Abstract
Background
Subclinical thyroid diseases are often the subject of debate concerning their clinical significance, the appropriateness of diagnostic testing, and possible treatment. This systematic review addresses the variation in international guidelines for subclinical hyperthyroidism, focusing on diagnostic workup, treatment, and follow-up recommendations.
Methods
Following the PRISMA guidelines, we searched PubMed, Embase, and guideline-specific databases and included clinical practice guidelines with recommendations on subclinical hyperthyroidism. Guideline recommendations were extracted, and quality assessment was performed using selected questions of the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument.
Results
Of the 2624 records screened, 22 guidelines were included, which were published between 2007 and 2021. Guideline quality was generally intermediate to low. Diagnostic approaches differed substantially, particularly in the extent of recommended testing. Treatment initiation depended on TSH levels, age, and comorbidities, but the level of detail regarding defining precise comorbidities varied. Recommendations for monitoring intervals for follow-up ranged from 3 to 12 months.
Conclusion
This review underscores the existing variability in (inter)national guidelines concerning subclinical hyperthyroidism. There isa need for clear recommendations in guidelines considering diagnostic workup, treatment, and follow-up of subclinical hyperthyroidism. In order to establish this, future research should focus on determining clear and evidence-based intervention thresholds.
Background
Subclinical thyroid diseases are often the subject of debate concerning their clinical significance, the appropriateness of diagnostic testing, and possible treatment. In subclinical hyperthyroidism, there is a mild thyroid overactivity, defined by a TSH (thyroid-stimulating hormone) concentration below the reference interval with fT4 (free thyroxine; thyroid hormone) within the reference interval (1). The prevalence of subclinical hyperthyroidism ranges from 0.7% to 1.8% in iodine-sufficient areas to 2–15% in (mild) iodine-insufficient areas (2).
It is classified as type 1 (TSH between 0.1 and 0.4 mU/L) or type 2 (TSH <0.1 mU/L) (1). Distinguishing these two types is relevant because of the different risks of progression to overt hyperthyroidism and the risk of adverse health outcomes. Progression to overt hyperthyroidism occurs in up to 7% of patients per year, and reversion to normal occurs in up to 12% of patients per year (3). Intuitively, a lower TSH increases the chances of progression and decreases the chances of spontaneous normalization (2).
Multiple observational studies and meta-analyses showed several associations between subclinical hyperthyroidism and cardiovascular disease (4, 5, 6). Population-based observational studies reveal that individuals with subclinical hyperthyroidism, with mild or severe TSH suppression, have an increased risk of nonfatal cardiovascular events (hazard ratio (HR): 1.39, 95% CI: 1.22–1.58, data from a population of total 595,111 persons) (7), cardiovascular morbidity (HR: 1.39, 95% CI: 1.22–1.58) (7), dysrhythmia (HR: 1.65, 95% CI: 1.26–2.1) (7), heart failure (HR: 1.20, 95% CI: 1.10–1.31, data from a population of total 563,700 persons) (8), and all-cause mortality (HR: 1.23, 95% CI: 1.16–1.30) (8) compared to the reference population (2). However, it is crucial to note that these associations remain contentious, with controversial data available in the literature.
Furthermore, evidence also supports an association with bone loss, osteoporosis, and an elevated risk of fractures. A meta-analysis, drawing data from a substantial cohort of 70,298 patients, demonstrated a more than two-fold increased fracture risk in severe subclinical hyperthyroidism (9). Limited and conflicting data also report associations with dementia, cognitive dysfunction, and stroke (2, 3, 10).
The strength of the association with all the aforementioned complications increases as the TSH level decreases and is thus clearer in severe subclinical hyperthyroidism than in mild subclinical hyperthyroidism. This observed biological gradient, indicating a dose–response relationship between TSH levels and the associated outcomes, lends support to the argument for causality. Nevertheless, it is essential to acknowledge the limitations of existing studies, including the lack of controlled trials investigating the potential benefits of treatment for subclinical hyperthyroidism (11, 12).
Despite the absence of randomized trials, several national and international guidelines aid in clinical decision-making when confronted with a patient with subclinical hyperthyroidism. We performed a systematic review of national and international guidelines on subclinical hyperthyroidism, focusing on diagnostic workup, treatment, and follow-up. In addition, we investigated whether potential differences in recommendations could be explained by differences in (primary or secondary) healthcare systems and quality scores.
Methods
This systematic review is reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The review protocol can be accessed if requested by contacting the corresponding author.
