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Parathyroid gland function after radioiodine (¹³¹I) therapy for toxic and non-toxic goitre

Czynność gruczołów przytarczycznych po leczeniu radiojodem (¹³¹I) toksycznego oraz nietoksycznego wola

Piotr Szumowski, Saeid Abdelrazek, Małgorzata Mojsak, Franciszek Rogowski, Agnieszka Kociura-Sawicka, Janusz Myśliwiec

Department of Nuclear Medicine, Medical University, Białystok, Poland

Piotr Szumowski M. D., Department of Nuclear medicine, Medical University Białystok, Poland, M. Skłodowskiej-Curie St. 24A, 15–276 Białystok, Poland, tel.: +48 85 746 87 70; fax: +48 85 746 87 71, e-mail: piotrmjs@wp.pl

Introduction

It is widely known that the therapeutic effect of the radioiodine isotope ¹³¹I for both non-toxic and toxic goitres is based on the fact that it emits strong ionising beta radiation, which causes damage to thyrocytes. As is known from physics, the maximum range of beta radiation from ¹³¹I decay is 2.4 mm [1–3]. That is why radiation affects not only the thyroid gland tissue but also reaches over 2 mm beyond it, and its effect increases with the magnitude of radiation dose. It is known from anatomy and histology that parathyroid glands are situated in the immediate vicinity of the thyrocytes, on the posterior lobe of the thyroid, and thus can be permeated by beta radiation from ¹³¹I absorbed by the thyroid gland.

It seems worth considering whether this type of radiation might lead to any parathyroid malfunction. Although the issue has been investigated by various researchers, the available conclusions — mostly based on a limited number of patients — are often widely discrepant or even contradictory [1–4, 6, 10–12]. Some authors maintain that radiation from thyroid-absorbed ¹³¹I causes temporary damage to parathyroid glands, resulting in their transient hypofunction, whereas others, on the contrary, believe that the same radiation causes parathyroid hyperfunction [4, 5]. There are also studies whose authors claim that the radiation from thyroid-absorbed ¹³¹I may lead to the development of parathyroid adenoma, as well as those which do not contain any evidence of increased risk for such a development [6–9].

For this reason, the purpose of this paper is to assess the parathyroid gland function in patients with toxic and non-toxic goitres after ¹³¹I therapy up to five years post-treatment.

Material and methods

The sample encompassed 325 patients with benign goitres, including 220 patients (180 women and 40 men) with toxic nodular goitres (TNG), 80 (70 women and ten men) with Graves’ disease (GD), and 25 (22 women and three men) with non-toxic nodular goitres (NTNG). The average age of the studied population was 45 ± 10 years. All the patients underwent radioiodine (¹³¹I) treatment at the Nuclear Medicine Department Clinic of the Medical University of Białystok between 2006 and 2012. The primary aim of the treatment was to eliminate hyperthyroidism and/or to reduce the size of goitre. Before the administration of therapeutic activity of ¹³¹I, all the patients were routinely qualified for the study: they had undergone physical examination and their past medical histories had been investigated. Further, the patients’ serum levels of thyroid-stimulating hormone (TSH) were measured by means of immunoradiometric assay, free thyroxine (fT₄) and free triiodothyronine (fT₃) were evaluated using the radioimmunological method (RIA). All the nodules were biopsied (in order to exclude cancer), USG examinations of the thyroid glands were performed, as were 24-hour (T₂₄) and 48-hour (T₄₈) radioactive iodine uptake tests and the scintigraphic evaluation using a gamma camera (Nucline^TM Th, Mediso). Moreover, serum concentrations of iPTH were determined by means of the immunochemiluminescence assay (ICMA), the ionised calcium method (Ca²⁺) using ion-selective electrodes, corrected for possible pH variations whereas total calcium (Ca) and phosphates (P) by means of chemical methods. It should be stressed that patients with diseases that might affect calcium-phosphorus homeostasis were excluded from the study.

Required therapeutic activity (A) of ¹³¹I was calculated using Marinelli’s formula [10]:

where

A — ¹³¹I therapeutic activity (MBq)

25 — unit conversion coefficient

m — mass of thyroid gland calculated from USG (g)

D — absorbed dose of ¹³¹I (Gy)

T₂₄ — 24-h ¹³¹I uptake (%)

T_eff — effective ¹³¹I half-life in thyroid gland (days) = T_biolog x T_phys/T_biolog+ T_phys, where T_biolog (rate of iodine excretion from the thyroid), T_phys (physical half-life of radioactive iodine)

The choice of thyroid absorbed ¹³¹I radiation dose depended on the type of hyperthyroidism and was consistent with the recommendations made by the European Association of Nuclear Medicine [11]. For toxic nodular goitre, the absorbed dose was 260Gy, for Graves’ disease it was 140Gy, while for non-toxic nodular goitre it was 180Gy.

