PERSPECTIVE: Prioritizing quality of life in the management of hyperthyroidism: an expert clinical perspective

Abstract

Graphical abstract

Abstract

Hyperthyroidism adversely affects quality of life (QoL), encompassing physical, mental and social functioning and well-being. Patients with hyperthyroidism often complain of anxiety, physical symptoms and tiredness. Concurrent thyroid eye disease (TED) further reduces QoL. With treatment of hyperthyroidism, QoL improves. Symptoms of hyperthyroidism, overall QoL and tiredness are among the domains that improve with a high effect size. Notwithstanding, the overall reduction in QoL persists compared to a matched general population, which seems to relate to residual tiredness, mental fatigue and concerns about levothyroxine substitution, ophthalmological symptoms and weight gain. Common factors contributing to reduced QoL in the long term have been described and include a high prevalence of thyroid dysfunction, the psychological burden of chronic illness, TED, possible inability of levothyroxine replacement to restore euthyroidism in all tissues, and central nervous system residual damage and/or dysfunction. The aetiology and treatment modality for hyperthyroidism may also play a role. In addition, a recently highlighted contributor and predictor of poor QoL is excessive weight gain, which given the global epidemic of obesity, mandates further attention. Regarding newer therapies for hyperthyroidism, notably radiofrequency ablation and molecular targeted immunotherapies, there is a dearth of objective data on QoL. New or improved tools for assessing QoL may be needed to better capture all concerns of these patients. There is a need for randomized controlled studies to guide practitioners regarding which pharmacological or non-pharmacological interventions offer the best long-term QoL outcomes in hyperthyroidism. Anti-obesity medications to mitigate weight gain could also be considered for such patients.

Plain language summary

Thyroid overactivity (hyperthyroidism) worsens patients’ QoL, which usually improves after treatment. However, QoL is not completely restored for many patients. The reasons are multiple, including excessive weight gain. New approaches in treating hyperthyroidism are needed to address the long-term effects on QoL.

Introduction

Hyperthyroidism affects approximately 1% of the population in iodine-sufficient areas, with Graves’ disease (GD) accounting for 70–80% of cases (1). The majority of patients treated for hyperthyroidism require life-long thyroid hormone replacement therapy, either as a result of treatment or due to the natural history of GD (2). Thus, a discourse on quality of life (QoL) in hyperthyroidism needs to be approached in the context of chronic disease.

Definition of quality of life

The World Health Organization describes QoL as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns” (3). QoL in disease states includes patients’ appraisal of the impact of illness and its treatment across physical, somatic, mental and social domains of functioning, well-being and satisfaction (4).

Measurement tools for quality of life

Multidimensional health-related QoL is an essential parameter for informing patient-reported outcome measures (PROMs) and patient-reported experience measures (PREMs), which have become an integral part of patient-centred health care and are increasingly utilized by healthcare commissioners and policy makers.

QoL measurement tools can be generic or disease-specific. Generic measures, such as the Medical Outcomes Study 36-item Short Form (SF-36) and EQ-5D (EuroQol group) instruments, can be used to compare patients across different illnesses or the general population. Disease-specific measures are validated for individual medical conditions and show better sensitivity for that illness. For benign thyroid diseases, the Thyroid Patient-Reported Outcome (ThyPRO) and its shorter version (ThyPRO-39) are the best evaluated tools (5, 6). Whenever possible, a combination of generic and disease-specific tools is preferred.

Hyperthyroidism-related quality of life

During the active phase of the disease, when patients are clinically and biochemically hyperthyroid, QoL is reduced (7). Such patients often complain of fatigue, cognitive impairment, emotional lability, agitation, memory and concentration deficits, anxiety and depression (7, 8, 9). Magnetic resonance imaging of the brain has shown reduced amygdala and hippocampi volumes in patients with GD compared with controls (10). The amygdala is involved in decision-making, emotional memory formation and social interactions, whereas the hippocampus is important in emotional and general memory formation and retrieval and spatial navigation. At the molecular level, there are changes in serotonin and noradrenaline receptors in the brain (8). The severity of anxiety and depression correlated with reduced glucose-uptake in the brain limbic and paralimbic systems as demonstrated by fluorodeoxyglucose positron emission tomography imaging (11). Thus, acute hyperthyroidism has a negative impact on brain morphology and function.