Data sources and searches
We conducted a systematic search in PubMed and Embase. In addition, we searched the following websites and guideline-specific databases: Guidelines International Network (G-I-N; http://g-i-n.net), Trip database (http://www.tripdatabase.com), and Clinical Practice Guidelines Infobase (CPG Infobase; http://joulecma.ca/cpg/homepage). We used predefined clinical queries using relevant MeSH terms. We did not restrict our search to a certain language. For the database extraction performed on 3 February 2023, we used corresponding search terms. The exact search strategies are presented in Supplementary File 1 (see section on supplementary materials given at the end of this article). In addition, we included clinical practice guidelines by using the online search engines Google and Google Scholar to search websites of national endocrine societies, national thyroid societies, or primary care guideline websites.
Guideline selection
After the removal of duplicate records, one investigator (SRU) screened the publications by title and abstract. Only clinical practice guidelines were included, defined by describing themselves as ‘guideline’ in the document title or having been extracted from one of the guideline-specific databases. In case of national guidelines, they were only included when endorsed by a national endocrine society, national thyroid society, or other professional medical association or governmental body. When the full version was unavailable or inaccessible online, publications were not included in the full-text screening. When a guideline was published more than 5 years before another included guideline from the same society, it was considered superseded. Summary reports or superseded documents were also not included. In cases of uncertainty of relevance, the titles, abstracts, and/or full texts were independently assessed by another author (WPJdE). Disagreement was resolved by consensus. Thyroid guidelines with no recommendations concerning subclinical hyperthyroidism were not included. Furthermore, reference lists given in the full papers were explored by the first author for additional relevant guidelines.
Data extraction
From the guidelines included, we extracted recommendations regarding diagnostic testing, including the intention to determine underlying etiology, therapy, and follow-up. We distinguished primary care guidelines from guidelines intended for secondary care. If necessary, we translated the guidelines using Google Translate and checked with native speakers whether the recommendations were adequately translated and interpreted. In addition, we extracted the expertise of panelists or committee members.
Guideline characteristics and quality assessment
Two investigators (SRU and WPJdE) individually assessed the quality of each included guideline using selected questions of the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. The AGREE II tool involves 23 items to be rated on a scale of 1 (strongly disagree) to 7 (strongly agree), corresponding to the extent to which the defined criteria are met (13). Seven questions were selected covering the following domains: stakeholder involvement, rigor of development, clarity of presentation, and editorial independence (questions 6, 7, 9, 12, 15, 22, and 23). Websites of guideline developers were examined for background information on the development process. After independent appraisal, SRU and WPJdE discussed each item with a difference of ≥3 points, and disagreements were resolved by consensus, similarly to other systematic review appraisals (14). The final score was calculated as the mean score of the appraisers.
Interpretation and analysis
To analyze potential differences in the comprehensiveness of diagnostic testing, threshold for starting therapy, and intensity of follow-up diagnostic between guidelines and between primary and secondary care, we scored these items as low, intermediate, or high. Concerning diagnostic testing, recommendations to perform only blood tests were considered ‘low comprehensiveness’, blood tests in combination with one imaging modality were considered ‘intermediate comprehensiveness’, and multiple diagnostic modalities were considered ‘high comprehensiveness’. For scoring the threshold for therapy, this was ranked based on a high threshold for therapeutic intervention (recommendation for most of the patient groups to not start treatment), an intermediate threshold for therapeutic intervention (consider treatment for specified patient groups), or a low threshold for therapeutic intervention (consider treatment for almost all patient groups). The intensity of follow-up if treated or untreated was defined as minimal follow-up (yearly interval or longer interval), intensive follow-up (frequent 3-monthly interval or shorter), or intermediate follow-up (in between these two). In addition, we analyzed differences in recommendations based on the presence of a primary care healthcare system and overall quality score.
Results
Selection of studies
A total of 2067 records were identified by Pubmed and Embase. Using the different guideline databases (G-I-N, TRIP, and CPG database), an additional 1262 records were identified. After the removal of duplicates, 2624 records were screened, of which 55 were assessed for inclusion criteria based on the full text. This yielded 11 unique guidelines. Reasons for exclusion entailed not being mentioned as a guideline, not being endorsed by a professional society, or being superseded. The PRISMA flowchart is depicted in Fig. 1. Also, thyroid guidelines were excluded if they lacked recommendations concerning subclinical hyperthyroidism. Another 11 guidelines were identified through the Google and Google Scholar search but were not published in medical journals.
PRISMA flowchart of guideline selection process.
