Primary hyperparathyroidism in young adults

BENZION JOSHUA, MD, RAPHAEL FEINMESSER, MD, DAVID ULANOVSKI, VARDA ESHED, MD, and THOMAS SHPITZER, MD, Tel Aviv, Israel
MD,

HANNA GILAT,

BSC,

JAQUELINE SULKES,

PHD,

OBJECTIVES: The purpose of this study was to compare the incidence of multiglandular disease and rate of treatment failure between younger and older patients with primary hyperparathyroidism. STUDY DESIGN AND SETTING: The medical charts of patients who underwent surgery for primary hyperparathyroidism at our tertiary-care institution between 1995 and 2001 were reviewed. RESULTS: Three hundred nineteen patients were identied, of whom 33 were aged 40 years or less. There were no statistically signicant differences between the younger and older groups in the incidence of multiglandular disease (9.1% for both, P 1.00) or in the treatment failure rate (12.1% and 8%, respectively, P 0.43). Sonography was signicantly more sensitive than technetium Tc-sestamibi in the younger group (96% vs 57%, P < 0.05). Parathyroid hormone level and gland weight were signicantly higher in the older group (P 0.004). CONCLUSION: Our results suggest that the same treatment strategy should be applied to all patients with primary hyperparathyroidism. Ultrasound appears to be the localization procedure of choice in younger patients. (Otolaryngol Head Neck Surg 2004;131:628-32.)

due to the increased rate of diagnosis, sometimes already in the preclinical state thanks to the recent incorporation of calcium blood level measurement into routine examinations, or to differences in the clinical and biological characteristics of the disease by age. According to most studies, hyperparathyroidism in very young patients (less than 20 years old) is associated with more severe symptoms,3-7 a higher incidence of hyperplasia vs adenoma,4,6,7 and multiendocrine neoplasia syndrome.4 The failure rate of treatment is also reportedly higher in this age group.3,6 It has been the policy of our department to treat primary hyperparathyroidism in young adults as a separate entity, using a broader endocrine examination to rule out multiple endocrine neoplasia, with bilateral exploration in every case. The purpose of the present study was to evaluate the utitlity of these practices. We also sought to further characterize primary hyperparathyroidism in young adult patients (40 years old), focusing on the rate of multiglandular disease and treatment failure, and the diagnostic accuracy of the imaging procedures. PATIENTS AND METHODS The study sample included 319 consecutive patients with primary hyperparathyroidism who were diagnosed and treated at our tertiary-care center between 1995 and 2001. Patients with familial benign hypercalciuric hypercalcemia were excluded. The medical records were reviewed for background data, clinical manifestations, laboratory ndings, imaging procedures, and treatment outcome. Ultrasonography was used as the rst diagnostic procedure in most cases; technetium 99m (Tc)-sestamibi was performed if the sonographic ndings were equivocal or if the referring physician was dissatised with the ultrasound report or localization. All patients in whom lesion localization was denitive underwent unilateral surgical neck exploration. If imaging failed to localize the adenoma, or if the surgeon failed to localize the adenoma in the position suggested by the sonogram or sestamibi scan, bilateral exploration was performed. Enlarged parathyroid glands were removed, and a sample was taken from the adjacent gland (when found); histological study was done by frozen section and later by permanent embedded section. For purposes of the study, patients were classied by age (less or more than 40 years old), and the groups

rimary hyperparathyroidism is a common disease, with an annual incidence of 4 to 112 per 100,000 person-years.1 It was rst described by Ashkenazy in 1904 in a patient with osteitis brosa cystica, though he believed the tumor was a result and not a cause of the bone disease.2 Although the average patient age in most early textbooks was the sixth decade,1 primary hyperparathyroidism is now encountered in much younger patients. Researchers have questioned whether this is
From the Department of OtolaryngologyHead and Neck Surgery, Epidemiology Unit, and Endocrinology Unit, Rabin Medical Center, Beilinson Campus, Petah Tiqva, afliated with Sackler Faculty of Medicine, Tel Aviv University. Presented at the Annual Meeting of the American Academy of OtolaryngologyHead and Neck Surgery, Orlando, FL, September 21-24, 2003. Reprint requests: B. Joshua, MD, Department of OtolaryngologyHead and Neck Surgery, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49 100, Israel; e-mail, bb-j@internet-zahav.net.il. 0194-5998/$30.00 Copyright 2004 by the American Academy of OtolaryngologyHead and Neck Surgery Foundation, Inc. doi:10.1016/j.otohns.2004.06.701