One study used effect sizes to quantify QoL differences; these were calculated by the mean change in QoL scores divided over the baseline standard deviation (7). At diagnosis, QoL was significantly worse than in the general population with a large effect size (Cohen’s d > 0.8). Anxiety, tiredness and physical symptoms were common complaints. Patients with GD were found to have comparatively worse QoL vs toxic multi-nodular goitre (TMNG), and this may be attributed to the more rapid onset, more severe clinical and biochemical thyrotoxicosis and the presence of thyroid eye disease (TED) (7, 8). The evidence is unequivocal that TED adversely affects QoL. Indeed, much emphasis has been given in recent decades to improving the management and care pathways of patients with hyperthyroidism and concurrent TED, as reflected in professional guidelines (12, 13).

Overall, the evidence is robust that acute hyperthyroidism causes a pronounced reduction in QoL, and concurrent TED has an amplifying adverse effect.

Quality of life after treatment of hyperthyroidism

Several landmark studies, with at least 50 participants, showed a reduction in QoL in cohorts with treated hyperthyroidism (Table 1). Treatment of hyperthyroidism significantly improves QoL within about six months (7, 14), which coincides with the approximate time interval needed to establish euthyroidism. A large effect size is seen in many scales, including tiredness, hyperthyroid symptoms and overall health-related QoL scales, as measured by ThyPRO (7, 15, 16, 17). However, treatment does not appear to restore QoL to the pre-morbid baseline, even many years post-diagnosis (18). Watt et al. (19) reported reduced general health perceptions in 26–69% of patients treated for hyperthyroidism. Classical symptoms of hypothyroidism were very frequent in this cohort (19), suggesting that iatrogenic hypothyroidism may be responsible for the adverse health perceptions (20). Interestingly, there was remarkable variability in weight-related concerns among patients with treated hyperthyroidism, ranging from 0 to 100%; however, the relationship between weight change and QoL was not examined in this study (19).

Table 1.

Evidence of reduced quality of life in treated hyperthyroidism.

First author	Tools	Main finding(s)/conclusion(s)/other comments
Year/country	n with hyperthyroidism
Study design	Control
Cramon (7) - 2016 - Denmark - Prospective controlled study	- ThyPRO and SF-36 - n = 156 assessed at Δ and 6 months after Rx - Compared to general population data	- Baseline scores were significantly worse vs general population - Significant improvement in QoL was observed 6 months’ post-therapy - Significant QoL deficits remained in multiple domains vs general population - Patients with GD had significantly worse QoL at baseline vs TMNG, but scores were similar at 6 months - Response rate was 65% at follow-up
Sjölin (29) - 2019 - Sweden - Longitudinal study	- Custom-made questionnaire, ThyPRO and SF-36 published separately (21) - n = 1,186 followed-up for mean 6–10 years after their Δ with GD	- 25% reported that they did not feel fully recovered; tiredness, ophthalmological symptoms, levothyroxine substitution issues and risk of recurrence were cited as most common culprits - Patients on levothyroxine replacement were significantly more likely to report not feeling fully recovered, whereas there is no difference between the three treatment modalities (surgery vs RAI vs ATDs) - Response rate was only 51%
Törring (21) - 2019 - Sweden - Longitudinal study	- ThyPRO and SF-36 - n = 1,186 followed-up for mean 6–10 years after their Δ with GD - Compared with matched general population normative data from Denmark	- QoL was reduced across all three treatment modalities vs general population - RAI group had significantly reduced QoL vs ATD or surgery, on majority of scales of both tools; result persisted when analysis was adjusted for the number of treatments received and comorbidities - TFTs were not assessed - Selection bias was still possible - Response rate was only 51%
Abraham-Nordling (32) - 2005 - Sweden - Randomized controlled study	- SF-36 - n = 179 randomized to ATDs, RAI or surgery and assessed 14–21 years later - Compared with age-matched general population	- QoL was significantly reduced compared to the reference population - Deficits were observed in vitality, general health score, mental health score and MCS - About half the patients had a TSH outside of the normal range at the time of study evaluation
Riguetto (33) - 2018 - Brazil - Cross-sectional study	- SF-36, MMSE and GO-QoL - n = 154 with mean duration of 8 years after their Δ with GD - No general population control	- Patients with ongoing thyrotoxicosis (17%) had reduced QoL vs euthyroid cohort - Male sex, euthyroid status, absence of TED and younger age at diagnosis were predictors of better QoL - Regression analysis was unadjusted; consequently, the association between male sex and young with better QoL may reflect general population trends
Al-Adhami (69) - 2012 - UK - Cross-sectional study	- SF-36 - 87 patients with GD who underwent ablative* or thyroid function-preserving surgery†; QoL assessed 7.9 or 18.4 years later, respectively - Compared with general population	- Reduced QoL was observed across all domains of SF-36, including PCS and MCS, vs general population - The lowest scores (i.e. worse QoL) were observed for vitality, general health perceptions and bodily pain - The two surgical groups had similar QoL scores - Response rate was at 65%

^*Total thyroidectomy.

