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Thyroid function tests
Evidence review C
NICE Guideline, No. 145
National Guideline Centre (UK).
1. Thyroid function tests
1.1. Review question: Which thyroid function tests should be requested?
1.2. Introduction
A Thyroid function test (TFT) commonly refers to the quantitation of thyroid stimulating hormone (TSH) and circulating thyroid hormones in serum to assess the ability of the thyroid gland to produce and regulate thyroid hormone production. TFTs are used for diagnosis and to monitor treatment of common thyroid gland disorders. These biochemical tests have both high analytical sensitivity and specificity and well established clinical utility. Consequently TFTs are amongst the most widely requested blood tests and are the first line investigation when thyroid disease is suspected. Despite their widespread use and high clinical efficacy, there is still considerable debate as to the optimum testing strategy for both the diagnosis and monitoring of thyroid dysfunction. Measurement of serum TSH concentration is considered as the most effective single marker for the exclusion of primary thyroid dysfunction. TSH is secreted by the pituitary gland in response to circulating thyroid hormone concentration in a classic endocrine feedback loop and can therefore be used as a marker of thyroid status. However there are notable exceptions when serum TSH concentration alone may not accurately reflect thyroid hormone production. This is most frequently encountered when the homeostatic mechanism has been impaired by long standing primary thyroid disease or the pituitary-thyroid axis has not reached equilibrium following changes to thyroid therapy. Secondary thyroid dysfunction due to pituitary disease is a less common confounder of TFTs. Both pituitary deficiency and autonomous TSH production by pituitary adenomas, can lead to erroneous classification of thyroid function if serum TSH is used as a sole biomarker. For these reasons the direct analysis of thyroid hormones is also recommended as an adjunct to TSH testing. Most UK labs would advocate the measurement of free thyroid hormones rather than total thyroid hormone (thyroid hormone that is not bound to thyroid carrier proteins) as the best marker for biologically active hormone. This avoids situations where variation in thyroid hormone binding proteins rather than thyroid function per se is responsible for abnormal test results.
Various TFT protocols are used in current clinical practice with no particular procedure dominating. Common protocols include an initial TSH measurement with thyroid hormone analysis (either free thyroxine - FT4 or free triiodothyronine - FT3) cascaded when TSH is outside the established reference interval, simultaneous analysis of both TSH and FT4 or open access to either test depending on requestor preference. Many laboratories offer FT3 testing but this is not universally, available. Of the laboratories that offer FT3 analysis, some provide open access where others will use FT3 instead of FT4 to confirm the diagnosis of hyperthyroidism when TSH is suppressed. Other indications for FT3 include exclusion of T3 toxicosis (when TSH is suppressed but FT4 is within the reference interval), the detection of non-thyroidal illness, to adjust levothyroxine dosage if TSH remains elevated in the presence of FT4 concentrations above the reference interval or more contentiously to direct thyroid replacement therapy in patients with TSH within the reference interval but with persistence of hypothyroid symptoms.
The latest authoritative UK guidance on TFT came from the British Thyroid Association in 2006. This guide recommends using both TSH and FT4 at the first investigation of thyroid disease, at the initial optimisation of therapy in both hyper or hypothyroidism, in patients treated with thionamides, in pregnancy or when pituitary disease is suspected. In other situations, such as longer term follow-up, the testing of TSH alone may be appropriate. The authors recognised the need for further studies in particular the use of TFTs as a screening test and for diagnosing and treating subclinical disease.
Given the widespread use of TFTs the addition of FT4 and FT3 to the TFT represents a considerable financial burden to the UK health economy. The purpose of this review is to establish if objective evidence is available to support the premise that the use of more complex thyroid function testing strategies leads to demonstrable health benefit.
1.3. PICO table
For full details see the review protocol in Appendix A:.
Table 1
PICO characteristics of review question.
1.4. Clinical evidence
1.4.1. Included studies
As per the protocol, given the lack of randomised controlled trials, non-randomised studies were also considered for inclusion for this evidence review. No relevant clinical studies comparing any thyroid function testing strategy with any other were identified.
See also the study selection flow chart in Appendix C:.
1.4.2. Excluded studies
See the excluded studies list in Appendix G:.
1.5. Economic evidence
1.5.1. Included studies
No relevant health economic studies were identified.
1.5.2. Excluded studies
No health economic studies that were relevant to this question were excluded due to assessment of limited applicability or methodological limitations.
See also the health economic study selection flow chart in appendix G.
1.5.3. Health economic modelling
This area was not prioritised for new cost-effectiveness analysis.
1.5.4. Resource costs
Relevant unit costs are provided below to aid consideration of cost effectiveness.
