29 May 2019

Society for Endocrinology & British Thyroid Association issue statement against new treatment recommendations for subclinical hypothyroidism

The Society for Endocrinology (SfE) and British Thyroid Association (BTA) have issued a statement challenging recommendations made in a clinical practice guideline on managing subclinical hypothyroidism (SCH), published recently in the British Medical Journal (BMJ). Both SfE and BTA disagree with the conclusion that most adults with SCH do not require treatment, as the guideline does not provide sufficient evidence, especially in younger individuals, to support this claim.

Subclinical hypothyroidism affects 4-20% of the adult population but approximately one third of patients experience no symptoms. Others report symptoms characteristic of hypothyroidism, including tiredness, weight gain, feeling the cold, muscle cramps and depression. Hypothyroidism and SCH are the result of reduced activity of the thyroid gland, which produces insufficient levels of hormones important for regulating the body’s metabolic function. Hypothyroidism is usually treated by taking daily hormone replacement tablets; however, there is some debate on the appropriate hormone level thresholds that should be used for diagnosis and treatment of SCH. The new BMJ guideline recommends a threshold for SCH treatment that SfE and BTA do not believe is supported by the data, and is far too stringent.

As outlined in the SfE and BTA statement, both disagree with the strong conclusion: “The panel concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones.”

Due to over-extrapolation from available data, most of which is from older patients with milder symptoms or from small-scale studies, the conclusions drawn are not justified. SfE and BTA are concerned that these recommendations could influence primary care physicians to dismiss patients with subclinical hypothyroidism, particularly younger ones, which could lead to some missing out on vital treatment if their condition progresses. SfE and BTA urge that larger studies, using more sensitive measures and taking factors, such as age and genetics, into consideration are needed before drawing such strong conclusions on the benefits or disadvantages of SCH treatment.

Peter Taylor, clinical senior lecturer and consultant endocrinologist at Cardiff University said, “What this detailed summary of the data does show is the urgent need for clinical trials of symptomatic patients with subclinical hypothyroidism especially in younger individuals.”

Onyebuchi Okosieme, consultant endocrinologist at Cardiff University School of Medicine said, “It is difficult to justify denying treatment to patients with fairly advanced degrees of subclinical hypothyroidism (TSH levels of 10-20 mU/L), as recommended by these guidelines. Many of such patients will have intrinsic thyroid disease and withholding treatment puts them at risk of disease complications.”

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Statement from the Society for Endocrinology and British Thyroid Association regarding the clinical practice guideline of Bekkering et al., BMJ on 14 May 2019

This clinical practice guideline which looked at thyroid hormone treatment in subclinical hypothyroidism summarises the evidence very well, but we are most concerned about the recommendations made. In particular we disagree with the strong conclusion “The panel concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones”.

For such a strong recommendation, the evidence supporting this must be compelling. We contend that this is simply not the case. This review of 21 trials only contained 2,192 participants of whom a significant number (737) were enrolled in what was originally a cardiovascular trial (TRUST) which focussed on older subjects (aged over 65 years) with many lacking thyroid symptoms at baseline. Thus, the remainder of the meta-analysis is based on predominantly small-scale trials. We therefore suggest that it is unwise to extrapolate from this analysis, particularly extending to younger individuals in whom existing trials have been small scale. This recommendation also ignores strong observational data that there may be an age interaction with regard to treatment response². As quality of life outcome assessments are likely to require large sample sizes to detect differences it is possible that current studies may have missed this, particularly if only a subgroup of trial participants derive substantial symptomatic benefit. Furthermore, with the degree of TSH elevations in the studies contained in this meta-analysis being modest, we contend that their recommendations based on a TSH cut off of >20 mIU/l go beyond the scope of the available primary data. A particular concern about the strong conclusion and high TSH threshold for intervention in this meta-analysis is that primary care physicians may now dismiss patients with subclinical hypothyroidism rather than institute ongoing surveillance, potentially resulting in some patients with progression of hypothyroidism being deprived of treatment.

Given how common subclinical hypothyroidism is throughout the world³ and the persistent concerns patients have regarding its treatment⁴ it is disappointing that current available evidence on therapeutic intervention is so limited. A more important conclusion from this meta-analysis is that carefully conducted trials of subclinical hypothyroidism, particularly in younger individuals (aged <65 years), are urgently warranted. Such studies should be an order of magnitude larger in size, consider whether other factors such as interindividual genetic variation could influence treatment response⁵ and use more sensitive and specific thyroid symptom measures (e.g. THYPRO) to assess outcome⁶.  Since TSH and FT4 levels may not reflect thyroid status of peripheral tissues, further work is needed to develop better markers of tissue hypothyroidism and include these in future trials.

References

1          Bekkering, G. E. et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ 365, l2006, doi:10.1136/bmj.l2006 (2019)

2          Razvi, S., Weaver, J. U., Butler, T. J. & Pearce, S. H. Levothyroxine Treatment of Subclinical Hypothyroidism, Fatal and Nonfatal Cardiovascular Events, and Mortality. Arch Intern Med,                                   

            doi:10.1001/archinternmed.2012.1159 (2012)

3          Taylor, P. N. et al. Global epidemiology of hyperthyroidism and hypothyroidism. Nature Reviews Endocrinology, doi:10.1038/nrendo.2018.18 (2018)

4          Peterson, S. J. et al. An Online Survey of Hypothyroid Patients Demonstrates Prominent Dissatisfaction. Thyroid 28, 707-721, doi:10.1089/thy.2017.0681 (2018)

5          Taylor, P. N., Peeters, R. & Dayan, C. M. Genetic abnormalities in thyroid hormone deiodinases. Current Opinion in Endocrinology, Diabetes and Obesity, doi:10.1097/med.0000000000000180 (2015)

6          Watt, T. et al. The thyroid-related quality of life measure ThyPRO has good responsiveness and ability to detect relevant treatment effects. J Clin Endocrinol Metab 99, 3708-3717, doi:10.1210/jc.2014-1322 (2014)