Normal PTH Levels in Primary Hyperparathyroidism: Still the Same Disease?

Transcription

1 Ann Surg Oncol (2011) 18: DOI /s x ORIGINAL ARTICLE ENDOCRINE TUMORS Normal PTH Levels in Primary Hyperparathyroidism: Still the Same Disease? Amanda L. Amin, MD, Tracy S. Wang, MD, MPH, Thomas J. Wade, MD, and Tina W. F. Yen, MD, MS Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI ABSTRACT Purpose. Previous studies have suggested that primary hyperparathyroidism (phpt) with only normal parathyroid hormone (PTH) levels is a milder, less symptomatic form of phpt. This study investigates symptoms, laboratory values, imaging, and outcomes of sporadic phpt patients with normal PTH values. Methods. We reviewed our prospectively collected database of 861 patients with sporadic phpt who underwent parathyroidectomy between December 1999 and June Patients with only normal PTH values for 6 months before surgery were compared to a randomized control group of sporadic phpt patients with elevated PTH, matched 1:2 for age and gender. Results. Fifty-eight (7%) patients had only normal PTH values within 6 months of surgery. The mean PTH was 55.1 pg/ml in the normal PTH group and pg/ml in the control group (n = 116). There was no difference in preoperative calcium values, subjective symptoms, bone health, or the frequency of single-gland disease (SGD; 88% vs. 91%) between the two groups, but the normal PTH group had higher preoperative vitamin D values (30.8 vs ng/ml; P \ 0.001), smaller adenomas (405 vs. 978 mg, P \ 0.001), and more frequently underwent bilateral neck exploration (57% vs. 49%). There was a trend toward lower sensitivity of preoperative imaging in the normal PTH group. Conclusions. Patients with phpt and either elevated or normal PTH levels present with similar symptoms and Poster presentation at the 64th Annual Society of Surgical Oncology Cancer Symposium, San Antonio, TX, March 2 5, Ó Society of Surgical Oncology 2011 First Received: 28 February 2011; Published Online: 3 May 2011 T. W. F. Yen, MD, MS tyen@mcw.edu calcium levels. The majority of patients with normal PTH have SGD, although adenomas are smaller. This may explain why patients with normal PTH values have less sensitive imaging and more frequently require four-gland exploration. Primary hyperparathyroidism (phpt) is a primary neoplastic parathyroid glandular disorder that is classically defined by elevated calcium values with inappropriately elevated parathyroid hormone (PTH) levels. 1 Up to 20% of patients with phpt have a normal PTH level, usually in the setting of other documented elevated PTH levels and more rarely in the setting of only normal PTH levels. 2 A few previous studies have investigated the presentation, pathology, and outcomes of patients with phpt and normal PTH levels, but these studies are relatively small and the preoperative timeframe and number of lab values assessed are not defined (Table 1). 2 5 Furthermore, to our knowledge, there is only one study that defines their cohort as having only normal PTH levels preoperatively, excluding patients who have both elevated and normal PTH values. 5 The patients in these studies typically were symptomatic and had an increased prevalence of multiple gland disease. 2 6 According to the Third International Workshop on primary hyperparathyroidism, surgery is an appropriate treatment for both symptomatic and asymptomatic patients with the classic presentation of phpt (elevated serum calcium values and an inappropriately elevated serum PTH value). 7 However, the management of asymptomatic patients with phpt who have elevated calcium but normal PTH levels remains controversial and is not addressed by the Third International Workshop guidelines. 7 We hypothesize that patients with phpt and no documented elevation in PTH levels have milder disease and therefore are more likely to be asymptomatic, have less severe bone disease, and have nonlocalizing preoperative imaging

2 3438 A. L. Amin et al. TABLE 1 Summary of studies on normal PTH primary hyperparathyroidism Study author (year) Normal PTH definition No. (%) with normal PTH Mean age (years) Symptoms (%) Bone loss (%) SGD (%) Mean gland weight (mg) BNE (%) Cure rate (%) Carneiro-Pla (2007) 3 PTH [30 pg/dl 28 (8%) NA a 71 NA Bergenfelz (2003) 2 Normal PTH 1 day 20 (9%) 53 NA NA NA NA before surgery Mischis-Troussard All ipth within 20 (7%) NA 95 NA NA (2000) 5 normal values Glendenning (1998) 4 One or more normal PTH values 11 (18%) b 72 NA 100 NA BNE bilateral neck exploration, NA not available, PTH parathyroid hormone, SGD single-gland disease a 21% with osteoporosis, osteopenia, or bone pain b 45% with osteoporosis studies. Compared to patients with elevated PTH levels, we hypothesize that these patients are more likely to