Risk of parathyroid adenomas in patients with thyrotoxicosis exposed to radioactive iodine

Abstract

External ionizing radiation is a risk factor for primary hyperparathyroidism. Whether exposure to radioactive iodine contributes to the risk of primary hyperparathyroidism is unknown. Patients with thyrotoxicosis are often treated with radioactive iodine and its accumulation in the thyroid gland exposes the adjacent parathyroid glands to radioactivity. Six thousand and eighty two patients with thyrotoxicosis (ICD-9 = 242) were identified from medical records. In a randomly selected subcohort we assessed the frequency of treatment with radioactive iodine to be 86%. The number of patient-years at risk was 77 118. Patients with parathyroid adenomas (ICD-9 = 195.1) were recruited from the Swedish Cancer Registry. Eleven patients with parathyroid adenomas following the diagnosis of thyrotoxicosis were identified. The standard incidence ratio (SIR) compared to the reference population of ∼900 000 was 1.14 (95% CI 0.57–2.03). The median age at exposure was 59 years and the latency period between diagnosis of thyrotoxicosis and parathyroid adenoma was 7.4 years (range <1–19 years). This study does not indicate that patients with thyrotoxicosis treated with radioactive iodine in adult age have increased risk of developing parathyroid adenoma.

Primary hyperparathyroidism is the result of excessive secretion of parathyroid hormone most often caused by parathyroid adenomas. These tumours are most often benign and occur two to three times more frequently in women compared to men. In some cases parathyroid adenomas are hereditary and part of a multiple endocrine neoplasia (MEN) syndrome. Several reports indicate that exposure to external ionizing radiation is an etiologic factor in parathyroid adenomas in young age [1–5], as well as in adult age [6].

The thyroid gland has a specific affinity for iodine, and patients with thyrotoxicosis are often treated with ¹³¹I. About 90% of the radioactivity generated from ¹³¹I is beta irradiation with a maximal penetration of ∼2 mm, while about 10% is gamma irradiation that could affect the adjacent parathyroid glands. The parathyroid glands themselves do not accumulate iodine. There are several reports on limited number of patients (altogether ∼40) that have developed hyperparathyroidism following treatment with radioactive iodine for hyperthyroidism or multinodular goiter [1], [7–11]. Fjälling et al. [12] evaluated a cohort of 125 patients treated with radioactive iodine for thyrotoxicosis and none of them developed hyperparathyroidism. Kawamura et al. [9] followed 180 patients treated with radioactive iodine for Graves’ disease and nor in this study did patients developed hyperparathyroidism. Bondeson et al. [13] reviewed 600 non-consecutive patients with primary hyperparathyroidism and found ten patients that had been treated with radioactive iodine, seven for Graves’ disease and three to ablate thyroid remnants after tumour operations. The reports seem to be inconclusive concerning the risk of developing hyperparathyroidism after exposure to radioactive iodine.

However, rats exposed to radioactive iodine had a significantly increased risk of developing parathyroid adenomas [14], [15]. A recent report on human exposure of radioactive iodine at young age in a region surrounding a nuclear site showed no increased incidence of hyperparathyroidism [16].

The aim of the present study was to assess the risk of parathyroid tumour development in a cohort of patients with thyrotoxicosis most of whom had been treated with radioactive iodine.

Material and methods

Patients included in this study were admitted to the Department of Oncology at Umeå University Hospital in northern Sweden, from 1940–2003. A total of 6 082 patients with thyrotoxicosis (ICD-9 = 242) were identified. Patients with parathyroid tumours in this cohort were identified from the Cancer Register in northern Sweden (ICD-9 = 195.1). According to the regulations, all patients with malignant as well as hormonally active benign tumours are to be reported to the Swedish Cancer Registry. Altogether 20 patients with parathyroid adenomas were identified in the cohort, however, nine of them were diagnosed with thyrotoxicosis after parathyroid adenomas and they were excluded from the risk evaluation. One of these patients was irradiated for otitis simplex 21 years before the diagnosis of hyperparathyroidism.

To estimate the frequency of treatment with radioactive iodine in the cohort of patients with thyrotoxicosis, 60 patients (1% of the cohort) were sampled. Among these 49/57 (86%) patients were treated with ¹³¹I with a median activity of 300 MBq. The mean age at exposure was 60.7 years. In three cases the medical records were not found.