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Table 1. Patients and characteristics

Younger (<40 years) (n 33) Age (year) Gender (females) Alkaline phosphatase (mg/dL) Phosphorus (mg/dL) Calcium (mg/dL) Parathyroid hormone (pg/mL) Specimen weight (mg) Adenoma volume (cm3)* 32.3 6.9 18 (55%) 111.9 61.3 (n 29) 2.69 0.58 (n 27) 11.7 0.83 (n 33) 137.4 69.8 (n 31) 1032 865 (n 24) 0.40 0.40 (n 11) Older (>40 years) (n 286) 60.9 9.6 214 (74%) 117.5 63.4 (n 219) 2.66 0.45 (n 224) 11.6 0.77 (n 286) 180 104.7 (n 271) 1790 2807 (n 234) 0.59 0.86 (n 111) Total (n 319) 57 12.8 232 (73%) 116.6 63.1 (n 248) 2.66 0.46 (n 251) 11.6 0.78 (n 319) 175.6 102.43 (n 302) 1720 2694 (n 258) 0.57 0.28 (n 122) P value (Signicance) P 0.001 P 0.01 P 0.65 (NS) P 0.77 (NS) P 0.37 (NS) P 0.004 P 0.004 P 0.2 (NS)

*Assessed by multiplying the three dimensions reported by the pathologist and then multiplying the result by divided by 6 [(W L D) 6 volume)].

were compared for the following variables: presence of multiglandular disease (double adenoma or hyperplasia); rate of treatment failure (dened as calcium levels above 10 g/dl 6 months postoperatively); and localization by imaging vs surgical exploration. Cases in which the lesion location matched the surgical nding were dened as true-positives, and cases in which the scan wrongly identied the side of the adenoma or the presence of multiglandular disease were considered falsepositives. Cases in which the scan failed to identify any lesion but at least one hypercellular parathyroid gland was found at surgery were dened as false-negatives. The association of the specic thyroid pathology with the ability to correctly identify parathyroid adenomas preoperatively was also assessed. In addition, the groups were compared for other variables associated with hyperparathyroidism, namely, male to female ratio, clinical manifestations, calcium levels, parathyroid hormone (PTH) levels, and weight of the pathological parathyroid glands. Statistical Analysis Continuous variables are given as means and standard deviations. Students t test was used to analyze statistically signicant differences in mean continuous parameters between two groups, and chi-square test was used for comparison of categorical variables. Pearson correlation coefcient (r) and the signicance for it (P) were calculated between the variables. To predict surgical failure or incidence of adenoma, a series of multivariate logistic regression models were tted to the data. P values less than or equal to 0.05 were considered statistically signicant. RESULTS Patient Characteristics Patient characteristics are shown in Table 1. Thirtythree of the 319 patients were less than 40 years old (16-81 years). The older group had a signicantly

