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Primary hyperparathyroidism in young adultsBENZION JOSHUA, MD, RAPHAEL FEINMESSER, MD, DAVID ULANOVSKI, MD, HANNA GILAT, BSC, JAQUELINE SULKES, PHD,

VARDA ESHED, MD, and THOMAS SHPITZER, MD, Tel Aviv, Israel

OBJECTIVES: The purpose of this study was to com-

pare 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 hyper-

parathyroidism at our tertiary-care institution be-

tween 1995 and 2001 were reviewed.

RESULTS: Three hundred nineteen patients were

identified, of whom 33 were aged 40 years or less.

There were no statistically significant differences

between the younger and older groups in the inci-dence 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 signifi-

cantly more sensitive than technetium Tc-sestamibi

in the younger group (96% vs 57%, P< 0.05). Para-

thyroid hormone level and gland weight were sig-

nificantly 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 ap-

pears to be the localization procedure of choice in

younger patients. (Otolaryngol Head Neck Surg2004;131:628-32.)

Primary hyperparathyroidism is a common disease,with an annual incidence of 4 to 112 per 100,000

person-years.1 It was first described by Ashkenazy in

1904 in a patient with osteitis fibrosa 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 hyper-

parathyroidism is now encountered in much younger

patients. Researchers have questioned whether this is

due to the increased rate of diagnosis, sometimes al-

ready in the preclinical state thanks to the recent incor-

poration of calcium blood level measurement into rou-

tine examinations, or to differences in the clinical and

biological characteristics of the disease by age. Accord-

ing 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 syn-

drome.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 sep-

arate 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 hyperpara-

thyroidism in young adult patients (40 years old),

focusing on the rate of multiglandular disease and treat-

ment failure, and the diagnostic accuracy of the imag-

ing procedures.

PATIENTS AND METHODSThe 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 hy-

percalcemia were excluded.

The medical records were reviewed for background

data, clinical manifestations, laboratory findings, imag-

ing procedures, and treatment outcome. Ultrasonogra-

phy was used as the first diagnostic procedure in most

cases; technetium 99m (Tc)-sestamibi was performed if

the sonographic findings were equivocal or if the refer-

ring physician was dissatisfied with the ultrasound re-port or localization. All patients in whom lesion local-

ization was definitive underwent unilateral surgical

neck exploration. If imaging failed to localize the ade-

noma, 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); histolog-

ical study was done by frozen section and later by

permanent embedded section.

For purposes of the study, patients were classified by

age (less or more than 40 years old), and the groups

From the Department of OtolaryngologyHead and Neck Surgery,

Epidemiology Unit, and Endocrinology Unit, Rabin Medical Center,

Beilinson Campus, Petah Tiqva, affiliated with Sackler Faculty of

Medicine, Tel Aviv University.

Presented at the Annual Meeting of the American Academy of Otolaryngolo-

gyHead 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, [email protected].

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

628


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were compared for the following variables: presence of

multiglandular disease (double adenoma or hyperpla-

sia); rate of treatment failure (defined as calcium levels

above 10 g/dl 6 months postoperatively); and localiza-tion by imaging vs surgical exploration. Cases in which

the lesion location matched the surgical finding were

defined as true-positives, and cases in which the scan

wrongly identified the side of the adenoma or the pres-

ence of multiglandular disease were considered false-

positives. Cases in which the scan failed to identify any

lesion but at least one hypercellular parathyroid gland

was found at surgery were defined as false-negatives.

The association of the specific thyroid pathology with

the ability to correctly identify parathyroid adenomas

preoperatively was also assessed. In addition, the

groups were compared for other variables associatedwith hyperparathyroidism, namely, male to female ra-

tio, clinical manifestations, calcium levels, parathyroid

hormone (PTH) levels, and weight of the pathological

parathyroid glands.

Statistical Analysis

Continuous variables are given as means and stan-

dard deviations. Students t test was used to analyze

statistically significant differences in mean continuous

parameters between two groups, and chi-square test

was used for comparison of categorical variables.

Pearson correlation coefficient (r) and the signifi-cance for it (P) were calculated between the variables.

To predict surgical failure or incidence of adenoma,

a series of multivariate logistic regression models were

fitted to the data.

P values less than or equal to 0.05 were considered

statistically significant.

