The Impact of Radioiodine (131I) Therapy of Thyroid Disease on Salivary Glands Function and Inflammation: A Comprehensive Review

Abstract

Radioactive iodine therapy has been a well-established treatment for various thyroid conditions since the 1940s, targeting both benign diseases and malignancies. Treatment for benign conditions typically involves low doses of 131I, often requiring no more than two treatments, with the dose either fixed or personalized based on thyroid tissue mass and iodine uptake. In contrast, differentiated thyroid cancer treatment often requires higher doses and multiple administrations, especially for metastatic cases. Recent guidelines and studies have proposed more conservative management strategies, including careful follow-up, due to concerns over the high risk–benefit ratio in selected cases with a low risk of disease recrudescence. Despite its possible efficacy, radioiodine therapy is associated with dose-dependent side effects, the most common of which is salivary gland dysfunction or inflammation, affecting approximately 30% of adult patients. These effects pose significant challenges in nuclear medicine practice. This review aims to summarize the latest evidence on the incidence, impact on quality of life, prevention strategies and the role of these side effects in the decision-making process regarding RAI therapy.

1. Introduction

Radioactive iodine (RAI) therapy is a well-established treatment for several thyroid conditions, performed since the 1940s [1]. The targets of RAI therapy include benign diseases such as multinodular goiter (MNG) and Graves’ disease (GD), as well as malignancies, particularly but not only differentiated thyroid cancer (DTC) [2,3,4].

The treatment of benign conditions typically necessitates a low dose of RAI [5,6], with the possibility of choosing between a fixed or personalized dose calculated by estimating the mass of thyroid tissue, typically no more than a few dozen grams, and the time function of iodine uptake in this mass. In addition, the therapy of benign thyroid diseases generally requires no more than two treatments [7,8]. Conversely, the therapy of DTC mandates a higher dose of RAI activity with the administration of at least 1.1 Gigabecquerel (GBq). Furthermore, multiple high-dose RAI administrations are sometimes required, especially in metastatic disease [9,10].

Recently, some international guidelines and studies have proposed the limitation of RAI therapy and the endorsement of a more conservative management approach, based on follow-up, particularly in the treatment of DTC. This is due to the presumed high risk–benefit ratio of the therapy in selected cases following thyroidectomy [11,12], during follow-up in the event of biochemical evidence of disease relapse and/or indeterminate data [13,14] and after a high cumulative dose of RAI [15]. In this context, it has been highlighted that RAI therapy is associated with some dose-dependent side effects, of which salivary gland dysfunction and/or inflammation is one of the most common, occurring in around 30% of adult patients [16]. Although other rare adverse effects such as male infertility and acute leukemia have been reported with high-dose RAI [11,17], xerostomy and sialadenitis may also occur with intermediate-dose RAI and represent a challenge in the daily practice of nuclear medicine [18].

The aim of this comprehensive review is to summarize the most recent evidence on the incidence, impact on quality of life, possible prevention and the possible impact on the decision whether or not to perform RAI therapy due to the possible resulting salivary gland effects. Finally, a schedule will be advanced as a possible reference for mitigating salivary gland toxicity in nuclear medicine clinical practice.

2. Mechanism of the Salivary Gland’s Damage and Pre-Clinical Studies

The biological distribution of 131I is mainly due to two different pharmacokinetic mechanisms: Firstly, the elimination route of radioiodine, which is mainly through the kidneys, bladder and urine. Secondly, the different expression of the sodium–iodine symport (NIS) in different organs [19,20], which can allow the concentration of iodine in the cells with an active transport. The thyroid gland, particularly the follicular thyroid cells, present the highest level of NIS expression due to the necessity of the iodine for thyroid hormone production. In any case, NIS is also highly expressed in other tissues such as the mammary glands during lactation, the stomach and the principal salivary glands, particularly the parotid and submaxillary glands, both located in the neck and with a weight of a few grams [21].

