Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline – The BMJ

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Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline – The BMJ

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Clinical question What are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised controlled trials, which could alter practice.

Current practice Current guidelines tend to recommend thyroid hormones for adults with thyroid stimulating hormone (TSH) levels >10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing.

Tavsiya The guideline panel issues a strong recommendation against thyroid hormones in adults with SCH (elevated TSH levels and normal free T4 (thyroxine) levels). It does not apply to women who are trying to become pregnant or patients with TSH >20 mIU/L. It may not apply to patients with severe symptoms or young adults (such as those ≤30 years old).

How this guideline was created A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach.

Dalillar The systematic review included 21 trials with 2192 participants. For adults with SCH, thyroid hormones consistently demonstrate no clinically relevant benefits for quality of life or thyroid related symptoms, including depressive symptoms, fatigue, and body mass index (moderate to high quality evidence). Thyroid hormones may have little or no effect on cardiovascular events or mortality (low quality evidence), but harms were measured in only one trial with few events at two years’ follow-up.

Understanding the recommendation The panel concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones. Other factors in the strong recommendation include the burden of lifelong management and uncertainty on potential harms. Instead, clinicians should monitor the progression or resolution of the thyroid dysfunction in these adults. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of thyroid hormones in multilayered evidence summaries and decision aids available in MAGIC (https://app.magicapp.org/) to support shared decisions and adaptation of this guideline.

Subclinical hypothyroidism (SCH) is a biochemical state. The thyroid stimulating hormone (TSH) level is elevated, but the free T4 (thyroxine) level is normal. Some people may experience symptoms linked to the abnormality. Other data have suggested links to overt hypothyroidism and adverse outcomes such as increased risk of coronary heart disease. So it is reasonable to ask whether treatment with thyroid hormones might help symptoms, prevent overt hypothyroidism, or avoid longer term heart problems. Box 1 extends and references this understanding.

Box 1

Overview of subclinical hypothyroidism (SCH)

What is SCH?

The definition of SCH varies. About 90% of all patients with SCH have TSH levels between 4 and 10 mIU/L.1 TSH levels may increase with age,2 and a slight increase of TSH may be normal for older people.

About 62% of TSH levels between 4 and 10 mIU/L normalise without intervention within five years.3 There is biological variation in TSH levels. Levels may rise in response to stress and transient disease.4 This biological variation in TSH values, means that one abnormal TSH level should be followed by a repeat blood test to confirm the diagnosis.5

According to the International Classification of Diseases (ICD), SCH does not have a separate code, but is typically labelled as “hypothyroidism, unspecified”.

How common is it?

It affects 4-20% of the adult population.6 This wide variation is due to poor consensus about the cut-off level for the diagnosis of SCH and regional variation between populations. It is more common in women, in older people, and those of white ethnicity.6

Qanday alomatlar bor?

Around 1 in 3 patients with SCH have no symptoms at all.7 The type of symptoms people link to SCH include those of overt hypothyroidism: fatigue, muscle cramps, cold sensitivity, dry skin, voice changes, and constipation.8 Other symptoms include poor memory, slowed thinking, weak muscles, puffy eyes, anxiety, and depression.7910 Many of these symptoms are not specific to hypothyroidism. Around 20-25% of people with normal TSH levels report one or two of these symptoms.7 The relation between symptoms and biochemical TSH levels remains unclear.

What is the long term outlook?

The risk of progression to overt hypothyroidism ranges between 2% and 5% a year.11 Presence of antibodies to thyroid peroxidase and, in particular, higher TSH levels increase this risk.111213

Observational data suggest that SCH is associated with an increased risk of coronary heart disease, heart failure, and cardiovascular mortality, particularly in those with TSH levels >10 mIU/L.114 Such associations were not found for most adults with TSH levels of 5-10 mIU/L.114

RETURN TO TEXT

This guideline was triggered by a systematic review,15 summarising all studies on this question. It includes a large and new trial specifically in older people with TSH.16 The results of the review might change practice. The main infographic provides an overview of the relative and absolute benefits and harms of treating SCH with thyroid hormones in standard GRADE format. Box 2 shows all of the articles and evidence linked in this Rapid Recommendation package.

Current practice

When to test for SCH

Historically, US guidelines recommended five-yearly screening of asymptomatic adults aged 35 years and older to identify thyroid dysfunction,17 but it is uncertain if such screening has any clinical benefits.18

In clinical practice, thyroid function can be checked as part of routine screening or for diagnostic purposes in those with possible hypothyroidism based on physical or mental health signs and symptoms. In the UK about 25% of adults have thyroid function tests every year.19 A recent overview showed an increase in the use of thyroid function tests over time.20

Patients and clinicians (general practitioners, internists, and endocrinologists) are commonly faced with abnormal thyroid function tests consistent with SCH. All parties collaboratively need to decide if and how to act.