^† Bilateral subtotal thyroidectomy or a unilateral total thyroidectomy with contralateral subtotal lobectomy.

Abbreviations: ThyPRO, Thyroid Patient-Reported Outcome (measure); SF-36, 36-item Short Form health survey; Δ, diagnosis; Rx, treatment; QoL, quality of life; GD, Graves’ disease; TMNG, toxic multi-nodular goitre; RAI, radioactive iodine therapy; ATDs, anti-thyroid drugs; TFTs, thyroid-function tests; MCS, mental component summary; TSH, thyrotropin; MMSE, mini-mental state examination; GO-QoL, Graves’ orbitopathy quality of life (questionnaire); TED, thyroid eye disease; PCS, physical component summary.

The magnitude of improvement and the degree of remaining deviation from the norm are important for determining clinical significance. In the study by Cramon et al., at six months post-treatment, the Graves’ cohort mean (range) difference from the general population was 20 (11–36) points on ThyPRO at diagnosis and 7 (3–11) points at six months; the former difference was significant on all scales and, for the latter, on all but one scale (7). In the study by Afsin et al., the mean (range) improvement from diagnosis to six months was at 16 (0.3–32.7) points on ThyPRO; the improvement was significant for all scales (14). In the Torring et al. study, at six-to-ten years post-treatment, the mean difference from the general population was 6 ThyPRO points, while that for the RAI-treated subgroup was 9 points; the difference was significant on all scales in the RAI-treated subgroup and on 7 out of 9 scales for the anti-thyroid drug (ATD)- and surgically treated subgroups (21). Finally, in the study by Stokland et al., the mean difference from the general population was 3 ThyPRO points for the ATD-treated cohort and 9 points for the subgroup, which developed (post-ablative or spontaneous) hypothyroidism at 25 years post-treatment; the difference was significant in 4 of 9 and 7 of 9 scales, respectively (18). The minimal important change for ThyPRO has been shown to be 6.3–14.3 points for group comparisons (22). Therefore, both the improvement in QoL following treatment of hyperthyroidism and the failure to achieve levels comparable to the background population are not only statistically but also clinically significant.

Causes of reduced quality of life in treated hyperthyroidism

There are several possible explanations for the reduced QoL in hyperthyroidism after diagnosis and restoration of euthyroidism.

Thyroid eye disease

A complication of GD, TED has a well-documented detrimental effect on QoL (23). Negative perceptions of physical and mental health and physical, social and role functioning were reported by such patients to the extent that QoL was worse than patients with diabetes mellitus, emphysema or heart failure, and a nearly three-fold increased prevalence of suicide has been reported (8, 24). In some studies, there was correlation with disease activity and severity (25); the lack of correlation in other studies may relate to the use of generic questionnaire tools. Overall, the combination of GD and TED causes a larger drop in physical and mental component summary (of SF-36) vs GD alone (8). Following treatment of TED, QoL improves but remains lower than in healthy controls (26). Access to TED specialist services is suboptimal in many countries and may contribute to reduced patient satisfaction (27, 28). Current guidelines on TED recommend evaluation of QoL, alongside emotional and psychological patient needs (23).

Fluctuation of thyroid function

Iatrogenic hypothyroidism is a biologically plausible mechanism that may explain reduced QoL (19, 29). While euthyroidism is achievable within 3 months of initiating treatment, empirically, fluctuations in thyroid status go on for much longer. Furthermore, around 40–50% of patients on long-term levothyroxine replacement have abnormal thyroid biochemistry at any one time (30, 31, 32), which may negatively influence their health and QoL (33). Conversely, there is evidence in both treated hyperthyroidism and hypothyroidism that QoL is independent of their thyroid function (17, 34), but these data are from cross-sectional studies and may not capture long-term effects of instability in thyroid status.