Table 2
UK costs of Tests.
1.6. Evidence statements
1.6.1. Clinical evidence statements
- No relevant published evidence was identified.
1.6.2. Health economic evidence statements
- No relevant economic evaluations were identified.
1.7. The committee’s discussion of the evidence
1.7.1. Interpreting the evidence
1.7.1.1. The outcomes that matter most
The committee considered mortality and quality of life to be critical outcomes. The committee considered symptom scores, patient/family/carer experience, healthcare contacts, the number of people receiving treatment, growth and neurodevelopment to be important outcomes.
No evidence was identified for this review.
1.7.1.2. The quality of the evidence
No evidence was identified for this review.
1.7.1.3. Benefits and harms
In the first investigation of possible thyroid disease the committee agreed based on their experience that a testing strategy of only using TSH with a FT4 measurement if TSH is above the reference range would be appropriate for the majority of adults. If TSH is below the reference range both FT4 and FT3 will be necessary as the results of both FT4 and FT3 will dictate decisions around which type of treatment the thyrotoxicosis may require. If TSH is normal, abnormal thyroid FT4 is unlikely based on the committee’s experience. If TSH is abnormal, it is important to determine whether a person has clinical or subclinical thyroid dysfunction (in other words if the abnormality is limited only to the TSH or not) as this impacts management decisions.
The committee agreed there may be some situations in which both tests could be ordered simultaneously, particularly if there is suspicion of secondary thyroid disease. This would apply generally for children as the aetiology of thyroid disease in children tends to include more secondary causes and fewer primary or autoimmune causes. The committee also noted that in children, it is often more distressing and challenging to obtain multiple blood samples and therefore strategies should aim to limit samples.
1.7.2. Cost effectiveness and resource use
There was no economic evidence identified in this review comparing thyroid function testing strategies, for people being investigated for hypothyroidism, hyperthyroidism, or thyroid enlargement. Unit costs of thyroid function tests were presented to the committee. The committee made consensus recommendations on the groups of people that different tests may be appropriate for.
The costs of different blood tests were collected from committee members at 5 different hospitals, the costs reported included cost of reagents, consumables, and staff pay. There were large variations between the costs reported and the committee agreed that this was due to differences in the way staff pay is calculated in the hospitals cost data was collected from. Due to the skewed data, a median was calculated (TSH £2.15, FT3 £3.12 and FT4 £2.10) and presented to the committee as estimates of the different costs of blood tests.
The committee highlighted that the reported costs did not include phlebotomy costs and therefore in instances when tests are ordered separately an additional cost of £3.04 will be incurred (NHS reference cost 2016–17, currency code DAPS08), each time. The committee were aware that some laboratories performing TFTs would conduct an additional test (FT4 and/or TF3) on the same blood sample (cascade), if they detect an abnormal TSH. This approach is not being followed everywhere but it can reduce unnecessary testing and avoid incurring the additional phlebotomy costs. The committee noted that TSH should be considered, as a first line blood test for anyone with a potential thyroid dysfunction or enlargement, and depending on the results, via cascade, FT4 then FT3 might be required. It was noted that this cascade approach, where a small population would require further tests depending on the results from the initial test, is likely to be cost saving to the NHS. It was also agreed that measuring both TSH and FT4 should be considered in people with suspected secondary thyroid disease, this would help speed the diagnosis and people can be treated for their condition sooner.
In addition, the committee acknowledged that repeat testing is often done too soon after diagnosis and that a recommendation considering repeat testing at least 6 weeks after diagnosis can help avoid misinterpretation of test results. This can be cost saving to the NHS and beneficial to the patient as misinterpreted test results can lead to unnecessary treatment or dose adjustments.
The recommendations broadly reflect current practice, although not all laboratories currently follow the cascading approach to testing. Where FT4 is currently a routine test for thyroid dysfunction, cascading will reduce NHS costs by avoiding extra tests for people with a TSH within the reference range. In areas where FT3 is not currently being measured, cascading will mean a cost increase. But this will be offset by the benefits of correctly diagnosing and managing thyrotoxicosis.
References
- 1.
- Brochmann H, Bjoro T, Gaarder PI, Hanson F, Frey HM. Prevalence of thyroid dysfunction in elderly subjects. A randomized study in a Norwegian rural community (Naeroy). Acta Endocrinologica. 1988; 117(1):7–12 [PubMed: 3381628]
- 2.
- Feldkamp CS, Carey JL. An algorithmic approach to thyroid function testing in a managed care setting. 3-year experience. American Journal of Clinical Pathology. 1996; 105(1):11–6 [PubMed: 8561076]
- 3.