Due to this heterogeneous distribution [22], the thyroid is not the only target organ of the radiation derived from RAI: in particular, salivary glands concentrate 131I through the high expression of NIS and result as one of the organs with the highest dose exposure [23]. However, this dose appears to be limited in the treatment of benign thyroid disease, and usually, the mean absorbed doses by these organs are about 0.63 Gray (Gy) for patients with Graves’ disease and 1.1 Gy for multinodular goiter [24]. Instead, in the case of RAI therapy for DTC, the absorbed dose in the salivary glands appears to be very variable and generally higher than 0.2 milligray/megabecquerel (mGy/MBq) for the parotid glands and 0.14 mGy/MBq for the submaxillary glands [25,26], resulting in a higher total absorbed dose depending on the amount of administered RAI activity. As in the thyroid tissue, low-penetration β-particles emitted by RAI (max energy 606 Kilo-electronvolt (keV), mean energy 190 keV) into tissues possess the capacity to ionize the surrounding atoms. This process subsequently results in the damage of cellular deoxyribonucleic acid (DNA), ultimately leading to the demise of the affected cells. If thyroid cells’ death represents the goal of the therapy in both the treatment of DCT and hyperthyroidism, the damage to salivary gland cells is a known and relatively frequent adverse effect resulting in subsequent xerostomia and/or possible sialadenitis [27].

Pre-Clinical Studies

The mechanisms related to genetic damage derived from RAI have been described in some studies in rats, with possible involvement of the ADAMTS genes, particularly with increased expression of ADAMTS2 and ADAMTS5 and decreased expression of ADAMTS12 [28,29]. Moreover, a single study described that the p53 gene does not appear to be involved in the process [30].

Considering the prevention of salivary gland damage, a number of potential protective agents, including alpha-lipoic acid, curcumin, keratinocyte growth factor-1 (KGF1) and ginseng, have been studied in murine models [31,32,33,34]. In particular, the group of researchers of Kim JM et al. wrote three papers [31,33,34] in which they demonstrated that use of KGF1, curcumin and red ginseng of Korea apparently may guarantee the protection of salivary glands in mice treated with RAI. Furthermore, in a single study on rabbit amifostine it apparently could reduce the risk of salivary gland damage after a high dose of RAI [35].

While murine studies demonstrate the protective effects of KGF1 and curcumin, translational challenges exist. For instance, rat salivary glands exhibit higher NIS expression than humans, and radiation sensitivity varies across species. Human trials are needed to confirm these findings. Future research should prioritize clinical validation of pre-clinical agents like KGF1, adjusting for interspecies metabolic differences [28,29,30,31,32,33,34,35].

3. Damage Diagnosis and Assessment

Despite the recognized potential for salivary gland damage to occur subsequently to RAI, the diagnostic process and the quantification of xerostomy grade and its impact on quality of life remain under debate. The evaluation of xerostomy and/or salivary gland inflammation, with the exception of patients enrolled in study protocols, is typically initiated only in instances where patients who have undergone RAI report symptoms. In other scenarios, these findings may be incidentally found during routine ultrasonographic examinations, particularly in the context of thyroid cancer surveillance [36,37].

The diagnosis and subsequent assessment of the patient can be performed by clinical evaluation and diagnostic imaging examinations, including radiological and nuclear medicine procedures.

Table 1. A summary of the potential and limitations of each of the main methods of diagnosing and quantifying salivary gland impairment after RAI.

Assessment Methods	Potential	Limitation	Routinary Application
Questionnaire	Administration easiness	Subjective perception of patients	Possible
Ultrasound	No radiation exposure, routinely performed in the DTC follow-up.	Possibility of false positive result (no clinical manifestation)	Yes
Salivary Gland Scintigraphy	Possibility of quantifying the reduction in functionality of a single salivary gland.	Possibility of false positive result (no clinical manifestation), radiation exposure	No
MRI, CT	/	Costs, radiation exposure (CT), availability (MRI)	No

at the end of this section summarizes the key characteristics of each method.