have multiple gland disease and smaller hyperfunctioning glands and therefore more frequently require bilateral exploration. Using our prospectively collected database of sporadic phpt patients, we explored these hypotheses by comparing patients with only normal PTH levels to those with consistently elevated PTH levels. METHODS This was a single-institution, retrospective case-control study of prospectively collected data from 861 patients with sporadic phpt. All patients underwent initial parathyroidectomy with intraoperative PTH (IOPTH) monitoring between December 1999 and June 2010 by six endocrine surgeons. Patients were included in the study cohort if all PTH levels were within the laboratory s normal range during the 6 months before surgery. Patients with elevated PTH levels at anytime during the 6 months before surgery were excluded. Patients who comprised the normal PTH group were compared to a randomly selected control group of sporadic primary HPT patients with elevated PTH levels who were matched 1:2 for age and gender. Preoperative serum calcium, PTH, and 25-hydroxy vitamin D levels and bone density results were recorded. The majority of the PTH values were obtained at our institution using the Immulite 1000 Turbo Intact PTH system, a two-site chemiluminescent immunometric assay (Diagnostic Products Corporation, Los Angeles, CA). Before September 24, 2002, the normal assay range was pg/ml; since September 24, 2002, the normal assay range has been pg/ml. Data were collected on subjective neurocognitive symptoms, including mood swings and fatigue, self-reported history of nephrolithiasis, and bony fracture. All preoperative imaging results (Sestamibi, ultrasound, and neck CT scans) were categorized as true positive (imaging correctly identified the side of the abnormal parathyroid gland), false negative (negative imaging and at least one abnormal parathyroid gland was found at surgery), or false positive (imaging finding of disease not confirmed at surgery). If the patient had multiple gland disease, each hyperfunctioning gland was individually assessed. For example, if a patient had two glands removed and an imaging study correctly identified one gland but failed to locate the second gland, that imaging study was recorded as both a true positive and a false negative. Surgical approach to parathyroidectomy was defined as minimally invasive (MIP; identifying and removing only one gland), unilateral (both parathyroid glands on one side of the neck were explored with no contralateral exploration), or bilateral (both sides of the neck explored). Final pathology reports were examined for the etiology of the phpt (single gland vs. multiple gland disease) and gland weight. Multiple gland disease was defined by the removal of two or more enlarged glands in which IOPTH criteria (decrease in IOPTH [50% and within the normal range 10 min after gland resection) was not met until two or more glands were removed. Calcium and PTH levels were obtained at the 1 week postoperative visit and requested at 3, 6, and 12 months after surgery. A curative parathyroidectomy was defined as normocalcemia for at least 6 months after surgery. Descriptive statistics (t test, chi-square or Fisher exact test, and z-test for proportions) were utilized to investigate for differences between the study and control groups. The Spearman s correlation coefficient was calculated to determine the association between preoperative PTH level and adenoma weight in all patients with SGD. All statistical analysis was performed with SigmaStat software (Systat Software, Inc., SigmaStat version 3.1; Richmond, CA). Institutional IRB approval was obtained for this study.

3 Normal PTH Primary Hyperparathyroidism 3439 RESULTS Of the 861 patients with sporadic phpt, 166 (19%) had at least one PTH value within the laboratory s normal range during the 6 months before surgery. Of these 166 patients, 108 also had at least one documented elevated PTH value preoperatively and were excluded from the study. Therefore, only 58 (7%) of 861 patients had all PTH levels within the normal range 6 months before surgery. Patients had an average of two PTH levels (range, one to three) drawn 6 months before surgery. The mean age of these 58 patients was 56 years (SD ± 10.2) and the majority (88%) was female. At the time of presentation, 90% were symptomatic (19% nephrolithiasis, 7% fractures, 72% neurocognitive symptoms); 70% of those with bone health information had osteoporosis or osteopenia. The clinical presentation of the normal PTH group was similar to the elevated PTH group (Table 2). Table 3 summarizes the preoperative laboratory values, preoperative imaging results, surgical approach, pathology, operative cure rate, and complications for the two