Inability of levothyroxine to restore normal thyroid hormone status in all tissues

All patients who undergo total thyroidectomy, about 80% of patients treated with radioactive iodine (RAI) and about 25% of patients who receive a full course of ATDs will develop permanent hypothyroidism (29, 35). Such patients will require life-long levothyroxine replacement therapy. Tetraiodothyronine (T4) is peripherally converted to the more ‘active’ T3 (triiodothyronine) under the control of deiodinase type 2. Deiodinase activity is downregulated by levothyroxine via ubiquitination and degradation (36). Consequently, some tissues could have subnormal intracellular T3 content, despite normal serum TSH. This hypothesis is supported by rodent experiments (20) and has been extrapolated to patients with treated primary hypothyroidism to explain persistent symptoms (36). However, in a systematic review and meta-analysis, there was no significant difference between combination levothyroxine and T3 therapy vs levothyroxine alone regarding QoL, psychological distress, depressive symptoms and anxiety (37). Similarly, numerous other studies, including meta-analyses, using combination therapy have not demonstrated superiority in QoL outcomes vs levothyroxine alone (38, 39).

Patient adherence to levothyroxine, levothyroxine formulations and pharmacokinetics

Patient adherence to levothyroxine, timing of taking medication and interaction between levothyroxine with other medications were not associated with QoL in a large community study (40). Likewise, the evidence that generic or branded levothyroxine formulations impact patient QoL is weak (41).

Central nervous system (CNS) damage and/or dysfunction

As previously alluded to, there are structural and biochemical brain changes in patients with GD (42). Medial temporal lobe volume loss has been observed, which improves with treatment, although some residual defects remain (43). However, these changes did not correlate with mental or other symptom scores nor results of neuropsychological tests (43). Kumar et al. reported metabolic alterations in subcortical brain regions in patients with hyperthyroidism, both prior to and following treatment with anti-thyroid medications; such metabolic changes do not fully normalize after restoration of euthyroidism (44). Another study found that hyperthyroidism and associated metabolic changes in major limbic and paralimbic structures correlated with psychic manifestations in patients with GD (11).

Psychological factors

This may relate to ‘the labelling effect’ where patients’ awareness of a chronic disease label such as ‘hyperthyroidism’ negatively affects their mood (45). Personification (attribution of human features into something non-human) and protagonization (placing the disease as the central character in a person’s life) can accompany chronic diseases. In the context of hypothyroidism, type D personality and somatization are associated with reduced QoL (46, 47). Correlation of type D personality, characterized by tendencies toward negative emotions and social inhibition, with QoL in hyperthyroidism has not been examined but may play a role. An alternative explanation for the observed impact may be a lasting disruption in social functioning. For instance, self-perceived impaired sex life persisted in women treated for GD, suggesting that normalization of thyroid function was insufficient to restore sexual function (48).

Socio-economic factors

Socio-economic factors, such as marital, educational, social and financial status, correlate with QoL in the general population and among patients with thyroid disorders (36, 49, 50). A study examined these variables using ThyPRO-39, among 885 patients diagnosed with thyroid disease (51). Both social support and adherence correlated with QoL; social support partially mediated the association between adherence and QoL (51). However, this study was limited by a cross-sectional design, potential recruitment bias (via social media) and no availability of thyroid function tests.

Conversely, a prospective study of 190 euthyroid patients who underwent surgery for benign non-toxic goitres overall demonstrated that socio-economic factors, such as family, education, financial and employment status, did not influence QoL (52). However, this did not include a cohort with hypothyroidism or hyperthyroidism and had other limitations, such as the use of a generic tool (EQ-5D).

Aetiology of hyperthyroidism

GD seems to be associated with greater reductions in QoL vs TMNG, both at presentation and after treatment, and this was confirmed by a prospective study that recruited patients who underwent surgery (16). Given that TMNG affects an older age group, it is important to adjust for age, alongside other variables (e.g. sex) in studies examining the correlation between different aetiologies of hyperthyroidism with QoL.

Treatment modality

An observational study in patients treated for Graves’ disease six-to-ten years before reported significantly reduced QoL in those who received RAI vs ATDs or thyroidectomy (21). In a randomized controlled study with 14–21 years of follow-up, however, there was no difference in QoL between the three treatment modalities (32). Notwithstanding, the latter study may have been under-powered (n = 179) and relied on the generic SF-36 tool for the QoL assessment. Similarly, there was no difference in the QoL between the three treatment arms in an older prospective randomized study (53), but this was also limited by a small sample size and use of weaker instruments.