3.1. Clinical Assessment

The clinical assessment of salivary gland impairment is typically performed by physical examination and the administration of specific questionnaires. In particular, different studies have applied this procedure, with the first method including the evaluation of the presence of specifics signs such as edema, redness in the area of the salivary glands, purulent discharge, cracking at the corners of the mouth, salivary glands atrophy, etc. [38].

The second instrument evaluated both symptoms and the impact on quality of life [39,40]. For example, Buchholzer S. et al. [39] proposed a six-question questionnaire (RAI-6) that assessed the degree of xerostomia, the frequency of salivary gland tingling and swelling, and the impact on quality of life, and produced a score related to the degree of impairment. The score obtained showed a statistical correlation with the administration of RAI therapy and the dose of RAI administered. Another study of Moreddu E. et al. [41] tested a self-administered questionnaire to check for the presence of pain, dry mouth or xerostomia, and discomfort or swelling. The use of the instrument was limited to checking the presence of these side effects after RAI therapy. Although these instruments appear easy to use clinically, they are limited by the subjective perception of symptoms by patients.

3.2. Ultrasound Assessment

Salivary gland damage can also be detected by ultrasound [42,43], which is usually performed as part of routine follow-up in thyroid cancer. Despite its convenience and availability, the examination has the limitation that ultrasound changes in the salivary glands sometimes appear before clinical manifestation: a proportion of patients could have a positive ultrasound without any clinical complaint [44]. Regarding ultrasound features, there is general consensus about the correlation between atrophy and xerostomia, and most of the studies focusing on this topic describe a reduced echogenicity and irregular margins in the parotid glands of patients treated with RAI [36,43,44]. There is literature consensus about the correlation between the dose of administered RAI and the probability and severity of these ultrasound findings [36,42]. A quite recent meta-analysis by Lima GAS et al. [45] summarizes these findings; in particular, echotexture heterogeneity was found with a significant difference in patients treated with 131I.

3.3. Nuclear Medicine Assessment

Nuclear medicine assessment of salivary gland damage after RAI therapy is not routinely performed in clinical practice. However, in the context of scientific research, it has been described that salivary gland scintigraphy with 99mTc-pertecnetate (99mTc-O4-) can assess the difference in salivary gland function before and after RAI administration, with the possibility of quantification [46,47,48,49]. The most recent of these studies was performed by Wu JQ et al. [49], which described a complete loss of the maximum secretion rate of the parotid glands in the case of treatment with 131I doses higher than 600 millicurie (mCi), but no significant decrease in them with doses lower than 150 mCi. As with the ultrasound findings, the scintigraphic assessment confirms the dose-dependency of the damage, the possible utility of sialagogue drugs/substances and the preferential involvement of the parotid glands. Another analogy with ultrasound findings is the possibility of detecting mild salivary gland damage without clinical manifestations [47].

3.4. Other Imaging Techniques

Computed tomography (CT) and magnetic resonance imaging (MRI) are described in a few studies as potentially useful techniques in the diagnosis of salivary gland damage after RAI therapy. In particular, Shen J et al. [50] described a correlation between symptoms and MRI findings. Furthermore, with regard to CT imaging, Nabaa B et al. [51] found that a reduction in salivary gland volume and an increase in attenuation on CT could be indicators of the degree of RAI-induced dysfunction. This technique does not have any practical application in everyday clinical practice.