groups. The two groups did not differ in their preoperative calcium values (10.7 vs mg/dl; P = 0.07) or 24-h urinary calcium values (313 mg vs. 364 mg; P = 0.07). In the normal PTH group, 25 (43%) were normocalcemic 6 months before surgery while 32 (28%) of patients were normocalcemic in the elevated PTH group. The normal PTH group had higher preoperative 25-hydroxy vitamin D levels (30.8 vs ng/ml; P \ 0.001) and lower PTH values (55.1 vs pg/ml; P \ 0.001). To evaluate the distribution of the PTH values within the normal PTH group, we divided the patients into quartiles (Table 4). The majority of patients (70%) were in the high normal PTH TABLE 2 Symptom and bone density results for the normal and elevated PTH groups Presenting symptoms Normal PTH group (n = 58) Elevated PTH group (n = 116) Presence of symptoms 0.11 Yes 52 (90%) 112 (97%) No 6 (10%) 4 (3%) Symptoms present 0.95 Nephrolithiasis 11 (19%) 25 (22%) Fracture 4 (7%) 12 (10%) Neurocognitive symptoms 42 (72%) 89 (77%) Bone density a 0.81 Normal 14 (30%) 23 (29%) Osteopenia 22 (58%) 32 (41%) Osteoporosis 10 (22%) 23 (30%) a Bone density results were available in 46 (79%) of the normal PTH group and 78 (67%) of the elevated PTH group P TABLE 3 Preoperative laboratory values, imaging results, surgical approach, and pathology for the normal and elevated PTH groups Variable Normal PTH group (n = 58) Elevated PTH group (n = 116) Laboratory values Preoperative calcium 10.7 (0.6) 10.9 (0.7) 0.07 (mg/dl) a Preoperative PTH 55.1 (12.0) (91.5) \0.001 (pg/ml) a Preoperative 25-OH 30.8 (13.7) 21.4 (11.2) \0.001 vitamin D (ng/ml) a,b Preoperative 24-h urine 313 (145) 364 (144) 0.07 calcium (mg) a,c Imaging studies Sestamibi d Sensitivity 40% 55% 0.09 PPV 92% 98% 0.46 Ultrasound e Sensitivity 52% 63% 0.22 PPV 88% 90% 0.99 Neck CT f Sensitivity 54% 67% 0.81 PPV 100% 67% 0.66 Surgical approach 0.07 MIP/unilateral 27 (43%) 67 (58%) Bilateral 33 (57%) 49 (42%) Pathology g 0.76 SGD 51 (88%) 106 (91%) MGD 6 (10%) 9 (8%) SGD gland weight 405 (393) 978 (1202) \0.001 (mg) a Operative cure h 93% 95% 0.69 Complications 6 (10%) 12 (10%) 0.57 Hypoparathyroidism 5 7 Nerve injury 1 5 MGD multiple gland disease, MIP minimally invasive parathyroidectomy, PPV positive predictive value, PTH parathyroid hormone, SGD single-gland disease a Expressed as mean (SD) b Excludes 75 patients with missing data c Excludes 73 patients with missing data d Total n = 176 studies (62 in normal PTH group and 114 in elevated PTH group) e Total n = 182 studies (62 in normal PTH group and 120 in elevated PTH group) f Total n = 17 studies (13 in normal PTH group and 4 in elevated PTH group) g Excludes 2 patients with missing data h Excludes 47 patients with follow-up \6 months range (51 72 pg/ml). One patient had only a c-terminal PTH value that was in the high normal range. Overall, there was no difference in the sensitivity and positive predictive P

4 3440 A. L. Amin et al. TABLE 4 PTH values divided into quartiles for the 58 patients in the normal PTH cohort PTH range \20 pg/ml pg/ml pg/ml pg/ml No. of patients (%) a 0 4 (7%) 13 (23%) 40 (70%) a Excludes one patient with only c-terminal PTH value value of Sestamibi, ultrasound, or CT scans for localizing disease in patients with normal or elevated PTH levels. There was a trend toward a lower sensitivity of Sestamibi scans in the normal PTH group (40% vs. 55%; P = 0.09). Compared with the elevated PTH control group, the normal PTH group underwent more bilateral neck explorations (57% vs. 42%; P = 0.07) than MIPs (28% vs. 39%) or unilateral explorations (16% vs. 19%), but the trend did not reach statistical significance. IOPTH was used in all cases to guide the extent of surgery. Baseline IOPTH values were obtained in all but one case in the normal PTH group because of a machine malfunction. Thirty (53%) patients in the normal PTH group had elevated baseline IOPTH values. The majority of patients in the normal PTH group with elevated baseline IOPTH had only a modest elevation in baseline IOPTH (mean = 108 pg/ml; median = 90 pg/ml). In the elevated PTH group, 104 (90%) had elevated baseline IOPTH values. The majority of patients in both groups had SGD (88% vs. 91%; P = 0.76). However, when comparing the adenoma weight for patients with SGD, the mean/median gland weight for the normal PTH group was significantly lower (405/270 mg) compared with the elevated PTH group (978/700 mg; P \ 0.001). In the 146 patients with SGD and documented gland weight (45 in normal PTH group and 101 in elevated PTH group), there was a correlation between preoperative PTH level and adenoma weight (r = 0.55, P \ ; Fig. 1). PTH (pg/ml) Gland weight (mg) PTH r = p < FIG. 1 Correlation between preoperative PTH level and adenoma weight in 146 patients with SGD (excludes 