Citation: European Thyroid Journal 13, 3; 10.1530/ETJ-24-0036
The main characteristics of the included guidelines are summarized in Table 1 (11, 12, 15, 16, 17, 18, 19, 21, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34). The 22 included guidelines were published from 2007 to 2021, in Europe (n = 16), the USA or Canada (n = 3), Asia (n = 2), or Australia and New Zealand (n = 1). The guidelines were written in English (n = 11), German (n = 2), Dutch (n = 2), Spanish (n = 2), Danish (n = 2), Swedish (n = 1), Turkish (n = 1), or Croatian (n = 1).
Main characteristics of the included guidelines (n = 22).
| Ref | Region | Title (translated) | Organization | Intended use in carea | Expertise of panelists/committee |
|---|---|---|---|---|---|
| (15) | Australia and NZ | Thyroid function testing for adult diagnosis and monitoring | The Royal College of Pathologists of Australasia | ? | Pathology |
| (16) | Austria | Laboratory diagnostic guidelines for the clarification of disorders of the thyroid gland | Austrian Society for Laboratory Medicine and Clinical Chemistry; Austrian Society for Endocrinology and Metabolism; Austrian Society for Nuclear Medicine | B | Clinical chemistry, internal medicine, endocrinology, nuclear medicine, general medicine |
| (17) | Alberta, Canada, | Investigation and management of primary thyroid dysfunction | TOP Endocrine Working Group | ? | Family medicine, pathology, endocrinology clinical biochemistry, laboratory technology |
| (18) | BC, Canada | Thyroid function testing in the diagnosis and monitoring of thyroid function disorder | Clinical Practice Guidelines and Protocols in BC | ? | ? |
| (19) | Croatia | Croatian Thyroid Society Guidelines for rRational Detection of Thyroid Dysfunction | Croatian Thyroid Society | ? | Nuclear medicine, oncology, endocrinology, internal medicine, pathology, otorhinolaryngology, pediatrics |
| (21) | Denmark | Thyrotoxicosis | Danish Endocrinological Society | 2 | Endocrinology |
| (21) | Denmark | Hypo- and hyper-thyroidism in adults | Danish Society for General Medicine | 1 | General medicine |
| (22) | Europe | 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism | European Thyroid Association | ? | Internal medicine, surgery, endocrinology, oncology, genetics |
| (11) | Europe | The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism | European Thyroid Association | ? | Internal medicine, surgery, endocrinology |
| (23) | France | Diagnostic procedure in suspected Graves’ disease | French Society of Endocrinology | ? | Internal medicine, endocrinology, oncology, biochemistry, radiology |
| (24) | France | Management of thyroid dysfunctions in the elderly. French Endocrine Society consensus statement 2019 | French Society of Endocrinology | ? | Internal medicine, endocrinology, nuclear medicine, cardiology, geriatrics |
| (25) | Malaysia | Management of thyroid disorders | Malaysian Endocrine And Metabolic Society | B | Endocrinology, pathology, general medicine, pediatrics, geriatrics, ophthalmology, gynecology, radiology, pharmacology, surgery, nuclear medicine, clinical genetics |
| (26) | Netherlands | NHG guideline thyroid disorders | Dutch Society for General Practitioners | 1 | General medicine, pharmacology, endocrinology, radiology, clinical chemistry, gynecology |
| (27) | Netherlands | Thyroid disorders | Dutch Society for Internists | 2 | Internal medicine, endocrinology, general medicine, occupational medicine, surgery, clinical chemistry, nuclear medicine, gynecology |
| (28) | Qatar | The diagnosis and management of hyperthyroidism in adults | Ministry of Public Health | B | General medicine, endocrinology, cardiology |
| (29) | Spain | Clinical guidelines for the diagnosis and treatment of subclinical thyroid dysfunction | Spanish Society of Endocrinology | ? | Endocrinology |
| (30) | Spain | Manual of Thyroid Pathology | Spanish Society of Endocrinology and Nutrition | ? | Endocrinology, pediatrics, gynecology |
| (31) | Skåne, Sweden | Hyperthyroidism | Caregiver Provider Scania | 1 | General medicine |
| (32) | Switzerland | Thyroid disorders | Association mediX Switzerland | 1 | Internal medicine, endocrinology |
| (33) | Turkey | Thyroid diseases diagnosis and treatment guide | Turkish Society of Endocrinology and Metabolism | ? | Endocrinology |
| (34) | UK | Thyroid disease: assessment and management | National Institute for Health and Clinical Excellence | B | Endocrinology, general medicine, pediatrics, pharmacology, radiology, pathology, surgery, biochemistry, psychiatry |
| (12) | USA | 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis | American Thyroid Association | B | Endocrinology, pediatrics, surgery, nuclear medicine |
aEntries in this column indicate the following - 1: primary care, 2: secondary care, B: both, ?: unknown.