4. Xerostomy and Sialadenitis in Radioiodine Therapy of Benign Thyroid Disease

Treatment of benign thyroid disease, such as hyperthyroidism in Graves’ disease or a hyperfunctioning multinodular goiter, usually requires low doses of RAI: the administered activity is usually between 370 and 555 MBq (10–15 mCi) and rarely, only in the case of a large goiter, exceeds the limit of 1000 MBq [52,53]. Consequently, as reported in the literature, the absorbed dose in the salivary glands appears to be low [26] and the possibility of RAI-induced damage to the salivary glands is very rare, and only occurs with the administration of the higher activity [52]. The risk of sialadenitis and xerostomy appeared to be so negligible that more than one set of international guidelines regulating RAI treatment for benign thyroid disease does not mention these side effects in their documents [54,55]. Concerning single studies, Chielens L et al. [56] described a single centre experience in treating Basedow with RAI in adolescents: in 14 patients treated with doses ranging between 5.8 and 15 mCi, only one presented with a transient salivary gland inflammation (7.14%). Furthermore, Okkalides D [57] reported similar results with only one hyperthyroid patient out of 16 treated with RAI showing persistent salivary gland dysfunction (6.25%). The patient in this study received activities ranging from 360 to 550 MBq. The author also pointed out that a negative psychology of the patients could influence their results negatively. Finally, Ford H et al. [58] carried out a study of salivary composition in patients with hyperthyroidism compared with euthyroid patients. As part of the study design, salivary flow (milliliters per minutes [mL/min]) was also assessed before and after treatment with 370 MBq of 131I in 26 hyperthyroid patients. The results showed a reduction in salivary flow of only 3.1% after RAI therapy, with no statistical difference between flow before and after treatment. These results confirm that xerostomia is a very rare finding in hyperthyroid patients treated with RAI. Anyway, one significant limitation of the reported studies was the small size of the sample groups.

In terms of international guidelines, the American Thyroid Association (ATA) provided its in 2016 [54], representing an example of the lack of indication in this setting. Instead, the European Association of Nuclear Medicine (EANM) published a recent version of its guidelines in 2023 [52], which reported a possible incidence of salivary gland side effects of 20–30%, especially in patients receiving more than 1 Gbq, but considering references about RAI treatment in DTC. Furthermore, the EANM 2023 guideline suggests the administration of lemon juice starting 24 h after treatment as a valid prevention.

5. Xerostomy and Sialadenitis in Radioiodine Therapy of DTC

Acute sialadenitis is a known challenge and a common side effect of RAI performed for thyroid cancer treatment. In addition, the possibility of chronic damage, particularly to the parotid glands, with the development of xerostomia, is well known. These effects are generally related to the administered dose and the number of treatments received by the patient [59]. A large number of studies and reviews have been carried out and are available in the literature: the topic will be treated by distinguishing between a single dose of RAI with the aim of remnant ablation and adjuvant intent and the high-dose therapy and/or multiple treatments performed in the case of structural disease due to DTC.

5.1. Remnant Ablation and Adjuvant Therapy

Radioiodine therapy in DTC always has the aim of remnant ablation: in this setting, patients generally receive RAI activity between 1.1 and 1.85 GBq (30–50 mCi), as suggested by international guidelines [11,60]. In the presence of adjuvant intent, particularly in patients with an intermediate and high risk of disease recurrence, the administration of RAI activity could be increased up to 3.7–5.55 GBq (100–150 mCi). In general, higher activity is limited to patients with suspected or certain persistence of structural disease.

With regard to the effects of a single dose of RAI on salivary gland inflammation and function, the literature is consistent in concluding that these depend on the activity administered; in particular, lower activities are associated with a low risk of sialadenitis and xerostomia [42,47,49,61,62,63,64], and these symptoms, if they occur, are in most cases transient [50,65,66].

Considering single studies, Horvath et al. [42], evaluating the possible salivary gland impairment by ultrasound examination, did not find any injury in 156 patients who received 1.1 GBq and 1.85 GBq of RAI. In a similar setting, Musso L et al. [63] described a probability of xerostomia of about 5.26% with a median duration of 3.5 months in patients treated with a dose not exceeding 50 mCi, An YS [62] reported a probability of sialadenitis of about 5.26% in patients treated with 30 mCi and Lin WY [64] suggested a probability of dry mouth of 5.35% with rapid resolution in most cases in patients treated with a dose of 40 mCi. These studies documented the very low probability of salivary gland impairment using an ablative dose of RAI in DTC treatment.