10 patients with no gland weight and 1 patient with c-terminal PTH value). PTH parathyroid hormone, SGD single-gland disease Overall, the median follow-up was 10.5 months (range, 1 week 79 months) in the normal PTH group and 10.5 months (range, 1 week 121 months) in the elevated PTH group. Among the 127 patients with 6 months or longer follow-up, the operative cure rate was high in both groups (93% vs. 95%; P = 0.69). In the normal PTH cohort, two patients had elevated PTH levels after at least 6 months of follow-up; both were normocalcemic at last follow-up. In the elevated PTH group, 34 (29%) normocalcemic patients had an elevated PTH value 6 months after surgery. Rates of hypoparathyroidism and recurrent laryngeal nerve injury were similar between the two groups (P = 0.57). DISCUSSION In this single institutional, retrospective, case-control study, 7% of patients with sporadic phpt had only normal PTH levels during the 6 months before surgery. This finding is consistent with a previously published study, which reported a 7.4% rate of patients with phpt who had all normal preoperative PTH levels. 5 Our results show that phpt patients with normal PTH levels do not have a significantly different presentation compared with patients with elevated PTH levels, supporting the concept that the PTH level does not correlate with patient symptoms. 2 The diagnosis of phpt should be considered in all patients with elevated serum calcium levels and inappropriately normal to high-normal PTH values. In our study, the majority of patients in the normal PTH group had serum PTH levels in the high-normal range (mean = 55.1 pg/ml; range, 32 71). Patients in the two groups did not have statistically different preoperative serum calcium values, although patients with normal PTH values did have significantly higher 25-hydroxy vitamin D levels (30.8 vs. 21.4; P \ 0.001). Vitamin D deficiency can occur in patients with phpt because of an accelerated conversion of 25-hydroxy vitamin D into calcitriol or 25-hydroxylated compounds compared with the general population. Vitamin D supplementation can decrease serum PTH concentrations. 8 A possible explanation for our finding that patients with normal PTH levels had higher preoperative 25-hydroxy vitamin D levels is that they were more likely to have been repleted with vitamin D during their workup for phpt to confirm whether they had phpt or a component of secondary HPT due to vitamin D insufficiency. In this study, 16 (28%) patients in the normal PTH group had vitamin D supplementation preoperatively compared with 22 (20%) patients in the elevated PTH group. Although a higher proportion of patients in the normal PTH group received vitamin D supplementation preoperatively, this difference was not statistically significantly (P = 0.27), likely due to the small sample size.

5 Normal PTH Primary Hyperparathyroidism 3441 Calcium supplementation is known to have suppressive effects on PTH values; this finding is confirmed by our study. In the normal PTH group, 11 patients (19%) were taking calcium supplementation. The mean PTH values for those taking calcium supplementation was statistically lower than those not taking supplementation (53.8 vs pg/ml; P \ 0.001). Likewise, for the 12 patients (10%) in the elevated PTH group who were taking calcium supplementation, the PTH was similarly suppressed (119 vs. 156 pg/ml; P \ 0.001). Our patients were not routinely counseled to restrict their calcium intake preoperatively. The majority of our patients underwent multiple imaging modalities to localize hyperfunctioning parathyroid glands preoperatively. All imaging modalities, especially Sestamibi, were less sensitive in the normal PTH group, although the findings were not statistically significant, likely due to small cohort size. We found a direct correlation between preoperative PTH level and adenoma weight in patients with SGD (Fig. 1), confirming the results of previous studies. 4,9 12 In addition, patients in the normal PTH group, as a whole, had significantly smaller adenomas compared with the elevated PTH group (405 mg vs. 978 mg; P \ 0.01), which is consistent with previous studies. 2,5 Smaller gland weight may explain the decreased imaging sensitivity in the normal PTH group. In contrast to other studies, we did not find that patients with normal PTH had a higher incidence of MGD compared with those with elevated PTH levels (10% vs. 8%; P = 0.76). 