RESULTSPatient Characteristics

Patient characteristics are shown in Table 1. Thirty-

three of the 319 patients were less than 40 years old

(16-81 years). The older group had a significantly

higher proportion of female patients (74%) compared to

the younger group (55%) (P 0.01). In addition, the

older group was characterized by a significantly higher

mean PTH level (180 104.7 pg/mL vs 137.4 69.8pg/mL, P 0.004) and mean gland weight (1790

280.7 mg vs 1032 865 mg, P 0.004). There were

no statistically significant differences in mean blood

levels of alkaline phosphatase, calcium, or phosphate

between the age groups.

Clinical Manifestations

There was no statistically significant difference be-

tween 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

significance (45% vs 38%, P 0.41). None of theindividual musculoskeletal, renal/urologic (including

asymptomatic nephrolithiasis), central nervous system,

or gastroenterologic symptoms assessed were signifi-

cantly different between the groups, except for hyper-

tension, which was noted in 33% of the older patients

and in none of the younger ones (P 0.001).

Multiglandular Disease and SurgicalFailure 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 sig-

nificance (P 0.43). (See Table 3.)

Thyroid Pathology and Surgical FailureRate

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

Table 1. Patients and characteristics

Younger

(40 years)

(n 286)

Total

(n 319)

P value

(Significance)

Age (year) 32.3

6.9 60.9

9.6 57

12.8 P

0.001Gender (females) 18 (55%) 214 (74%) 232 (73%) P 0.01

Alkaline phosphatase (mg/dL) 111.9 61.3 (n 29) 117.5 63.4 (n 219) 116.6 63.1 (n 248) P 0.65 (NS)

Phosphorus (mg/dL) 2.69 0.58 (n 27) 2.66 0.45 (n 224) 2.66 0.46 (n 251) P 0.77 (NS)

Calcium (mg/dL) 11.7 0.83 (n 33) 11.6 0.77 (n 286) 11.6 0.78 (n 319) P 0.37 (NS)

Parathyroid hormone (pg/mL) 137.4 69.8 (n 31) 180 104.7 (n 271) 175.6 102.43 (n 302) P 0.004

Specimen weight (mg) 1032 865 (n 24) 1790 2807 (n 234) 1720 2694 (n 258) P 0.004

Adenoma volume (cm3)* 0.40 0.40 (n 11) 0.59 0.86 (n 111) 0.57 0.28 (n 122) 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)].

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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 pa-

tients with a single nodule (P 0.05). The difference

in surgical failure rate between patients with multinod-

ular goiter and patients with normal thyroid pathology

or a single nodule (13.8% vs 6.5%) was statistically

significant (P 0.05), irrespective of age.

Imaging Sensitivity by Pathology and Age

As shown in Table 4, similar to the surgery findings,

imaging was less successful if multinodular goiter was

present, regardless of patient age. Ultrasound sensitiv-

ity was 78% in the patients with multinodular goiter

and 89% in those without (P 0.05); sestamibi sensi-

tivity was 63% and 76%, respectively (P 0.05).

Table 5 shows the imaging performance. In the

younger group, sonography was significantly more sen-

sitive than sestamibi (96% vs 57%, P 0.05). Sonog-

raphy was also more sensitive in the younger patients

compared to the older ones (96% vs 85%, P 0.02).

Sestamibi was significantly less sensitive in the

younger age group (57% vs 71%, P 0.05).

DISCUSSION

Primary hyperparathyroidism has been studied ex-

tensively in the past 80 years. Despite the many

changes in the management of this lesion since Mandel

first operated on a patient with a hyperfunctioning

gland in 1925,2 questions regarding its pathogenesis

and clinical behavior remain unanswered. To shed fur-

ther light on these issues, we evaluated a large group ofconsecutive patients with primary hyperparathyroidism

by age. Previous studies suggested that hyperparathy-

roidism 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 findings agree with the

epidemiologic observation of a higher female predom-

inance in older patients compared to an equal sex

distribution in younger ones. In our sample, there were

Table 2. Clinical manifestations*

Younger (40 years)

(%)

P value

(Significance)

Musculoskeletal 8 (24%) 98 (34%) P 0.24 (NS)

Renal and urologic 8 (24%) 71 (25%) P 0.9 (NS)