- Henze M, Brown SJ, Hadlow NC, Walsh JP. Rationalizing Thyroid Function Testing: Which TSH Cutoffs Are Optimal for Testing Free T4? Journal of Clinical Endocrinology and Metabolism. 2017; 102(11):4235–4241 [PubMed: 28938415]
- 4.
- Koulouri O, Gurnell M. How to interpret thyroid function tests. Clinical Medicine. 2013; 13(3):282–6 [PMC free article: PMC5922674] [PubMed: 23760704]
- 5.
- National Institute for Health and Care Excellence. Developing NICE guidelines: the manual [updated October 2018]. London. National Institute for Health and Care Excellence, 2014. Available from: http://www
.nice.org.uk /article/PMG20/chapter /1%20Introduction%20and%20overview - 6.
- Notas G, Kampa M, Malliaraki N, Petrodaskalaki M, Papavasileiou S, Castanas E. Implementation of thyroid function tests algorithms by clinical laboratories: A four-year experience of good clinical and diagnostic practice in a tertiary hospital in Greece. European Journal of Internal Medicine. 2018; 54:81–86 [PubMed: 29605463]
- 7.
- Snabboon T, Sridama V, Sunthornyothin S, Suwanwalaikorn S, Vongthavaravat V. A more appropriate algorithm of thyroid function test in diagnosis of hyperthyroidism for Thai patients. Journal of the Medical Association of Thailand. 2004; 87 (Suppl 2):S19–21 [PubMed: 16083155]
Appendices
Appendix B. Literature search strategies
The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2018 https://www.nice.org.uk/guidance/pmg20/resources/developing-nice-guidelines-the-manual-pdf-72286708700869
For more detailed information, please see the Methodology Review.
B.1. Clinical search literature search strategy
Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the search where appropriate.
B.2. Health Economics literature search strategy
Health economic evidence was identified by conducting a broad search relating to a thyroid disease population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase for health economics, economic modelling and quality of life studies.
Appendix C. Clinical evidence selection
Figure 1. Flow chart of clinical study selection for the review of thyroid function tests
Appendix D. Health economic evidence selection
Figure 2. Flow chart of health economic study selection for the guideline
Appendix E. Health economic evidence tables
None
Appendix F. Health economic analysis
None
Appendix G. Excluded studies
G.1. Excluded clinical studies
G.2. Excluded health economic studies
None
FINAL
Intervention evidence review underpinning recommendations 1.2.8 to 1.2.10 in the guideline
Developed by the National Guideline Centre, hosted by the Royal College of Physicians
Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and, where appropriate, their carer or guardian.
Local commissioners and providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.
NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.
- Are thyroid function tests too frequently and inappropriately requested?[J Endocrinol Invest. 1999]Are thyroid function tests too frequently and inappropriately requested?Roti E, Gardini E, Magotti MG, Pilla S, Minelli R, Salvi M, Monica C, Maestri D, Cencetti S, Braverman LE. J Endocrinol Invest. 1999 Mar; 22(3):184-90.
- Analysis of current thyroid function test ordering practices.[J Eval Clin Pract. 2018]Analysis of current thyroid function test ordering practices.Kluesner JK, Beckman DJ, Tate JM, Beauvais AA, Kravchenko MI, Wardian JL, Graybill SD, Colburn JA, Folaron I, True MW. J Eval Clin Pract. 2018 Apr; 24(2):347-352. Epub 2017 Nov 3.
- Should Free Thyroxine Go Back into the Routine Thyroid Profile?[Exp Clin Endocrinol Diabetes. ...]Should Free Thyroxine Go Back into the Routine Thyroid Profile?Livingston M, Twomey PJ, Basu A, Smellie S, Kane JW, Heald A. Exp Clin Endocrinol Diabetes. 2015 Nov; 123(10):594-7. Epub 2015 Nov 24.
- Review Monitoring thyroid disease: Thyroid disease: assessment and management: Evidence review F[ 2019]Review Monitoring thyroid disease: Thyroid disease: assessment and management: Evidence review FNational Guideline Centre (UK). 2019 Nov
- Review [Thyroxine (T4) and tri-iodothyronine (T3) determinations: techniques and value in the assessment of thyroid function].[Ann Biol Clin (Paris). 2003]Review [Thyroxine (T4) and tri-iodothyronine (T3) determinations: techniques and value in the assessment of thyroid function].Sapin R, Schlienger JL. Ann Biol Clin (Paris). 2003 Jul-Aug; 61(4):411-20.
- Thyroid function testsThyroid function tests
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