Raza H et al. [46] documented by salivary gland scintigraphy that patients treated with less than 150 mCi showed just a small reduction in the maximum secretion and uptake rate of both the parotid and submandibular glands, with no statistical difference with patients not treated with RAI. Similar and better results were found by Wu JQ et al. [49] who analyzed salivary gland scintigraphy in 368 patients with DTC, 194 treated with RAI and 178 untreated with RAI: they found that 78 patients in the treatment group with a dose of less than 150 mCi showed no difference in the maximum glandular secretion rate and the uptake indexes of both the parotid and submandibular glands in comparison to patients in the control group, and only 5 of 78 patients had a mild sensation of dry mouth. Furthermore, an interesting prospective study published by Baudin C et al. [61], which evaluated the possible impact of RAI therapy on the salivary glands 6 months after treatment, confirmed a dose dependency of the occurrence of dry mouth sensation and stimulated salivary flow (−0.08 mL/min per 1 Gy), but without the appearance of pain or an increase in the number of patients with hyposalivation when compared to pretreatment conditions. Although some dysfunctions were noted, no obvious clinical disorders were found after 131I therapy. Summarizing, these studies quantified the possible salivary gland damage and described a very low impact of a single RAI treatment.

Le Roux MK et al. [65] presented a study considering patients treated with adjuvant doses of RAI (3.7 GBq): 162 patients were enrolled and all the symptoms of salivary gland impairment significantly decreased in number after 6 years, with the exception of the xerostomia which was also the most frequent (39.4% of the patients after RAI, 31.9% of the treated patients at the end of the follow-up). Moreover, Grewal RK et al. [66] describe a significant decrease in the number of salivary gland side effects during follow-up of patients treated with RAI (39% of patients after treatment, 5% of patients after 7 years of follow-up). Again, 14% of the patients treated with a low dose (30 mCi) and 40% of the patients treated with 75 mCi or more developed these transient problems.

These studies described a transient nature of most of the symptoms associated with salivary gland involvement, but at the same time underline that high RAI activity could induce the presentation of some problems, especially xerostomia. The main limitations of these studies were the small sample size in some cases, the retrospective nature of most of them and the different methods used to assess salivary gland impairment.

5.2. High-Dose Therapy and Multiple Treatments

Doses of RAI equal to or higher than 3.7 GBq, especially in multiple treatments, are clearly associated with the onset of salivary gland side effects with an incidence higher than 30% in cases of doses higher than 3.7 GBq and over 50% in patients receiving more than 7.4 Gbq [42,47]. The aforementioned paper by Musso L et al. [63] described a possible increase in the probability of salivary gland impairment with higher doses of RAI. Some other articles and reviews confirmed these findings and described that salivary gland involvement was also frequently bilateral, parotid gland involvement was most common, the probability of recovery was low and complete impairment seemed possible when more than 500 mCi (18.5 GBq) was administered [67,68,69,70,71,72,73].

In particular, Alexander C et al. [67] reported an incidence of sialadenitis of 33% in 203 patients treated with RAI at doses equal to or greater than 3.7 GBq. In particular, sialadenitis and dry mouth occurred in less than 10% and 25% of the patients treated with doses between 3.7 and 5 GBq, respectively; in contrast, more than 45% and 60% of patients treated with doses between 10 and 18.5 GBq, respectively, developed these symptoms. Dingle IF et al. [68] reported that sialadenitis was 2.47 times more likely to occur in patients who received doses greater than 150 mCi when compared with those who received less than 150 mCi. Furthermore, Klein Hesselink EN et al. [69] performed a prospective study reporting a decrease of at least 25% in stimulated whole saliva flow rate in 34% of patients treated with RAI doses ranging from 3.7 to 5.55 GBq and a ≥50% drop in saliva in 10% of patients treated with higher activity. Similar results were reported by Lee NH et al. [70], who described a probability of sialadenitis of 8.7% in patients treated with 30 mCi, 46.7% in subjects treated with 100 mCi and 69.4% in patients treated with 150 mCi. Again, considering single studies, Jeong SY et al. [71] reported a probability of salivary gland impairment and xerostomia, respectively, of 20 and 16% in patients treated with a single RAI therapy using an activity ranging from 3.7 to 5.55 GBq. This probability was higher in patients treated with higher activity. Considering these studies, the same limitations reported in studies performed on patients undergoing remnant ablation and adjuvant treatment were evident.