BC, British Colombia; NZ, New Zealand; Ref, Reference; TOP, Toward Optimized Practice.
Quality assessment
The quality appraisal scores for the individual questions of the guidelines are shown in Supplementary File 2. Half of the guidelines specified the target users to be either primary care providers or secondary/tertiary care providers, as can be seen in the world map in Supplementary File 3 (12, 16, 21, 21, 25, 26, 27, 28, 31, 32, 34). Therefore, quality scores for this topic were either close to 1 (target users not specified) or 7 (target users specified). In countries where the target users could not be defined as primary or secondary healthcare providers as there is no primary care system, this question was scored based on the target specialism of the guideline (i.e. endocrinologists or other specialists). The guidelines with unspecified target users, with the exemption of the European guideline, all had a mean score of 3.0 or lower. In countries with a separate primary and secondary care guideline (Denmark and the Netherlands), the primary care guideline scored higher than the secondary (21, 21, 26, 27).
Concerning rigor of development, the mean scores were appraised lowest of all tested domains. The mean score for the question regarding the use of systematic methods for collecting evidence was 3.0, as 12 guidelines did not mention a search strategy. Several guidelines had no or very little reference to literature concerning subclinical hyperthyroidism (15, 16, 17, 23, 31, 32). Ten guidelines mentioned a level of evidence concerning the evidence behind the recommendations (11, 12, 21, 22, 24, 25, 27, 28, 30, 34). The level of evidence was rarely high, primarily due to the limited availability of randomized trials. Comparing or reporting these levels was complicated by the methods used in different guidelines; some use letters, some use symbols, and others employ numerical scales.
The clarity of presentation was scored the highest with a mean score of 5.2. Flowcharts and tables aided in making recommendations specific and unambiguous. In the domain concerning editorial independence, specifying the funding body and the effect on the content of the guideline was scored either very high or low, as this was well specified or not at all. This also accounted for addressing the competing interests of the development group members.
Recommendations concerning diagnostics
The recommendations of the guidelines are summarized in Supplementary File 4. There were significant variations in diagnostic recommendations for subclinical hyperthyroidism across the different clinical guidelines. Notably, the majority of guidelines emphasized the importance of measuring free T3 levels to exclude T3 thyrotoxicosis. However, the extent of recommended diagnostic testing and the intention to determine the underlying etiology of subclinical hyperthyroidism differed considerably. Some guidelines advocated for a comprehensive battery of tests (11, 16, 25), adopting a cautious and defensive approach, while others favored a more minimalist strategy, suggesting limited or stepwise testing (15, 17, 32), and sometimes restricting to physical examination, such as assessing heart rate irregularities as a screening tool for atrial fibrillation (21). Additionally, several guidelines tailored testing based on the TSH concentration. These guidelines posited that as TSH concentrations decreased, the risk of comorbidities increased, leaving less room for a ‘wait and see′ approach. Furthermore, several guidelines stipulated the necessity for a second measurement after a specified duration, before making the diagnosis subclinical hyperthyroidism, or before further diagnostic testing. The timing of this second measurement varied according to factors such as symptom severity, presence of comorbidities, and initial TSH levels. The comprehensiveness of diagnostic testing was more limited in primary care guidelines compared to secondary care, as can be seen in Supplementary File 4.
The European guideline, while comprehensive in scope, adopts a notably defensive stance (11). This guideline advocates observation of the condition only if there are no risk factors and all diagnostic testing results are normal, mandating elaborate laboratory tests, thyroid ultrasound, scintigraphy, ECG, and a BMD measurement. In the national guidelines of European countries, this conservative approach is often not followed, which could partially be explained by local differences in healthcare systems. Also compared with the American Thyroid Association guideline, being the other international available guideline, the European Thyroid Association stands out in the comprehensiveness of diagnostic testing (12).
In 15 of the included guidelines, the risk of progression, as well as cardiovascular and bone risks, was assessed to provide evidence for diagnostic testing and treatment (11, 12, 18, 21, 21, 22, 24, 25, 26, 27, 29, 30, 32, 33, 34).