Throughout the first year following radioiodine therapy, all the subjects were re-examined every two months, and additionally after three and five years post-treatment. The check-ups involved fT₃, fT₄, TSH, iPTH, Ca²⁺, Ca and P blood serum tests.

The study was approved by the Ethics Committee for Medical Research, Medical University of Bialystok, and is in accordance with GCP (good clinical practice). Informed consent was given by all patients participating in the study.

Statistical analysis

All statistical analyses were performed using the software package Statistica 10 (Stat Soft, Tulsa, OK, USA).

The Friedman test was used for assessment of the differences between preand post-treatment levels of fT₄, fT₃, TSH, iPTH, Ca²⁺, Ca and P.

The extent to which variations of the thyroidabsorbed dose of ¹³¹I influence the iPTH serum levels was determined by means of linear regression function.

Results

Two months after the administration of therapeutic radioiodine, all the patients showed statistically significant (p < 0.005) increases in above-normal iPTH serum levels. The highest (slightly over two-fold) rise in serum levels of iPTH occurred in TNG patients, a little lower — in NTNG ones, and relatively the lowest — in GD patients. In the next four months, iPTH concentrations remained similarly high in all the patients. Six months after radioiodine administration, the hormone level started to decrease, to come back to normal in the tenth month post-treatment. The follow-up examinations — three and five years following radioiodine therapy — revealed that the concentrations of iPTH, Ca²⁺, Ca and P did not exceed normal limits in any of the patients (Figs. 1 and 2).

Figure 1. Variations of native parathyroid hormone (iPTH) serum levels in patients with TNG, GD and NTNG within one year and after 3 and 5 years following radioiodine administration. Part of the graph marked by clip corresponds statistically significantly (p < 0.05) with elevated iPTH concentrations above normal in all patients. (The grey area indicates normal concentrations of iPTH in blood serum)

Rycina 1. Zachowanie się stężeń natywnej postaci parathormonu (iPTH) w surowicy krwi u pacjentów z TNG, GD, NTNG poddanych radiojodoterapii w okresie do 1 roku oraz po 3 i 5 latach od podania izotopu. Część wykresu objeta klamrą odpowaida istotnie statystycznie (p < 0,05) podwyższonym powyżej normy wartościom iPTH u wszystkich pacjentów (Obszar zaznaczony szarym kolorem pokazuje zakres norm stężenia PTH w surowicy krwi)

Figure 2. Variations of serum levels of A) Ca²⁺, B) Ca, C) P in patients with TNG, GD and NTNG within one year and after 3 and 5 years following radioiodine administration. (The grey area indicates normal concentrations of above factors in blood serum)

Rycina 2. Zachowanie się stężeń A) Ca²⁺, B) Ca, C) P w surowicy krwi u pacjentów z TNG, GD, NTNG poddanych radiojodoterapii w okresie do 1 roku oraz po 3 i 5 latach od podania izotopu. (Obszar zaznaczony szarym kolorem pokazuje zakres norm stężenia Ca²⁺ w surowicy krwi)

As can be seen from Figure 2, the differences between blood serum concentrations of Ca²⁺, Ca and P pre- and post-treatment were very small in all the patients, and thus statistically insignificant.

Analysis of iPTH concentrations in the blood serum of patients who underwent radioiodine therapy leads to the conclusion that, depending on the thyroid absorbed dose, the most significant increase in iPTH above the upper normal range (starting from the 2^nd month post-administration, and persisting as long as until the 10^th month) occurred in those patients whose thyroids absorbed the highest accumulated dose, i.e. 260Gy. With the thyroid absorbed dose of ¹³¹I at 180Gy, the rise in iPTH above normal levels is slightly lower, and its concentration returns to normal more rapidly. In thyroids with the lowest absorbed dose (140Gy), iPTH levels were found to increase to the least extent, and the time necessary for achieving normal parameters was the shortest: only six months after the administration of ¹³¹I. The increase in iPTH was statistically significant at p < 0.005 for all the three absorbed doses (Fig. 3).