In a longitudinal study of 84 patients with hyperthyroidism treated with RAI, there was a significant improvement in all ThyPRO domains at 6 months (14). The ThyPRO-documented change was about −0.3 to −32.7 points (i.e. improvement). The top 5 domains with biggest improvements were general condition (i.e. overall QoL), fatigue, nervousness and mental fatigue, vitality and psychological well-being (14). These reassuring results contrast with the findings of the aforementioned studies, which had a longer follow-up. The obvious explanation for this discrepancy is the lack of a control/alternative therapy group in the latter study, in addition to a small sample size.

In regard to ATDs, a distinction needs to be made between the conventional use of ATDs (for 12–28 months post-presentation) and the use of long-term ATDs (LT-ATDs, often defined as ≥24 months of therapy). In a narrative review of the literature, more than 70 publications were identified comparing LT-ATDs, RAI and surgery (54). QoL appeared better in those with LT-ATDs vs RAI. The authors also concluded that LT-ATDs were correlated with increased likelihood of euthyroidism vs RAI-treated patients on levothyroxine replacement, and less post-treatment weight gain vs levothyroxine-treated ablative hypothyroidism (RAI and surgery) (54). Another retrospective study assessed outcomes of 155 patients with Graves’ disease 25 years post-initiation of ATDs; 82 age- and sex-matched healthy controls were also recruited (18). In an analysis adjusted for age and sex, participants on LT-ATDs had ThyPRO-assessed QoL outcomes that were comparable to the general population, whereas those with hypothyroidism (whether post-ablation or spontaneous) had worse QoL, with higher symptom burden on most scales (18). In particular, although the mean scores of the general population and ATD-treated cohort were similar, the RAI-treated, surgically treated and spontaneous hypothyroidism subgroups had comparatively worse QoL with a mean difference of 4, 9 and 10 points, respectively (18).

Recurrent goitre following thyroidectomy has been shown to impair QoL. A study involving 481 patients who underwent thyroidectomy identified recurrent goitre as a contributing factor to decreased QoL (55), corroborating the recommendation that total (or near-total) thyroidectomy is the procedure of choice and should be performed by high-volume thyroid surgeons (12).

In summary, treatment modality is associated with QoL in patients treated for Graves’ disease, but the development of hypothyroidism is an important confounder and significant methodological differences between studies are noted, which limit interpretation of the evidence. Short-term improvements in QoL are noted after any therapy; however, long-term data suggest that maintenance of euthyroidism, which is more frequently achieved by ATD than other modalities, may be a key determinant of QoL. In patients with concurrent goitre, surgery is favoured, while RAI in some studies is associated with worse QoL.

Excessive weight gain

The relationship between weight change in hyperthyroidism and QoL has received little attention. Excessive weight gain following treatment of hyperthyroidism has been consistently observed, with 40–50% of patients having a percentage weight gain of ≥10% and an increase in overweight and obesity levels by approximately 50% (56, 57, 58). In some studies, the post-treatment weight gain among women was shown to be largely due to a marked increase in fat mass, with an impact on adipokine secretion (59). Risk factors for weight gain include markers of disease severity, primarily disease-related weight loss and presentation serum free thyroxine levels (56, 58). In some, but not all, studies, RAI and iatrogenic hypothyroidism were also cited as risk factors (57, 60, 61). In a retrospective study of 238 patients with relapsed Graves’ disease and a mean follow-up of 5–7 years, the weight gain was significantly and persistently higher with RAI vs the low-dose LT-ATD cohort (62). Interestingly, post-treatment weight gain at three months correlated with an excessive final weight gain (58).