A relatively old review of Mandel SJ et al. [72] reported a probability of abnormal salivary gland function in as many as 80% of the patients treated with dosages of 500 mCi (18.5 GBq), approaching 100% when higher doses were used. Another review by Van Nostrand et al. [73] described an incidence of sialadenitis ranging from 2 to 67%, but excluding the study with the smaller sample, this range was restricted to 2 to 39%. The studies reported in this review, although generally old, confirmed the relationship between the dose and number of RAI treatments and the likelihood of developing salivary gland side effects. Finally, an interesting systematic review by Clement SC et al. [74], which included the study of Jeong SY et al. [71], reported that the incidence of symptomatic salivary gland dysfunction ranged from 16 to 54% of patients treated with RAI, with a general association with the dose administered and, in one study, with the number of treatments. Unfortunately, only two trials included in the review reported the mean or median dose administered, both of which were significantly higher than 3.7 Gbq.

Table 2. Summary of the main characteristics of the reported studies on possible salivary gland impairment after RAI administration.

References	Authors	RAI Dose (GBq)	Number of Patients	Incidence of Side Effects (%)	Study Design
[42]	Horvath E et al.	1.1–1.85	156	0 **	Retrospective
[62]	An YS et al.	1.1	19	5.26 ****	Retrospective
[63]	Musso L et al.	1.1–1.85	66	0 *	Retrospective
[70]	Lee HN et al.	1.1	46	8.7 ****	Retrospective
[64]	Lin WY	1.48	56	5.35 *	Retrospective
[42]	Horvath E et al.	3.7	219	21 **	Retrospective
[62]	An YS et al.	3.7	44	38.6 ****	Retrospective
[70]	Lee HN et al.	3.7	45	46.7 ****	Retrospective
[71]	Jeong SY et al.	3.7	Nd	7.8 ***	Retrospective
[42]	Horvath E et al.	5.55	177	46.9 **	Retrospective
[62]	An YS et al.	5.55	49	34.7 ****	Retrospective
[63]	Musso L et al.	2.96–5.55	76	5.26 *	Retrospective
[67]	Alexander C et al.	4.4–5	38	20–25 ***	Retrospective
[68]	Dingle IF et al.	1.1–5.55	58	11.9 ****	Retrospective
[69]	Klein Hesselink EN et al.	3.7–5.55	56	34 *****	Prospective
[70]	Lee HN et al.	5.55	62	69.4 ****	Retrospective
[71]	Jeong SY et al.	5.55	Nd	17.9 ***	Retrospective
[68]	Dingle IF et al.	>5.55	58	23.8 ****	Retrospective
[62]	An YS et al.	7.4	3	66.7 ****	Retrospective
[70]	Lee HN et al.	7.4	4	50 ****	Retrospective

* xerostomia, ** salivary gland alteration detected by ultrasound, *** dry mouth, **** sialadenitis, ***** reduction > 25% in saliva flow rate.

summarizes the main results of studies with complete information.

Regarding the administration of high and/or multiple doses of RAI, it is fundamental to establish the setting to have a clear evaluation: as previously reported, a second dose of RAI could actually only be considered in the presence of biochemical or structural persistence of DTC disease, and only patients with metastatic disease require multiple RAI treatments [11]. Patients with DTC could have a real impact on their life expectancy through RAI treatment [75,76], and second-line therapies, such as tyrosine kinase inhibitors (TKIs), also present possible serious side effects [77,78] and they appear as a “one-way street” therapy without the possibility of suspension [79].