Figure 3. Variations of native parathyroid hormone (iPTH) serum levels depending on absorbed dose of 131I in patients after radioiodine therapy within one year following radioiodine administration. Part of the graph marked by clip corresponds statistically significantly (p < 0.05) with elevated iPTH concentrations above normal irrespectively of absorbed dose. (The grey area indicates normal concentrations of PTH in blood serum)

Rycina 3. Zachowanie się stężeń natywnej postaci parathormonu (iPTH) w surowicy krwi w zależności od dawki pochłoniętej 131I w tarczycy u pacjentów poddanych radiojodoterapii w okresie do 1 roku od podania izotopu. Część wykresu objeta klamrą odpowaida istptnie statystycznie (p < 0,05) podwyższonym powyżej normy wartościom iPTH bez względu na dawkę pochłoniętą (Obszar zaznaczony szarym kolorem pokazuje zakres norm stężenia PTH w surowicy krwi)

Using the linear regression model, it has been proved that there exists a correlation between the absorbed dose and the level of iPTH, which is expressed by the formula below:

iPTH = 0.54 absorbed dose + 10.24 r² = 0.97 p < 0.05

From the formula it can be seen that the higher the absorbed dose, the greater the rise in the concentration of iPTH in blood serum.

As far as the hormonal function of the thyroid is concerned, only TNG patients showed statistically significant (p < 0.001) alterations in levels of hormones after radioiodine treatment: mean levels of fT₃ and fT₄ returned from above the upper limit to normal as a result of treatment. In all the patients, the blood serum levels of fT₃ and fT₄ remained within normal limits for a year following radioiodine administration, i.e. throughout the period covered by this study (Figs. 4 and 5).

Figure 4. Variations of mean concentrations of fT₄ in patients, from before radioiodine administration to12 months post-dose. (The grey area indicates normal concentrations of fT₄ in blood serum)

Rycina 4. Zachowanie się średnich stężeń hormonu fT₄ u chorych w okresie od momentu przed podaniem radiojodu do 12 miesięcy po podaniu. (Obszar zaznaczony szarym kolorem pokazuje zakres norm stężenia fT₄ w surowicy krwi)

Figure 5. Variations of mean concentrations of fT₃ in patients, from before radioiodine administration to 12 months post-dose. (The grey area indicates normal concentrations of fT₃ in blood serum)

Rycina 5. Zachowanie się średnich stężeń hormonu fT₃ u chorych w okresie od momentu przed podaniem radiojodu do 12 miesięcy po podaniu. (Obszar zaznaczony szarym kolorem pokazuje zakres norm stężenia fT₃ w surowicy krwi)

Discussion

The abovementioned figures prove that the use of radioactive isotope of iodine (¹³¹I) in the treatment of benign thyroid disease (i.e. hyperthyroidism and large, euthyreotic goitre) not only normalises hormonal function of thyroid but also has an influence on the hormonal function of parathyroid glands. In the therapeutic process, the transitory hyperparathyroidism was observed (independently of the type of hyperthyroidism); however, it usually subsided ten months after administration of I-131. A statistically significant increase in the level of iPTH in all patients does not change the concentrations of calcium and phosphate in the blood.

As in other scientific studies into the issue, our sample consisted of patients with thyroid goitres (toxic: in the case of TNG and GD, or non-toxic). Before the administration of ¹³¹I, the concentrations blood serum of calcium and iPTH in all our patients were within normal limits, as in studies conducted by other authors [4, 5, 13]. This makes it possible to conclude that hyperthyroidism usually does not affect the levels of calcium and iPTH in blood serum. Admittedly, it is an established fact that hyperthyroidism may lead to hypercalcaemia (in 20–30% of hyperthyroid patients), which consequently contributes to decreased serum levels of iPTH) [14].

