivity but at lower levels the data seemed mixed (12). Chiavistelli et al. theorized that the mixed results at lower PTH values may be due to the pulsatile nature of PTH secretion over a 24-hour period (16); whereas serum total and ionized calcium levels may be more stable. Timing of blood draws may have an impact on peak vs nadir PTH values (4,16); and in our study all blood samples were drawn between a.m. in a fasting state. Serum phosphate levels may be decreased or low normal in patients with primary hyperparathyroidism. The mean phosphate level for our total patient population was 2.7 mg/dl, with a range of mg/dL (reference range: mg/dl). In our study, we found phosphate levels to have significant association with positive Tc scan at a cut-off point of 3.0 mg/dl both individually (p=0.004) and in multivariate setting (p=0.016) along with serum ionized calcium and PTH levels. Few studies have investigated serum phosphate levels in positive and negative Tc scan group. Although, it has been found that phosphate levels were low in patients with positive scan, the data on its significance has been mixed (17,18). In our study, we found similar but significant results with average phosphate levels of 2.58±0.58 mg/dl in positive parathyroid group and 2.82±0.68 in those with negative scan with p-value of It is interesting that there was no significant association of positive Tc scan at serum phosphate levels less than 2.5 mg/dl since we expect severe PHPT is usually associated with low serum phosphate levels due to phosphaturic effect of PTH. The possible explanation for this finding may be due to limited role of phosphate in cellular uptake and wash out mechanism of Tc scan (18). Recently it has been reported that other imaging modalities or a combination of various imaging modalities can increase the sensitivity of parathyroid localization over Tc scan (19). In cases of normocalcemic or mild hypercalcemic hyperparathyroidism with levels below the serum

14 ionized calcium cutoff of 6.0 mg/dl, we recommend additional imaging studies such as ultrasound or 4D CT scan in conjunction with Tc scan if additional localization studies are pursued. Cheung et al. reported Tc scan (sensitivity 71-79%, PPV 72-95%) and single-photon emission computed tomography (SPECT) (sensitivity of 79-81%, PPV 91-95%) (20). SPECT for parathyroid adenoma localization increased the detection rate compared to planar imaging as demonstrated in one study (21). In the present study, the sensitivity and specificity for the Tc scan range from 71-87% and 78-99%, respectively. Other imaging modalities such as ultrasound (sensitivity 64-91%, PPV 83-96%), 4D-CT (sensitivity 70-81%, PPV 88-99%) and C-11 methionine-positron emission tomography-computed tomography (MET-PET-CT) scan (sensitivity 79-90%, PPV93-94%) should also be considered to improve detection rates in patient with low ionized calcium levels (20, 22, 23). Limitations of our study include an overall small cohort and the retrospective nature of the study. Generally, younger patients will likely have normal BMD compared with older subjects, despite significant hyperparathyroidism. We did not control for image acquisition and processing techniques which may have influenced parathyroid optimization and scan sensitivity in our patients. Further studies with larger patient populations may elucidate predictive factors in determining parathyroid localization. Ultimately, we conclude that all patients should undergo testing for serum ionized calcium, intact PTH, and phosphate levels which may be beneficial in determining the likelihood of parathyroid adenoma localization, using our logistic probability model. REFERENCES

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19 Number of Patients Entire Patient Population (n=218) Positive Tc Scan (n=138) Negative Tc Scan (n = 80) Figure 1. Comparison of clinical characteristics of entire population with positive and negative Technetium-99 sestamibi parathyroid (Tc) scan groups. DXA dual energy absorptiometry; ultrasound, positive for parathyroid adenoma; parathyroid adenoma; hypercellular parathyroid gland.

20 Table 1: Clinical characteristics of the entire patient population Clinical Characteristics Mean (Range) Age (years) 61 (22-91) Serum total calcium ( mg/dl) 11.2 ( ) Serum phosphate ( mg/dl) 2.7 ( ) Serum intact PTH (15-65 pg/ml) 173 ( ) Serum ionized calcium ( mg/dl) 6.1 ( ) 24hr urine calcium ( mg) 322 (24-945) Serum magnesium ( mg/dl) 2.2 ( ) 25-OH vitamin D ( ng/ml) 42.9 ( ) 1, 25 (OH) 2 vitamin D (20-80 pg/ml) 73 (6-588) Serum albumin ( g/dl) 4.5 ( ) Serum alkaline phosphate ( U/L) 109 (46-591) *Data are given as mean (range). The reference values are given in parenthesis. Abbreviations: PTH: parathyroid hormone 25-OH vitamin D: 25-hydroxy vitamin D 1,25 (OH)2 vitamin D: 1,25-dihydroxy vitamin D Tc scan: Technetium-99 sestamibi parathyroid scan

21 Table 2: Various biomarkers in the positive and negative-tc scan groups. Clinical Characteristics Positive Tc Scan (n=138) Negative Tc Scan (n = 80) P-value Serum total calcium, mg/dl 11.27± ± Serum phosphate, mg/dl 2.58± ± Serum intact PTH, pg/ml ± ± Serum ionized calcium mg/dl 6.13± ± hr urine calcium, mg ± ± Serum magnesium, mg/dl 2.24± ± OH vitamin D, ng/ml 42.58± ± , 25 (OH) 2 vitamin D, pg/ml 74.26± ± Serum albumin, g/dl 4.44± ± Serum alkaline phosphate, IU/L ± ± * Mean values of various biomarkers in both positive and negative Tc scan groups. Three biomarkers (serum ionized calcium, phosphate, and intact PTH levels) showed significant association with parathyroid scan. Abbreviations: PTH: parathyroid hormone 25-OH vitamin D: 25-hydroxy vitamin D 1,25 (OH)2 vitamin D: 1,25-dihydroxy vitamin D Tc scan: Technetium-99 sestamibi parathyroid scan

22 Table 3: Association of various cut-off points for serum ionized calcium, phosphate and intact PTH with Tc scan positivity and its statistical significance. Cut-off point Tc scan positivity P-value Odds ratio Serum ionized calcium(mg/dl) % Serum phosphate (mg/dl) % % Serum intact PTH (pg/l) % % *Association of various cut-off points for serum ionized calcium, phosphate, and intact PTH levels with Tc scan positivity. At serum ionized calcium level of 6.6 mg/dl, there was a 91.3% probability of positive Tc scan (p-value = 0.005, OR 6.7). At serum phosphate level of 2.5 mg/dl, there was a 72.6% probability of positive Tc scan (p-value = 0.024, OR 2). At serum intact PTH level of 90 pg/l, there was a 87.9% probability of positive Tc scan (p-value = 0.023, OR 2.33). Abbreviations: PTH: parathyroid hormone 25-OH vitamin D: 25-hydroxy vitamin D 1,25 (OH) 2 vitamin D: 1,25-dihydroxy vitamin D Tc scan: Technetium-99 sestamibi parathyroid scan

23 Table 4: Statistical significance of independent variables in multivariate setting Independent variable P-value Serum ionized calcium Serum intact parathyroid hormone Serum phosphate *Sustained significance of three variables, serum ionized calcium (cut-off point 6.0 mg/dl), phosphate (cut-off point 3.0 mg/dl), and intact parathyroid levels (cut-off point 90 pg/ml) in the multivariate setting using a binary logistic regression model.