higher proportion of female patients (74%) compared to the younger group (55%) (P 0.01). In addition, the older group was characterized by a signicantly higher mean PTH level (180 104.7 pg/mL vs 137.4 69.8 pg/mL, P 0.004) and mean gland weight (1790 280.7 mg vs 1032 865 mg, P 0.004). There were no statistically signicant differences in mean blood levels of alkaline phosphatase, calcium, or phosphate between the age groups. Clinical Manifestations There was no statistically signicant difference between the groups for most of the clinical manifestations (see Table 2). The younger group was slightly less symptomatic, but the difference did not reach statistical signicance (45% vs 38%, P 0.41). None of the individual musculoskeletal, renal/urologic (including asymptomatic nephrolithiasis), central nervous system, or gastroenterologic symptoms assessed were signicantly different between the groups, except for hypertension, which was noted in 33% of the older patients and in none of the younger ones (P 0.001). Multiglandular Disease and Surgical Failure Rate The rate of multiglandular disease was 9.1% in both groups (P 1.00). The failure rate was slightly higher in the younger patients (n 4, 12.19% vs n 23, 8.00%), but the difference did not reach statistical signicance (P 0.43). (See Table 3.) Thyroid Pathology and Surgical Failure Rate Sonography detected a thyroid pathology, either multinodular goiter or a single nodule, in 40.2% of the older group and 12% of the younger group (P 0.007) (see Table 4). Eighty-four patients in the older group (29.4%) had multinodular goiter and 31 had a single nodule (10.8%); in the younger group, 3 patients (9.1%) had mutinodular goiter and 1 (3%) had a single

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Table 2. Clinical manifestations*

Younger (<40 years) (%) Musculoskeletal Renal and urologic Central nervous system Gastroenterologic Hypertension Asymptomatic 8 (24%) 8 (24%) 3 (9%) 3 (9%) 0 (0%) 15 (45%) Older (>40 years) (%) 98 (34%) 71 (25%) 25 (9%) 47 (17%) 91 (33%) 106 (38%) P P P P P P P value (Signicance) 0.24 (NS) 0.9 (NS) 0.98 (NS) 0.25 (NS) 0.001 0.4 (NS)

*Numbers add up to more than 100% since some patients had more than one symptom. In addition, patients who had only hypertension were considered asymptomatic.

Table 3. Multiglandular disease and surgical failure rate

Younger (<40 years) (n 33) Multiglandular disease Failure rate 3 (9.1%) 4 (12.1%) Older (>40 years) (n 286) 26 (9.1%) 23 (8.0%) Total (n 319) 29 (9.1%) 27 (8.5%) P value (Signicance) P 1.00 (NS) P 0.4 (NS)

Table 4. Imaging sensitivity and surgical failure rate with multinodular goiter of thyroid
With MNG n 87 (27%) Surgical failure Ultrasonography sensitivity Sestamibi sensitivity MNG, multinodular goiter. 12 (13.8%) 78% 63% Without MNG n 232 (73%) 15 (6.5%) 89% 76% P value (Signicance) P 0.04 P 0.05 P 0.05

nodule. The surgical failure rate in patients with thyroid pathology was 10% compared to 8.5% for the whole group (P 0.05) (see Table 4). Analysis by type of thyroid pathology yielded a failure rate of 13.8% in the patients with multinodular goiter and zero in the patients with a single nodule (P 0.05). The difference in surgical failure rate between patients with multinodular goiter and patients with normal thyroid pathology or a single nodule (13.8% vs 6.5%) was statistically signicant (P 0.05), irrespective of age. Imaging Sensitivity by Pathology and Age As shown in Table 4, similar to the surgery ndings, imaging was less successful if multinodular goiter was present, regardless of patient age. Ultrasound sensitivity was 78% in the patients with multinodular goiter and 89% in those without (P 0.05); sestamibi sensitivity was 63% and 76%, respectively (P 0.05). Table 5 shows the imaging performance. In the younger group, sonography was signicantly more sensitive than sestamibi (96% vs 57%, P 0.05). Sonography was also more sensitive in the younger patients compared to the older ones (96% vs 85%, P 0.02).