Apart from two papers, one by Ross and Nussbaum (1985) and the more recent one by Komorovsky and Raghavan, the literature does not offer any assessment of the early effects of ¹³¹I radiation used for the treatment of benign thyroid diseases on parathyroid function [4, 5]. Similarly to Ross and Nussbaum, we observed an above normal rise in the levels of iPTH as soon as two months post-dose. Nevertheless, our further results and their interpretation are markedly different. Ross and Nussbaum associated increased iPTH levels with the drop in blood serum calciumcaused by ¹³¹I-induced hypothyroidism, since thyroid hormones have resorptive properties and thus, by leading to high bone turnover, contribute to higher concentrations of serum calcium. They also found that exogenous thyroxine normalises the levels of thyroid hormones and TSH, which leads to a rise in calcium and a drop in iPTH. Therefore, the authors emphasise the impact of the thyroid hormones and iPTH on bone metabolism, and thus on the level of calcium in the body. Meanwhile, our study showed that elevated iPTH did not result from impaired hormonal function of the thyroid gland, since in most patients treated with radioactive iodine (except several cases of GD patients where hormonal supplementation with thyroxine was necessary post-therapy), the thyroid glands functioned normally. Moreover, elevated iPTH levels were observed up to approximately the eighth month post-dose, to return to normal limits and remain within them until the end of the period covered by this study (five years post-dose), with regular thyroid function throughout the period. Interestingly, the serum concentrations of calcium were stable throughout the study, in spite of temporary increases in iPTH, even up to twice the upper normal limit. Similar stability was observed as far as the serum concentration of phosphates was concerned. This is probably because the elevated iPTH acted for too short a time, and also because other regulatory mechanisms of calcium homeostasis could have been involved [15]. The temporary increase in iPTH in all our patients can presumably be explained by post-radiation inflammation of the parathyroid glands, which, in the initial stage, caused excessive release of iPTH accumulated in the main parathyroid cells. In the next stage, such excessive release continues also as a result of the stimulation of the remaining, undestroyed, main cells, which are prompted to hypersecretion of iPTH [16]. We have also noticed that the higher the thyroid-absorbed dose of ¹³¹I, the greater the impact on the parathyroid glands, and the higher the secretion of iPTH due to parathyroid inflammation. Precise interdependence between iPTH concentration and absorbed dose has been described by means of a linear regression model. That is why, in our study, the rise in iPTH was the highest in toxic nodular goitre patients, who had received the largest absorbed dose, whereas in the case of NTNG and GD (where the absorbed doses were accordingly lower), the above normal increase in iPTH was smaller and the time needed for it to return to normal limits was shorter.

It should also be added that not taking into account the distribution of the absorbed radiation dose in thyroid on parathyroid function was a certain limitation of our study. This is due to the fact that a thorough evaluation of the relation between parathyroid function and distribution of the absorbed dose of ¹³¹I in the thyroid gland requires knowledge of the exact location of the parathyroid glands. It is widely known that pinpointing this exact location is very difficult, and in clinical practice turns out to be nearly impossible.

Komorovsky and Raghavan describe the case of a child suffering from GD who underwent radioiodine therapy and, at three months post-treatment, developed hypocalcaemia [4]. The authors’ conclusions as regards the assessment of calcium concentrations in patients after ¹³¹I therapy aimed at establishing the possibility of post-radiation hypoparathyroidism have not been confirmed by our data. Perhaps this is due to the difference between study samples. Our sample consisted of patients whose average age was 45 ± 10, while Komorovsky and Raghavan analysed the case of a child.

The majority of other researchers have only examined the possibility of delayed effects of ionising radiation of therapeutic ¹³¹I on the adjacent parathyroid glands. So any comparisons between those studies and ours are far more difficult and must, to a large extent, be based on assumptions. Our research was concluded after a five-year observation period of the hormonal function of parathyroid glands after radioiodine administration. Throughout that time, apart from elevated iPTH levels in the first months post-dose, no abnormalities were discovered in either the hormonal function of the parathyroid glands or the serum concentrations of ionised calcium. Notwithstanding the first ten months post-treatment, we can agree with the authors who have studied late effects of radiation (some of them describe patients at 35 years post-dose) that radioiodine therapy for benign thyroid disease does not affect the parathyroid function [6, 7, 17]. Mortensen et al. chose an interesting methodology to assess the secretory function of the parathyroid glands after radiation [7]. They emphasise that merely measuring iPTH serum levels is not sufficient for adequate assessment of the glands’ function. Additional stimulation tests are necessary to examine the secretory reaction of the parathyroids to a pharmacologically achieved decrease in ionised calcium levels by using EDTA, which binds to calcium. Also these authors concluded that radioiodine radiation does not alter the parathyroid function.

It is also necessary to mention those authors who have conducted research among patients treated (up to over a decade prior to studies) for benign thyroid diseases with ionising radiation and found evidence for increased likelihood of parathyroid adenoma in those cases [13, 18, 19]. In addition, Colaco claims that the risk of parathyroid adenoma grows with age [8].

To sum up, one must bear in mind that in order to determine the cause of hyperparathyroidism, it is essential to consider whether a patient’s past medical history includes radioiodine therapy. It seems that this thesis will be an important factor that aims at improving the diagnosis of hyperparathyroidism.

Conclusions

• Radioactive iodine therapy for benign thyroid diseases contributes to temporary (up to ten months post-treatment) hyperparathyroidism.
• The resultant above normal iPTH levels in the blood serum of treated patients does not significantly affect the concentration of calcium and phosphates in the body.
• Above normal increase in serum iPTH has a positive correlation with thyroid absorbed dose of radioactive iodine.
• In the diagnostic process, radioiodine therapy should be taken into consideration as one of the potential causes of hyperparathyroidism.