Weight gain is a frequent concern in patients treated for hyperthyroidism, as evidenced by empirical clinical experience, as well as in a patient engagement event, where patients ‘were concerned about the risk of excessive weight gain and its long-term cardio-metabolic consequences’ (63). Indeed, we observed congruent evidence from quantitative (via a custom-made questionnaire) and qualitative (via an open-ended item that underwent thematic analysis) data, and their subsequent triangulation, that weight gain is the most prominent symptom/concern from the patients’ perspective (64). Similarly, in a recent survey of British Thyroid Association (professional) members, 70% reported that they consider an excessive weight gain in hyperthyroidism as a significant clinical problem, but only 23% discuss it with their patients (63), perhaps because there are no relevant guideline recommendations. Therefore, we could hypothesize that the higher the weight gain in the post-treatment period, the more the psychological and physical burden, e.g. with anxiety, depression, physical limitations, cosmetic concerns and tiredness, with consequent reduced QoL. Emerging evidence from a cross-sectional study in 108 patients with treated hyperthyroidism indicated a percentage weight gain of 8.8%, over a mean disease duration of 41 months, and that treatment-related weight gain can predict aspects of QoL, namely appearance and the combined ‘tiredness and overall QoL’ complaints (64). Given the correlation of weight gain with an adverse cardiometabolic profile in the general population, and the increased long-term cardiovascular and overall mortality in hyperthyroidism (65), alongside the availability of effective lifestyle, pharmacological and bariatric surgical treatments, the argument for incorporating weight management in the long-term management of hyperthyroidism is strong.

Other factors

Initial misdiagnosis and ‘uncertainty about the future’ (66) may contribute to poor QoL. This may relate to the amount and quality of health-related information and how well healthcare professionals or other sources (such as the Internet) convey it to patients (67). Other parameters that ought to be considered include factors that influence QoL in the general public, such as age, sex, comorbidities, polypharmacy, smoking status and features of the metabolic syndrome, including adiposity parameters (68); for example, young age (<40 years) and smoking could affect QoL via their known association with Graves’ disease recurrence (18).

Methodological considerations

There is some heterogeneity in the measurement tools utilized by different studies, with some relying only on generic questionnaire tools (32, 69). From a research perspective, there is a dearth of QoL data obtained via qualitative methodologies, such as interviews and focus groups, or with the application of grounded theory.

Most studies assessed QoL in northern European populations, so the results may not be generalizable to other ethnicities. Study design heterogeneity was also present, and some studies were not appropriately adjusted, e.g. for age, sex, comorbidities, thyroid function at study evaluation and disease duration. QoL is a subjective concept and is affected by how a person feels and reflects their experiences in the short term. Thus, when measuring the QoL months or years after treatment, unmeasured confounders may influence the results, and recall bias is a concern. The research question about which treatment modality offers the best QoL outcomes is complicated by the fact that there is inherent selection bias in choosing different therapies in hyperthyroidism.

Quality of life with newer therapies

Ablative techniques, such as radiofrequency ablation (RFA) have been successfully applied for benign nodular disease, including toxic nodules. In a recent prospective study, 56 patients with 76 benign thyroid nodules were subjected to RFA and followed up over a period of 3–12 months. The median volume reduction was about 80% at one year. At final evaluation, significant improvements were reported for goitre symptoms, anxiety, appearance and overall QoL, with a moderate effect size (70). However, this study did not have a control group. Comparative studies of RFA vs surgical management exist, confirming a nodular volume reduction with RFA with mild complications (71), but there is a lack of QoL data and most studies suffer from small sample sizes, lack of long-term outcome data and recruitment of patients with benign goitre rather than hyperthyroidism.

Newer pharmacological therapies are now emerging for GD, such as monoclonal antibodies disrupting CD40-CD40L signalling (e.g. iscalimab), B-cell activating factor (e.g. belimumab), Fc receptor (e.g. batoclimab) and TSH receptor blocking antibodies (e.g. K1–70) and small molecule TSH receptor antagonists (e.g. ANTAG-3) (72). Some of these may also treat TED, which will further enhance QoL. It remains to be seen what the impact of these therapies will be on QoL in hyperthyroidism.

Future directions and perspectives

While there are several possible triggers/risk factors for the reduction in QoL in hyperthyroidism, it is unclear which parameters affect specific domains of QoL, what the effect size is and how they can be tackled in routine clinical care (Table 2). Another question is whether we should be measuring QoL using validated tools in routine clinical practice. This is promoted by patient advocates and may aid individualized care.

Table 2.

Future research proposals for improving QoL in the long-term management of hyperthyroidism.