Recommendations concerning treatment
Also, discrepancies became apparent in the treatment recommendations. A pivotal determinant for the initiation of treatment often revolved around the TSH concentration. Frequently, a threshold of [TSH] ≤0.1 mU/L was adopted as a criterion for considering therapeutic interventions. Additionally, advancing age, particularly in patients aged >65 years, and the presence of comorbidities also played a substantial role in treatment decisions. However, the level of specificity in defining these comorbidities varied among guidelines; some provided explicit details, pinpointing conditions such as cardiovascular disease and risk factors for osteoporosis, while others remained less prescriptive in categorizing comorbidities. Both the strength of treatment recommendations and the level of supporting evidence decreased with higher TSH concentrations and fewer comorbidities. In countries with separate primary and secondary care guidelines (Denmark and the Netherlands), the secondary care guideline had a lower threshold for starting treatment. Remarkably, the secondary care guideline recommended considering treatment for patient groups who would not be referred from primary care to secondary care when following the primary care guidelines.
If treatment was recommended, several guidelines mentioned specific treatment modalities based on the underlying etiology (11, 12, 21, 22, 25, 29, 30, 33). If Graves’ disease was the underlying pathology, most advised treating with antithyroid drugs, whereas for multinodular goiter and autonomous nodules, there was more variation with a slight preference for radioactive iodine (see Supplementary File 4). The guideline of the European Thyroid Association also mentioned nine recommendations to avoid adverse effects of treatment (11).
Recommendations concerning follow-up
Examining recommendations on follow-up, it became evident that explicit recommendations regarding the follow-up of subclinical hyperthyroidism were frequently absent, brief, or lacking references to supporting evidence. Among the guidelines that did address follow-up, substantial heterogeneity was observed in the recommended intervals for monitoring. These intervals spanned from as frequent as every 3 months (21, 24) to every 12 months (27). After the initial diagnosis, commonly frequent assessments were recommended, with the timing of subsequent evaluations varying based on the stability of the condition. Only the guideline from the UK provided explicit guidance on when to cease monitoring. There was no pattern in recommendations concerning follow-up based on continent, healthcare setting, or quality score.
Discussion
This systematic review sought to elucidate the differences in guidelines for subclinical hyperthyroidism, with a particular focus on diagnostic workup, treatment, and follow-up recommendations. Several noteworthy findings emerged from this analysis.
First and foremost, the relatively limited number of guidelines identified worldwide highlights the need for a more standardized approach to subclinical hyperthyroidism, especially considering its clinical significance and potential impact on patient health. The majority of recommendations were extracted from guidelines for thyroid disorders, hyperthyroidism, or Graves’ disease. Furthermore, our quality assessment of these guidelines revealed that the general quality of the available guidelines was notably different per guideline.
The predominant reliance on observational research in the field of subclinical hyperthyroidism contributes to the overall low level of evidence underpinning the recommendations identified in this review. However, the limited evidentiary basis is not solely the cause of the appraised quality of the guidelines; this also hinges on factors such as the transparency of the evidence-gathering process, clear follow-up procedures, the rationale behind recommendations based on (the lack of) available evidence, and the presence of statements on conflicts of interest among those involved in formulating the guidelines. Nevertheless, the availability of controlled studies would undoubtedly enhance the precision and reliability of the recommendations. Fostering a more standardized approach could contribute to improved evidence extraction from registry studies, offering valuable insights into the efficacy of various treatment strategies for subclinical hyperthyroidism.
It was evident that relatively limited research had been conducted in the primary care setting. Given that the majority of evidence also utilized in primary care emanates from secondary care, there is a palpable need for more research to bridge this gap. In addition, there were discrepancies in guidelines intended for primary and secondary care on when to treat or refer for treatment. In the Netherlands and Denmark, there was no harmonization between the primary and secondary care guidelines, meaning that patients eligible for treatment based on the secondary care guidelines were not eligible for referral to secondary care based on the primary care guideline (21, 21, 26, 27). It is logical to anticipate differences in recommendations based on the distinct epidemiological profiles and natural courses of diseases in either a primary or secondary care setting (35). However, it is important to harmonize guidelines between these two settings to provide consistent and optimized management of subclinical hyperthyroidism.
Additionally, almost all guidelines in primary and secondary care recommend in the diagnostic workup to determine the (free) T3 concentration in order to exclude T3 (thyro)toxicosis. However, it is noteworthy that there is a lack of information regarding the prevalence and incidence of T3 (thyro)toxicosis. The complexity of free T3 measurements further compounds this issue, necessitating further research (36).