Sestamibi was signicantly less sensitive in the younger age group (57% vs 71%, P 0.05). DISCUSSION Primary hyperparathyroidism has been studied extensively in the past 80 years. Despite the many changes in the management of this lesion since Mandel rst operated on a patient with a hyperfunctioning gland in 1925,2 questions regarding its pathogenesis and clinical behavior remain unanswered. To shed further light on these issues, we evaluated a large group of consecutive patients with primary hyperparathyroidism by age. Previous studies suggested that hyperparathyroidism in young patients may be a different entity from that in older ones.3-7 Although most of the studies in the literature used 20 years as the cutoff age, there have been only 5 relevant reports to date, and all set the break-point arbitrarily. As our series had only one patient younger than 20 years, we limited our analysis to younger and older adults. Our ndings agree with the epidemiologic observation of a higher female predominance in older patients compared to an equal sex distribution in younger ones. In our sample, there were

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Table 5. Performance of ultrasonography vs Tc-sestamibi scan

TruePositive Ultrasonography 40 years 40 years Total Sestamibi 40 years 40 years Total FalsePositive TrueNegative FalseNegative Positive Predictive Value

Sensitivity*

Total

27 (81.8%) 209 (73.6%) 236 (74.5%) 8 (47.1%) 119 (64.7%) 127 (63.2%)

3 (9.1%) 36 (12.7%) 39 (12.3%) 3 (17.7%) 14 (7.6%) 17 (6.4%)

2 (6.1%) 2 (0.7%) 4 (1.3%) 0 (0%) 3 (1.6%) 3 (1.5%)

1 (3.0%) 37 (13.0%) 38 (12.0%) 6 (35.3%) 48 (26.1%) 54 (26.9%)

96% 85% 86% 57% 71% 70%

90% 85% 86% 73% 89% 88%

33 284 317 17 184 201

*Sensitivity: true-positives/(true-positives false-negatives) Positive predictive value: true-positives/(true-positives false-positives)

18 female patients and 15 male patients in the 40-year group, for a ratio of 1.2 to 1. However, most of the other characteristics examined did not differ signicantly between the groups. Some earlier studies found that young patients with primary hyperparathyroidism may have a higher rate of multiglandular disease,4,6,7 whereas others3 did not. This difference has important implications for the need for wide bilateral exploration. Indeed, earlier studies also reported a higher surgical failure rate in young patients3,6 up to 25% for a single procedurewhich they attributed to their higher rate of multiglandular disease6 or higher rate of ectopic parathyroid tissue in the mediastinum. In the present study, only 3 patients in the younger group had multiglandular disease (9%), including those with multiple endocrine neoplasia and a familial history, similar to the rate in the older group (9%). There was also only one case of mediastinal tumor in the young age group. Our surgical success rate was 88% in the younger group and 92% in the older one. Although the numbers are small, our study suggests that a single adenoma identied preoperatively by imaging in a young adult patient should be managed in the same manner as in older patients. Since primary hyperparathyroidism is considered a neoplastic state, the adenoma is expected to be smaller and less productive in the earlier stage of the disease. Previous studies by Harman et al3 reported no difference in adenoma size between age groups. By contrast, we found a signicantly smaller mean tumor size and lower mean PTH value in the younger age group, reecting an earlier stage of disease. Indeed, an interesting nding of the present study was the good correlation between PTH levels and adenoma size and volume (r 0.47, P 0.001), regardless of patient age. Similar ndings were reported by Bindlish et al,8 although Locchi et al9 noted no such correlation. Sestamibi scan had a signicantly lower sensitivity in the younger age group (57% vs 71% P 0.05) (Table 5). This nding might be explained by a smaller

size or lower activity of the adenoma in young patients, or a higher incidence of hyperplasia, although the latter was not found to be true in our sample. The high sensitivity of ultrasound in detecting adenomas in the younger age group (96% vs 85%, P 0.02) (Table 5), despite the relatively smaller size of their lesions, might be attributed to their lesser thyroid pathology, so that the parathyroid glands were less obscured. The reported sensitivity of ultrasound in detecting parathyroid adenoma ranges from 40 to 90%, depending on the skill and experience of the radiologist.10 The accuracy and sensitivity of sestamibi, which is less operator-dependent, is 70 to 100%.11,12 Our overall sensitivity of 86% for ultrasound vs 70% for sestamibi is in line with these data, and with a previous study in our institute wherein ultrasound proved to be superior to sestamibi in patients with parathyroid adenoma.10 Both ultrasound and sestamibi were less sensitive in patients with multinodular goiter than in those without (Table 4), in agreement with earlier studies.13,14 We also had a signicantly higher surgical failure rate when multinodular goiter was present (Table 4). Surgeons should keep these ndings in mind when discussing treatment options with the patient. The younger patients in our study were less symptomatic than the older ones (45% vs 37%), but this difference was not statistically signicant (P 0.41). By contrast, studies in children reported more severe symptoms than in adults.3-7 This was explained by the delayed diagnosis in children or their more severe disease.3 In our sample, the disease was detected at an earlier stage in the younger patients because of our inclusion of calcium measurement in the screening tests. However, the results may also have been biased by the fact that asymptomatic older patients with primary hyperparathyroidism are not necessarily referred for surgery, whereas all younger patients are advised to undergo parathyroidectomy. Furthermore, some of the gastroenterologic and musculoskeletal symptoms may