Potential cause of reduced QoL/dissatisfaction	Knowledge gaps/research questions
In all patients	- Does use of ThyPRO in routine clinical care help to address QoL?
	- Does provision of good-quality health information improve QoL?
	- Does shared decision-making improve long-term QoL?
TED	- Does early specialist referral improve long-term QoL?
	- Does access to smoking cessation services improve long-term QoL?
	- What is the long-term effect on QoL of newer medications for TED?
Fluctuation of thyroid function	- Does regular laboratory testing improve long-term QoL?
	- Do electronic communication systems for prompt and efficient interaction with patients improve long-term QoL?
	- Does long-term access to specialist care improve long-term QoL?
	- Does supervision of primary care services from secondary/tertiary care improve long-term QoL?
	- Does endocrine nurse support improve long-term QoL?
Inability of levothyroxine to restore normal function in all tissues	- Does intervention with combination levothyroxine and triiodothyronine therapy improve long-term QoL?
Central nervous system damage and/or dysfunction	- Is cognitive dysfunction in hyperthyroidism reversible and how does it affect QoL?
Psychological factors	- How effective are different psychological interventions in patients with hyperthyroidism and impaired QoL?
Aetiology of hyperthyroidism	- Does the aetiology of hyperthyroidism affect long-term QoL?
Treatment modality	- Does radioactive iodine therapy per se impair long-term QoL, and why?
Excessive weight gain and cardiometabolic health	- How effective are lifestyle interventions in patients with hyperthyroidism for weight control?
	- Does metformin have a useful role in cases of mild weight gain and/or dysglycaemia?
	- Should incretin-based therapies be used to treat excessive weight gain? If so, in which subgroup of patients, and when should they be initiated?

Abbreviations: ThyPRO, Thyroid Patient-Reported Outcome (measure); QoL, quality of life; TED, thyroid eye disease.

We need better tools to capture concerns about the impact of weight gain on QoL for patients with hyperthyroidism, as there are no relevant items in SF-36 and EQ-5D; the ThyPRO cosmetic complaints domain is very heterogeneous, with inclusion of items relating to neck swelling/scar and ophthalmological symptoms.

Ultimately, the question arises of what interventions can improve long-term QoL in patients with hyperthyroidism. The ideal treatment would be one that restores euthyroidism rapidly without destroying the thyroid gland, does not render the patient permanently hypothyroid, can treat/prevent TED effectively, can reduce goitre size, have minimal or no side effects and is cost-effective. Most of the molecular targeted treatments in development for GD (belimumab, batoclimab, K1–70 and small molecule TSH receptor antagonists) would not be expected to alter the natural history of GD and will probably require long-term therapy, could be unaffordable by many healthcare systems, are likely to be associated with significant side-effects, and are unlikely to offer significant advantages to conventional treatments. Radiofrequency and other topical ablative techniques may offer cheap and effective solutions for toxic nodules, but the probability of achieving long-term euthyroidism without requirement for thyroid hormone replacement for patients with GD is, in our view, low and reminiscent of the futile experiences of calculated small doses of radioiodine. We anticipate that targeted therapies aimed at restoring immunological tolerance are a promising treatment of GD and for improving QoL but will not be forthcoming for a while. Meanwhile, avoidance of unnecessary iatrogenic dysthyroidism while using conventional treatments is likely to improve QoL, is safe and is cost-effective.

Whether RAI per se is truly associated with poor QoL remains unclear, and it would help clinicians to have a definitive answer to this conundrum. However, its popularity is in decline and such knowledge is unlikely to influence clinical decisions significantly (73). Conversely, as alluded to earlier, LT-ATD therapy is an effective alternative, with a comparable adverse event profile, even though long-term randomized studies are lacking. Notwithstanding, existing evidence should be utilized to support patients with hyperthyroidism when they chose which treatment pathway to follow.

Another critical unanswered question is whether measures to curtail weight gain following treatment of hyperthyroidism can affect QoL positively. Metformin therapy has been suggested for mitigating the adverse metabolic effects of steroid therapies (74) and could similarly be beneficial in countering the weight gain and associated cardiometabolic risks in patients treated for hyperthyroidism. Likewise, there may be a future role for targeted anti-obesity medications, such as the incretin-based liraglutide, semaglutide, tirzepatide and other emerging novel molecules (75).

Conclusion

On presentation with hyperthyroidism, QoL is undoubtedly reduced. An improvement in QoL should be a major objective in the management of hyperthyroidism. While a significant improvement in QoL is expected with all treatment modalities, a residual impairment in QoL is observed post-treatment compared with matched controls. Some of the ongoing problems described include tiredness, ophthalmological symptoms, levothyroxine substitution issues and weight-related concerns. Further research is needed to guide practitioners regarding which pharmacological and non-pharmacological interventions offer the best QoL outcomes in hyperthyroidism.

Declaration of interest

We declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this work.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.