The person-years at risk were calculated from the time of diagnosis of thyrotoxicosis to the time of diagnosis of parathyroid adenoma, death, or December 2003. The expected number of cases was calculated by multiplying age and calender-specific incidence rates in the reference population by the corresponding numbers of person-years in the cohort. The reference population contained the total population in the region with ∼900 000 inhabitants, where the cases were identified. The ratio between observed and expected incidence was calculated giving the standard incidence ratio (SIR).

Results

The cohort of patients with thyrotoxicosis contained 1 089 men and 4 993 women, with a mean age of 60.1 years. The number of person-years at risk in the cohort was 77 118. Eleven women developed parathyroid adenomas, with a median latency period of 7.4 years (range, <1–19 years) between the time of radioactive iodine exposure and the diagnosis of parathyroid adenoma. Table I presents the patients, age at exposure, and the activities of radioactive iodine prescribed. The expected number of parathyroid adenomas calculated from the incidence in the general population was 9.68 and the observed number was 11, giving a SIR of 1 (95% CI 0.57–2.03). Nine of eleven women (82%) in the cohort that developed parathyroid adenomas had been treated with ¹³¹I, with a median activity of 225 MBq.

Table I.  Patients with parathyroid adenoma following diagnosis of thyrotoxicosis.

Patient	age TT (years)	age PTA (years)	T24 ^131I (%)	Activity ^131I (MBq)	Latency (years)
1	69	71	58	370	2
3	64	80	38	–	17
4	59	76	47	220	18
5	70	75	50	200	6
6	61	71	62	275	10
7	56	67	44	740	11
8	75	82	21	600	7
9	47	66	54	1370	19
10	47	53	67	200	6
11	50	58	67	225	8
12	22	22	–	–	<1
Median	59	71	50	225	8

TT, thyrotoxicosis; PTA parathyroid adenoma; T24, thyroid uptake of iodine after 24 hours; MBq, MegaBequerel.

Discussion

In this cohort of adult patients with thyrotoxicosis most of who were treated with radioactive iodine, no elevated risk of developing parathyroid adenomas was found. This result supports the observations of Fjälling et al. [12] who followed patients treated with ¹³¹I for thyrotoxicosis in relation to untreated controls matched for age and sex. This cohort was followed-up for an average of 21 years, and no increased risk was observed. In a similar study by Kawamura et al. [9] no cases with hypercalcaemia were found among patients treated with radioactive iodine for Graves’ disease. However, these results are opposed to the findings presented by Esselstyn et al. [8] who found four women aged 8–63 years with hyperparathyroidism after treatment with radioactive iodine for Graves’ disease. The median time interval in their study was 23.5 years. Rosen et al. [10] present eight middleaged women exposed to radioactive iodine who later developed parathyroid adenomas, with a latency period varying from four to 20 years. Bondeson et al. [13] reviewed 600 cases with primary hyperparathyroidism and identified ten patients with a history of ¹³¹I treatment. All but one patient were women, and the time interval varied between three and 27 years.

The main reason for the discrepancies between these results is probably differences in the age at exposure. The risk for persons exposed to external ionizing radiation at young age seemed to be higher than for those exposed at adult age [4], [6]. This is in agreement with the observation that young age at exposure is associated with increased risk of developing thyroid cancer compared to exposure at adult age [17], [18].

Glazebrook [19] reviewed the effects of exposure to radioactive iodine on the parathyroid glands. Several patients developed diminished parathyroid reserve, some even with overt tetany, after exposure to high activities of radioactive iodine. Whether this effect contributes to later adenoma development is unknown.

A limitation to the risk assessment is the difficulty to estimate the absorbed radioactive dose in the parathyroid glands. Hamilton et al. [16] found no dose-relationship between the radioactive exposure and the incidence of parathyroid tumours. The results observed in rats exposed to radioactive iodine may not be relevant for humans due to their young age at exposure and the high doses given to rats compared to humans [14], [15]. Anatomical differences in the location of the parathyroid glands between rats and humans must also be considered. Results from the randomly chosen subcohort indicate that 86% of the patients in our study were exposed to therapeutic activity of ¹³¹I (median 300 MBq), the rest only to trace activities of <3 MBq. The exposure among patients with parathyroid adenoma was in the same order of magnitude, 82%, and the median activity was 225 MBq.

In summary this retrospective cohort study failed to demonstrate any increased risk of parathyroid adenomas in patients with thyrotoxicosis exposed to radioactive iodine. Factors that may influence this result are the relatively high age at exposure and the low radioactive dose that reaches the parathyroid glands when patients are exposed to ¹³¹I.

This study was supported by the Medical Faculty Umeå University, Sweden.