Central nervous system 3 (9%) 25 (9%) P 0.98 (NS)

Gastroenterologic 3 (9%) 47 (17%) P 0.25 (NS)

Hypertension 0 (0%) 91 (33%) P 0.001

Asymptomatic 15 (45%) 106 (38%) P 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 286)

Total

(n 319)

P value

(Significance)

Multiglandular disease 3 (9.1%) 26 (9.1%) 29 (9.1%) P 1.00 (NS)

Failure rate 4 (12.1%) 23 (8.0%) 27 (8.5%) P 0.4 (NS)

Table 4. Imaging sensitivity and surgical failure rate with multinodular goiter of thyroid

With MNG

n 87

(27%)

Without MNG

n 232

(73%)

P value

(Significance)

Surgical failure 12 (13.8%) 15 (6.5%) P 0.04

Ultrasonography sensitivity 78% 89% P 0.05

Sestamibi sensitivity 63% 76% P 0.05

MNG, multinodular goiter.

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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 signifi-cantly 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 para-

thyroid tissue in the mediastinum. In the present study,

only 3 patients in the younger group had multiglandular

disease (9%), including those with multiple endocrineneoplasia 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 identified preop-

eratively 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 differ-ence in adenoma size between age groups. By contrast,

we found a significantly smaller mean tumor size and

lower mean PTH value in the younger age group,

reflecting an earlier stage of disease. Indeed, an inter-

esting finding of the present study was the good corre-

lation between PTH levels and adenoma size and vol-

ume (r 0.47, P 0.001), regardless of patient age.

Similar findings were reported by Bindlish et al,8 al-

though Locchi et al9 noted no such correlation.

Sestamibi scan had a significantly lower sensitivity

in the younger age group (57% vs 71% P 0.05)

(Table 5). This finding 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 highsensitivity 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 ade-

noma 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-depen-

dent, 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 whereinultrasound 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 significantly higher surgical failure rate when

multinodular goiter was present (Table 4). Surgeons

should keep these findings in mind when discussing

treatment options with the patient.

The younger patients in our study were less symp-

tomatic than the older ones (45% vs 37%), but this

difference was not statistically significant (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 dis-

ease.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 pri-

mary 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

Table 5. Performance of ultrasonography vs Tc-sestamibi scan

True-

Positive

False-

Positive

True-

Negative

False-

Negative Sensit ivit y*

Positive

Predictive

Value Total

Ultrasonography40 years 27 (81.8%) 3 (9.1%) 2 (6.1%) 1 (3.0%) 96% 90% 33

40 years 209 (73.6%) 36 (12.7%) 2 (0.7%) 37 (13.0%) 85% 85% 284

Total 236 (74.5%) 39 (12.3%) 4 (1.3%) 38 (12.0%) 86% 86% 317

Sestamibi

40 years 8 (47.1%) 3 (17.7%) 0 (0%) 6 (35.3%) 57% 73% 17

40 years 119 (64.7%) 14 (7.6%) 3 (1.6%) 48 (26.1%) 71% 89% 184

Total 127 (63.2%) 17 (6.4%) 3 (1.5%) 54 (26.9%) 70% 88% 201

*Sensitivity: true-positives/(true-positives false-negatives)

Positive predictive value: true-positives/(true-positives false-positives)

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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 hyper-parathyroidism present with more severe disease than

adults, there is little difference in clinical manifesta-

tions between younger adults and older ones (40 vs40). The rates of multiglandular disease and of treat-

ment failure are also similar. Therefore, the manage-

ment approach should be the same in both these age

groups. Sonography seems to be superior to Tc-sesta-

mibi 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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3. Harman CR, van Heerden JA, Farley DR, et al. Sporadic primaryhyperparathyroidism in young patients: a separate disease entity?Arch Surg 1999;134:651-6.

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and thallium-technetium subtraction scintigraphy in localizingparathyroid lesions in patients with hyperparathyroidism. AmSurg 1993;59:509-11.

14. Gofrit ON, Lebensart PD, Pikarsky A, et al. High-resolutionultrasonography: highly sensitive, specific technique for preop-erative localization of parathyroid adenoma in the absence ofmultinodular thyroid disease. World J Surg 1997;21:287-90.

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