The variable rates of xerostomia/sialadenitis are also probably due to differences in study design, RAI dosing protocols and patient populations. Future research is also desirable to highlight and clarify the remaining gaps regarding long-term salivary function after RAI and the comparative effectiveness of protective agents.

6. Prevention of Salivary Glands Disfunction

Salivary gland protection during radioiodine therapy for DTC has become an important concern due to the potential for long-term damage. Several strategies have been explored to mitigate the negative effects of radioiodine on salivary glands, such as the use of antioxidants, pharmaceuticals and non-pharmacological methods.

6.1. Vitamin C and Lemon Juice

Vitamin C and lemon juice have shown promise in reducing the absorbed dose of radioiodine in the salivary glands, with studies suggesting that their administration can minimize damage and improve glandular function after treatment [80,81,82]. Similarly, the optimal timing of vitamin C and lemon juice administration has been investigated to determine the best approach to reduce salivary gland dysfunction: in particular, Liu Y et al. [80] described an optimal timing to maximize beneficial effects with administration starting 2 h after RAI, whereas Nakada et al. [82] reported 24 h after RAI as the optimal timing for lemon candy administration.

Regarding salivary gland exposure, a study by Liu B et al. [83] described only a limited effect of vitamin C, whereas Kulkarni K et al. [84] and Van Nostrand et al. [85] reported a significant effect of lemon juice in reducing the dose absorbed in the salivary glands, especially with repeated administration. In general, the administration of lemon juice is considered effective in reducing parotid gland damage and is good practice in patients treated with 131I for DTC [60].

6.2. Amifostine

The radioprotective agent amifostine has also been studied for its potential role in salivary gland protection in patients undergoing high-dose radioiodine therapy for DTC [86,87,88], with contrasting results. In particular, Bohuslavizki KH et al. [87] found positive results in a double-blind, placebo-controlled study, with a reduction in glandular damage. In contrast, Kim SJ et al. [88], who quantitatively evaluated the effect of amifostine use by salivary scanning, did not report any improvement in salivary gland preservation.

6.3. Pilocarpine

Pilocarpine, a cholinergic agent, has also been tested for its potential ability to restore salivary function by stimulating glandular activity and reducing the dose rate of radioiodine to the glands [89,90]. As for amifostine, the results were inconclusive: the study by Haghighatafshar M et al. [89] did not show a different dose rate between patients treated or not treated with pilocarpine; instead, Aframian DJ et al. [90] found that it may be beneficial in the case of impaired salivary function in patients treated with radioiodine.

6.4. Mechanical Interventions

Mechanical interventions have been explored as adjunctive methods to further protect the glands: in this setting, massage of the parotid glands, as reported by Hong CM et al. [91], could significantly reduce the dose rate to the glandular tissue and thus its potential damage.

6.5. Vitamin E

Vitamin E has been shown to play a possible role in mitigating the damage to salivary glands caused by RAI therapy. Upadhyaya et al. [92] conducted a randomized controlled trial that highlighted a beneficial impact of vitamin E supplementation in preserving salivary gland function following radioiodine therapy, noting improvements in glandular secretion and a decrease in xerostomia. Similarly, Fallahi et al. [93] reported that vitamin E provided protective effects against 131I radiation, suggesting a potential therapeutic strategy to prevent or reduce salivary gland dysfunction in this setting. These findings collectively support the inclusion of vitamin E as a possible adjunctive treatment in the management of RAI-induced salivary gland damage.

In addition, at least two interesting systematic reviews on possible salivary gland protective agents are available in the literature [94,95]: Firstly, Christou A et al. [94], which included References [82,83,84], reported the results of studies without pharmacological intervention, describing good results with sialoanalogues such as lemon juice or candy and vitamin E, and the same positive correlation with salivary gland massage. The administration of vitamin C appeared to have a limited protective effect and chewing gum was ineffective. Moreover, Auttara-Atthakorn A et al. [95] conducted a systematic review of randomized controlled trials which confirmed that not only parotid gland massage and vitamin E, but also aromatherapy, selenium, amifostine and bethanechol, may be beneficial in minimizing RAI-induced salivary gland dysfunction in patients with DTC.