When to treat SCH

Guidelines generally recommend thyroid hormones for adults with TSH levels above 10 mIU/L. For those with lower TSH levels, most guidelines recommend treatment only when people are younger, symptomatic, or have other indications for prescribing (such as cardiovascular disease or antibodies to thyroid peroxidase). 1 stol summarises current guidance from various organisations.582122

1 stol

Current guidance on thyroid hormone treatment for subclinical hypothyroidism

In many countries, the use of levothyroxine is increasing,4 with a top ranking among the most prescribed drugs in the US in 2015.23 Increasing treatment of SCH with thyroid hormone, and of levothyroxine in particular, is the most likely explanation for this increase. Research showed that prevalence of treated SCH has doubled from 1996 to 2006 and that people with TSH <10 mIU/L were prescribed levothyroxine 1.3 times more in 2009 than in 2001 in the UK.19 This increased prevalence of treated SCH was confirmed in Norwegian population surveys, despite a stable prevalence of the condition itself.24 Other evidence includes a study by Taylor19 showing that a third of adults were offered treatment after a single TSH testing. Not all of these adults may actually have SCH as TSH levels fluctuate and may revert to normal without treatment.

Finally, some patients with symptoms may receive a trial of levothyroxine to evaluate improvement of symptoms, but in such an approach it is difficult to separate real from placebo effects. Once levothyroxine is started, most adults stay on the drug for several years.19

How was this recommendation created?

Our international panel included methodologists, general practitioners, internists, endocrinologists, and patient partners with subclinical hypothyroidism (SCH) (see appendix 1 on bmj.com for details of panel members). They decided on the scope of the recommendation and identified patient-important outcomes to inform the recommendations.

The panel met online to discuss the evidence and formulate a recommendation. No member had a financial conflict of interest; intellectual and professional conflicts were minimised and are transparently described (appendix 2 on bmj.com). The panel followed the BMJ Rapid Recommendations procedures for creating a trustworthy recommendation,27 including using the GRADE approach to critically appraise the evidence and create recommendations (appendix 3 on bmj.com).28 The panel considered the benefits, harms, and burdens and other practical issues related to thyroid hormones in the context of SCH, as well as expected variations in patient values and preferences.29 Within the GRADE approach, recommendations can be either strong or weak (also known as conditional), and for or against a specific course of action.30

Dalillar

The systematic review that triggered this guideline compared the effects of thyroid hormone treatment to that of no treatment or placebo in adults with SCH.15Shakl 2 presents an overview of the characteristics of the randomised controlled trials (RCTs) and participants included in the review.

Fig 3

Practical issues about the use or non-use of thyroid hormones for subclinical hypothyroidism (SCH)

Cost and resources

Although we did not take costs and resources into account beyond direct costs to patients (such as out-of-pocket costs), thyroid hormones cannot be cost effective given the lack of important benefit, potential for harm, and associated costs.

Noaniqlik

Future research could explore whether there is an unidentified subgroup of patients who do benefit from treatment. No evidence of a potential subgroup or even a trend was observed in the current body of evidence, consistently across outcomes. Such research could consider whether there is more benefit in groups of people for whom there is less direct evidence and therefore more uncertainty, such as

There is uncertainty about potential harms, as these were studied only in the TRUST trial, which found only a few events after a follow-up of only two years. However, this uncertainty becomes important only when there is evidence of benefit.

Updates to this article

2 stol shows the evidence that has emerged since the publication of this article. As new evidence is published, a group will assess this new evidence and make a judgment on the extent that it is expected to alter the recommendation.

2 stol

New evidence which has emerged after initial publication

At the time of publication, we identified one new trial in trial registries:

  • IEMO, assessing the effect of thyroid hormones versus placebo in elderly aged 80 years with SCH, 80-plus thyroid trial (NTR3851 in Netherlands Trial Register).

How patients were involved in the creation of this article

Two people with lived experience of subclinical hypothyroidism were members of the panel and participated in the whole process. They identified and rated outcomes, and helped lead the discussion on values and preferences in a videoconference and in email discussions with the full panel. They noted patients may feel anxious about deteriorating or developing overt hypothyroidism when no treatment was given. To address this, regular follow-up is very important. They also mentioned that it is difficult for patients to make a decision when feeling unwell. We thank them for their contribution.