In the majority of included guidelines, absolute TSH cutoffs are mentioned in aiding diagnostic and therapeutic decisions. This is irrespective of assay differences and population and region-specific reference intervals. However, the clinical impact of standardization differences in TSH assays seems to be limited concerning the often-used cutoff value of TSH = 0.1 mU/L (37). This cutoff probably originated from the limited sensitivity of the second generation TSH assays, where TSH < 0.1 mU/L was considered severely suppressed (38, 39). This sensitivity has improved to around 0.01 mU/L for decades, but the 0.1 mU/L cutoff is still used for grading subclinical hyperthyroidism as ‘severe’ or grade 2. It is important to exercise caution in the use of terms such as ‘severe’ and ‘mild’ subclinical hyperthyroidism, especially in asymptomatic conditions. Although associations of clinical endpoints increase with more suppressed TSH values in subclinical hyperthyroidism, it is crucial to acknowledge that the use of a dichotomic score in clinical practice for therapeutic decision-making has not been validated through prospective clinical trials.
However, controlled studies are costly, and the occurrence of subclinical hyperthyroidism is relatively low compared to other thyroid disorders, making it challenging to enroll a sufficient number of participants for clinical trials. For these reasons, earlier trials were terminated prematurely (40, 41). To the best of our knowledge and available trial registration databases, there are no current trials concerning subclinical hyperthyroidism. Target trial emulation offers a promising solution to some of the challenges associated with conducting randomized controlled trials (42). By simulating a hypothetical target trial based on observational data, researchers can effectively address issues such as low incidence and prevalence in certain conditions like subclinical hyperthyroidism. This approach allows for the estimation of treatment effects in a population that closely resembles real-world clinical scenarios, providing valuable insights into the efficacy and potential advantages of therapeutic interventions. Moreover, target trial emulation enables researchers to explore various treatment strategies and compare their effectiveness, thereby facilitating evidence-based decision-making and guiding future clinical research efforts in a more cost-efficient manner.
We did not observe a trend in the comprehensiveness of diagnostic testing, threshold for starting therapy, and intensity of follow-up when analyzing the accessibility of specialist care with or without primary care referral. In countries such as Denmark, the UK, the Netherlands, and Sweden, a referral from primary care is needed, whereas this is not the case in countries such as Austria, France, Germany, Sweden, and the USA (43). We could also not find a relationship in countries where, in general, more diagnostic testing is performed, for example, based on the amount of imaging performed per country, which is relatively high in the USA and France and relatively low in the Netherlands and Spain (44).
Strengths of our study include being the first systematic review focused on subclinical hyperthyroidism guidelines. In addition to summarizing recommendations, we conducted a thorough assessment of the quality of these guidelines. By imposing no language restrictions in our search strategy, we aimed to encompass a broad range of guidelines. However, it also has limitations. Despite employing a thorough search strategy, guidelines could have been missed due to the diverse channels through which guidelines are disseminated. Furthermore, we scored a selection of the AGREE questions. Despite these constraints, our systematic review provides valuable insights into subclinical hyperthyroidism guidelines, offering a comprehensive overview of their recommendations and methodological characteristics.
Conclusion
In conclusion, this systematic review highlights the need for standardized, high-quality guidelines for subclinical hyperthyroidism, given the substantial discrepancies concerning diagnostic workup, treatment, and follow-up recommendations. We observed disparities between primary and secondary care recommendations, emphasizing the importance of harmonization. Furthermore, the quality of the included guidelines was generally low. Therefore, in future guideline development on subclinical hyperthyroidism, it is crucial to focus on rigorous methodology using a well-defined approach (45). Despite the clinical significance of subclinical hyperthyroidism and its potential impact on patients’ outcomes, research is lacking concerning treatment. Future efforts should focus on the determination of clear and evidence-based intervention thresholds. The absence of such controlled studies underscores the importance of further research in this domain to ascertain the efficacy and potential advantages of therapeutic interventions in managing subclinical hyperthyroidism-associated complications.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ETJ-24-0036.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Author contribution statement
SRU, AB, ACH, and WPJdE conceived the study. SRU and WPJdE designed the study and carried out the review. SRU prepared the first draft of the article. SRU, AB, EB, PE, JG, RKEP, ACH, and WPJdE were involved in the revisions of the draft article and have agreed to the final content.
Acknowledgements
We express our gratitude to Luisa Martinez, Etienne Cavalier, Ömer Özcan, Darko Kastelan, Philip Elders, and Chantal Stockem for their contribution in identifying and/or translating the guidelines.
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