Table 3. Summary of the main characteristics of the reported studies on possible prevention strategies for salivary gland impairment after RAI administration.

References	Authors	Prevention Agent	Number of Patients	Efficacy	Study Desing
[80]	Liu Y et al.	Vitamin C	460	Yes *	Retrospective
[81]	Jafari E et al.	Vitamin C	58	Yes	Prospective randomized
[82]	Nakada K et al.	Lemon candy	230	Yes **	Prospective
[83]	Liu B et al.	Vitamin C	72	Limited	Prospective randomized
[84]	Kulkarni K et al.	Lemon juice	9	Yes ***	Prospective
[85]	Van Nostrand et al.	Lemon juice	29	Yes ***	Retrospective
[87]	Bohuslavizki KH et al.	Amifostine	17	Yes	Retrospective
[88]	Kim SJ et al.	Amifostine	80	No	Prospective
[89]	Haghighatafshar M et al.	Pilocarpine	22	No	Prospective randomized
[90]	Aframian DJ et al.	Pilocarpine	5	Limited ****	Nd
[91]	Hong CM et al.	Parotid gland massage	44	Yes ***	Prospective
[92]	Upadhyaya et al.	Vitamin E	82	Yes	Prospective randomized
[93]	Fallahi B et al.	Vitamin E	36	Yes	Prospective randomized

* administration from 2 h after RAI, ** administration from 24 h after RAI, *** reduction in salivary gland irradiation, **** the study reported some benefit in the administration after RAI damage.

summarizes the principal characteristics of the studies reported in this section.

Collectively, these studies highlight the importance of different protective strategies to minimize the risk of salivary gland damage and improve the quality of life of DTC patients undergoing radioiodine therapy. The mixed results for all the methods warrant a clearer hierarchy of evidence. The strongest evidence of efficacy is provided by lemon juice and sialoanalogues, which are therefore strongly recommended; conversely, amifostine shows limited or conflicting evidence, necessitating further studies. From a practical point of view, the recommendation could be to suggest lemon juice, vitamin E and gland massage as first-line measures due to their safety with minimal side effects and accessibility. The ATA guidelines for DTC management [11] report in recommendation 85 that no prevention strategies appear to be clearly associated with benefit and therefore do not recommend them, particularly for lemon juice, as despite clear evidence of its efficacy, the problem of the timing and frequency of administration was reported. Furthermore, the EANM guidelines for the management of DTC [60] suggest the administration of lemon juice and/or sour candy without a clear indication of timing and frequency. Parotid massage and vitamin E were not included in these guidelines. By reviewing all the reported studies and prioritizing them in the clinical workflow, we try to propose a possible simple flowchart for the prevention and monitoring of salivary gland side effects, which is subsequently shown in Figure 1.

7. Conclusions

Salivary gland damage, coupled with the subsequent occurrence of xerostomia and sialadenitis, is a potential adverse effect associated with RAI therapy in thyroid disease. However, low doses of RAI present a very low risk of these side effects, and when high doses are administered, the clinical rationale may justify the risk of salivary gland damage. Furthermore, available evidences suggest that measures exist to prevent gland impairment. However, for high-dose RAI in metastatic DTC, a strong emphasis on shared decision making in a dedicated tumor board is desirable, weighing survival benefits against quality-of-life impacts and aligning with modern patient-centered care. In this setting, clinicians should engage patients in shared decision making, explicitly addressing salivary risks versus oncologic benefits and prophylactic measures must be prioritized. In conclusion, while the potential for a decline in quality of life exists, it does not appear to clearly influence the indication for RAI in most cases.