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be related to age per se, and not to the disease. This is probably true for hypertension, which was not found in any of the younger patients. CONCLUSION Although very young patients with primary hyperparathyroidism present with more severe disease than adults, there is little difference in clinical manifestations between younger adults and older ones (40 vs 40). The rates of multiglandular disease and of treatment failure are also similar. Therefore, the management approach should be the same in both these age groups. Sonography seems to be superior to Tc-sestamibi for disease detection in young adults because of its higher sensitivity (96% vs 57%). Unilateral exploration with preoperative sonogram localization could be a good approach.
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1. Wermers RA, Khola S, Atkinson EJ, et al. The rise and fall of hyperparathyroidism: a population-based study in Rochester, Minnesota 1965-1992. Ann Intern Med 1997;126:433-40. 2. Coffey RJ. Historical highlights of hyperparathyroidism. Am Surg 1972;38:649-52. 3. Harman CR, van Heerden JA, Farley DR, et al. Sporadic primary hyperparathyroidism in young patients: a separate disease entity? Arch Surg 1999;134:651-6.

4. Allo M, Thompson NW, Harness JK, et al. Primary hyperparathyroidism in children, adolescents and young adults. World J Surg 1982;6:771-6. 5. Rapaport D, Ziv Y, Rubin M, et al. Primary hyperparathyroidism in children. J Pediatr Surg 1986;21:395-7. 6. Loh KC, Duh QY, Shoback D, et al. Clinical prole of primary hyperparathyroidism in adolescents and young adults. Clin Endocrinol (Oxf) 1998;48:435-43. 7. Hsu SC, Levine MA. Primary hyperparathyroidism in children and adolescents: the Johns Hopkins Children Center experience 1984-2001. J Bone Miner Res 2002;Suppl 2:44-50. 8. Bindlish V, Freeman JL, Witterick IJ, et al. Correlation of biochemical parameters with single parathyroid adenoma weight and volume. Head Neck 2002;24:1000-3. 9. Locchi F, Tommasi M, Brandi ML, et al. A controversial problem: Is there a relationship between parathyroid hormone level and parathyroid size in primary hyperparathyroidism? Int J Biol Markers 1997;12:106-11. 10. Ulanovski D, Feinmesser R, Cohen M, et al. Preoperative evaluation of patients with parathyroid adenoma: role of high-resolution ultrasonography. Head Neck 2002;24:1-5. 11. Song AU, Phillips TE, Edmond CV, et al. Success of preoperative imaging and unilateral neck exploration for primary hyperparathyroidism. Otolaryngol Head Neck Surg 1999;121:393-7. 12. Malhotra A, Silver CE, Deshpande V, et al. Preoperative parathyroid localization with sestamibi. Am J Surg 1996;172:637-40. 13. Thompson CT, Bowers J, Broadie TA. Preoperative ultrasound and thallium-technetium subtraction scintigraphy in localizing parathyroid lesions in patients with hyperparathyroidism. Am Surg 1993;59:509-11. 14. Gofrit ON, Lebensart PD, Pikarsky A, et al. High-resolution ultrasonography: highly sensitive, specic technique for preoperative localization of parathyroid adenoma in the absence of multinodular thyroid disease. World J Surg 1997;21:287-90.