3,5 Although a MIP or unilateral approach was possible in 43% of patients with normal PTH levels, the majority (57%) underwent a bilateral neck exploration. A more extensive operation may have been required due to the higher rate of preoperative nonlocalization and smaller adenoma weight. Despite the higher proportion of bilateral neck explorations in the normal PTH group, complication rates and cure rates were similar between the two groups. Although there are limitations with any retrospective, single-institution study, our cohort of 58 sporadic phpt patients with normal PTH levels is the largest cohort in the literature to date. 2 5 In addition, our study focused on a select group of patients who had only normal PTH levels (no elevated PTH levels) during the 6 months before surgery. Although the choice of 6 months was arbitrary, we felt it was important to provide a definitive timeframe, because the lack of a defined time period was a limitation in previous studies. In our normal PTH cohort, only 13 (22%) had an elevated PTH value more than 6 months before surgery (range, 7 96 months). Finally, because we conducted a case-control study, matching the normal PTH patients by age and gender to an elevated PTH group, we were able to look for differences in clinical and laboratory presentation, preoperative imaging, surgical approach, and pathology. In conclusion, we have shown that 7% of patients with sporadic phpt have consistently normal PTH levels. Physicians should be aware of the possibility of phpt in patients with hypercalcemia, even if PTH levels are within the normal range. These patients tend to be equally symptomatic compared with patients with the classic biochemical profile of phpt. Surgeons should be aware that the majority of these patients have single-gland disease but that these adenomas tend to be smaller and more difficult to localize on preoperative imaging. Our study s 93% cure rate after surgery in patients with primary hyperparathyroidism and normal PTH levels is consistent with the cure rates quoted in the literature for patients with the classic presentation of phpt Therefore, these patients should be considered for parathyroidectomy, although they may be more likely to require a bilateral neck exploration. Future studies should address the longer term benefits and outcomes of parathyroidectomy in this patient population. CONFLICT OF INTEREST All authors have no commercial interests or financial support to disclose. REFERENCES 1. Younes NA, Shafagoj Y, Khatib F, Ababneh M. Laboratory screening for hyperparathyroidism. Clin Chim Acta. 2005;353: Bergenfelz A, Lindblom P, Lindergard B, Valdemarsson S, Westerdahl J. Preoperative normal level of parathyroid hormone signifies an early and mild form of primary hyperparathyroidism. World J Surg. 2003;27: Carneiro-Pla DM, Irvin GL III, Chen H. Consequences of parathyroidectomy in patients with mild sporadic primary hyperparathyroidism. Surgery. 2007;142:795 9; discussion 799.e Glendenning P, Gutteridge DH, Retallack RW, Stuckey BGA, Kermode DG, Kent GN. High prevalence of normal total calcium and intact PTH in 60 patients with proven primary hyperparathyroidism: a challenge to current diagnostic criteria. Aust N Z J Med. 1998;28: Mischis-Troussard C, Goudet P, Verges B, Cougard P, Tavernier C, Maillefert JF. Primary hyperparathyroidism with normal serum intact parathyroid hormone levels. QJM. 2000;93: Gulcelik NE, Bozkurt F, Tezel GG, Kaynaroglu V, Erbas T. Normal parathyroid hormone levels in a diabetic patient with parathyroid adenoma. Endocrine. 2009;35: Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin MR. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94: Souberbielle JC, Maury E, Friedlander G, Cormier C. Vitamin D and primary hyperparathyroidism (PHPT). J Steroid Biochem Mol Biol. 2010;121: Bartsch D, Nies C, Hasse C, Willuhn J, Rothmund M. Clinical and surgical aspects of double adenoma in patients with primary hyperparathyroidism. Br J Surg. 1995;82: Williams JG, Wheeler MH, Aston JP, Brown RC, Woodhead JS. The relationship between adenoma weight and intact (1 84) parathyroid hormone level in primary hyperparathyroidism. Am J Surg. 1992;163:301 4.

6 3442 A. L. Amin et al. 11. Gough IR, Thompson NW, Eckhauser FE. The value to the surgeon of parathyroid hormone assays in primary hyperparathyroidism. Aust N Z J Surg. 1988;58: Almquist M, Bergenfelz A, Martensson H, Thier M, Nordenstrom E. Changing biochemical presentation of primary hyperparathyroidism. Langenbecks Arch Surg. 2010;395: Grant CS, Thompson G, Farley D, van Heerden J. Primary hyperparathyroidism surgical management since the introduction of minimally invasive parathyroidectomy: Mayo Clinic experience. Arch Surg. 2005;140:472 8; discussion Irvin GL III, Carneiro DM, Solorzano CC. Progress in the operative management of sporadic primary hyperparathyroidism over 34 years. Ann Surg. 2004;239:704 8; discussion Udelsman R, Lin Z, Donovan P. The superiority of minimally invasive parathyroidectomy based on 1650 consecutive patients with primary hyperparathyroidism. Ann Surg. 2011;253: