Authors' objectives: BACKGROUND: Thyroid function tests are used for the diagnosis and monitoring of patients with thyroid disorders. The most common thyroid function tests include thyroid stimulating hormone (TSH) tests, total and/or free thyroxine (T4/fT4) tests, and total, free and/or reverse triiodothyroxine (T3, fT3, rT3) tests. Depending on the clinical situation, the choice of test(s) can be modified. For the diagnosis of suspected primary or secondary thyroid dysfunction two typical test approaches include a one-step test approach (i.e. measurement of TSH and (f)T4/(f)T3 simultaneously) and a two-step test approach (i.e. testing TSH first, only followed by the measurement of (f)T4/(f)T3 when TSH is out of the reference range). For suspected primary hypothyroidism TSH is complemented with (f)T4 and for suspected primary hyperthyroidism TSH is complemented with (f)T4 and (f)T3. OBJECTIVE: Although most guidelines recommend a two-step test approach for the diagnosis of suspected primary or secondary thyroid dysfunction, it is observed that TSH and (f)T4/(f)T3 are often measured simultaneously (one-step test approach). The focus of this HTA is to evaluate the clinical and financial consequences of the two-step as compared to the one-step thyroid function test approach for the diagnosis of patients with suspected primary or secondary thyroid dysfunction. The difference in the number of missed cases, the diagnostic subcategory distribution of missed cases, and the costs and budget impact of thyroid function tests performed with the one-step versus the two-test test approach are addressed. Ethical, legal, social, and organisational issues are also addressed.

Authors' results and conclusions: RESULTS: For the clinical systematic literature search 9’474 unique records were identified, 53 studies were screened in full-text, and 3 studies in populations tested for suspected thyroid disorders were included for full analysis. The included studies were case series conducted in Asia, all with a high risk of bias. One large case series analysed 2’768 blood samples with both TSH and fT4 assayed in inpatients and outpatients with clinically suspected primary or secondary thyroid dysfunction from a general hospital. In 5.3% of the thyroid function tests, the TSH level was within the reference range and the fT4 level abnormal. These discordant test results, reflecting missed diagnoses, would have been missed when a two-step test approach would have been applied. The study authors state that in daily praxis this percentage of patients with thyroid disease will likely be lower when combined with information on known clinical history of these patients and other external factors. The two other case series did not report discordant test results for the TSH and T3/T4 serum levels, but reported the distribution of thyroid disorder diagnoses in clinically suspected patients. The economic systematic literature search retrieved ten studies after screening 353 records. All studies shared a consistent opinion on thyroid function tests likely being unnecessary used or overused, supporting the potential for cost-savings if a step-wise approach is adopted. The included studies investigating different test approaches concluded the two-step test approach the most costsaving approach as compared to the one-step test approach. The studies conducted on hypothetical goals of the fT4/TSH ratio concluded that the reduction of unnecessary tests was deemed economically favourable. As these studies did not provide relevant cost data for constructing a Swiss budget impact model, additional sources were used for the inputs of the budget impact model. A budget impact model, over a time horizon of five years (2020-2024), was developed to assess the potential for cost-savings in Switzerland by accounting the number of thyroid function tests at the population-level. Compared to the one-step thyroid function test approach the two-step test approach (i.e. including second blood draw) was cost-saving (approximately 6.1 million CHF in year 2020). The impact of implementing reflex testing (i.e. using the initial blood sample without the need for a second blood draw) in the two-step test approach was also taken into account. Reflex testing was considered the most favourable (cost-saving) test approach compared to the two-step test approach (approximately 2.1 million CHF in year 2020) and one-step test approach (approximately 8.2 million CHF in year 2020), respectively. The results for year 2021, year 2022, year 2023 and year 2024 were similar. Nine observational studies and two guidelines informed the ethical, legal, social, and organisational issues related to the use of thyroid function tests in adults with suspected thyroid dysfunction. Physicians expressed a degree of fear of possibly missing positive diagnoses, as well as experiencing pressure from patients requesting the complete diagnostic profile, when applying a two-step instead of a one-step test approach. The importance of good instructions to physicians were flagged as pivotal for a successful implementation of a two-step test approach. CONCLUSION: The clinical evidence was sparse, and the low quality does not permit to draw conclusions on a concrete number of cases missed when the two-step instead of the one-step test approach is applied in adults with suspected primary or secondary thyroid dysfunction in the Swiss setting. The budget impact analysis showed that the two-step test approach can be considered cost-saving compared to the one-step test approach. From a clinical perspective the two-step test approach seems to be justified, given the likely low risk of missed cases when applying this approach. The impact of reflex testing was also assessed and was more cost-saving compared to the one-step and two-step test approach, since the initial blood sample is used for possible additional thyroid function tests without the need for a second blood draw. When applying a two-step or reflex test approach instead of the one-step test approach, the possible impact of missing or misclassifying diagnoses and practical aspects of how to successfully implement the reflex testing approach should be considered.

Authors' methods: METHODS: For the clinical review, a systematic literature search was performed in PubMed (MEDLINE) and Embase.com. The search was worldwide, in English, German, French, and Italian with the publication period ranging from 1990 to September 2021. Studies in adults tested for suspected primary or secondary thyroid dysfunction were included. Studies on thyroid disorder screening and monitoring, and those including only pregnant females were excluded. The included studies were critically appraised, and the extracted data were summarised in evidence tables and narrative text. For the economic review, the costs and budget impact literature search followed the principles of the clinical systematic literature search. After applying the quality control measures, data synthesis was done using descriptive comparisons. A budget impact model was developed using Swiss inputs, publicly available sources, and expert opinion. Evidence found with the clinical and costs and budget impact systematic literature searches was used to inform the ethical, legal, social, and organisational domains of the report. In addition, grey literature searches were conducted on these HTA domains.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/schilddruesenhormontests.html

URL for protocol: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0050t3t4-hta-protocol.pdf.download.pdf/h0050t3t4-hta-protocol.pdf

Year Published: 2022

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0050t3t4-hta-report.pdf.download.pdf/h0050t3t4-hta-report.pdf

URL for additional information: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-programm.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health