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Practice Rapid Recommendations

Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline

BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l2006 (Published 14 May 2019) Cite this as: BMJ 2019;365:l2006

Visual summary of recommendation

or No thyroid hormones Thyroid hormones Levothyroxine Interventions compared Recommendation Population Adults with subclinical hypothyroidism Does not apply to: May not apply to: Including: Women who are or trying to become pregnant Patients with no symptoms (diagnosed after screening) Patients with non-specific symptoms Patients with severe symptoms Patients with TSH above 20 mIU/L Young adults (such as <30 years) Elevated levels of thyroid stimulating hormone (TSH) Normal free T4 (thyroxine) levels

We recommend against thyroid hormone therapy for patients with subclinical hypothyroidism Moredetails Strong All or nearly all informed people would likely want this option. Benefits outweigh harms for almost everyone. Weak Most people would likely want this option. Benefits outweigh harms for the majority, but not for everyone. Weak Most people would likely want this option. Benefits outweigh harms for the majority, but not for everyone. Strong All or nearly all informed people would likely want this option. Benefits outweigh harms for almost everyone.

COMPARISON OF BENEFITS AND HARMS
For the elderly - about 65 years and older All the evidence, including from the largest TRUST trial conducted among an elderly population with comorbidities (see Figure 2)
No thyroid hormones Thyroid hormones Evidence quality EQ-5D score: -0.59-1 (High better) After 1 year No important difference The panel found that this difference was not important for most patients, because the intervention effects were negligible and/or very imprecise, for example confidence intervals that include both important benefit and harm

No important difference General quality of life High More 0.85 0.83

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone has little or no effect on general quality of life High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Mean score: 0-100 (Low better)

No important difference Thyroid-related symptoms High More 16.7 16.5

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone has little or no effect on thyroid-related symptoms High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

No important difference Fatigue / tiredness High More 28.6 29.0

Minimum clinically important difference is 9 points 9 CID Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone has little or no effect on fatigue / tiredness High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Mean score: 0-21 (Low better)

3.6 Depressive symptoms High More No important difference 3.3

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone has little or no effect on depressive symptoms High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Mean score: 0-infinity (High better) After 1.5 years

No important difference Cognitive function High More 27.1 28.1

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone has little or no effect on cognitive function High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Events per 1000 people After 2 years

27 Mortality Low More 14 No important difference

Risk of Bias No serious concerns Imprecision Very serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone may have little or no effect on mortality Low GRADE score, because of: Only a few deaths were observed, in a single trial. We are 95% confident that the difference is between 5 fewer to 62 more deaths per 1000 patients taking levothyroxine GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

48 Cardiovascular events Low More 54 No important difference

Risk of Bias No serious concerns Imprecision Very serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone may have little or no effect on cardiovascular events Low GRADE score, because of: Only a few cardiovascular events were observed, in a single trial. We are 95% confident that the difference is between 28 fewer to 62 more events per 1000 patients taking levothyroxine GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Mean score: 0-100 (Low better)

10.9 Side effects Moderate More No important difference 10.3

Risk of Bias No serious concerns Imprecision Serious Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone probably has little or no effect on side effects Hyperthyroidism due to overdosing Moderate GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
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For younger people (such as 65 and younger) Lorem ipsum dolor sit amet, consectetuer adipiscing elit, sed diam nonummy nibh euismod tincidunt ut Evidence excluding the large TRUST trial, conducted among the elderly, which dominated the results of the systematic review
No thyroid hormones Thyroid hormones Evidence quality EQ-5D score: -0.59-1 (High better) After 1 year No important difference The panel found that this difference was not important for most patients, because the intervention effects were negligible and/or very imprecise, for example confidence intervals that include both important benefit and harm

No important difference General quality of life Moderate More 0.85 0.82

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency Serious Publication bias No serious concerns Thyroid hormone probably has little or no effect on general quality of life Moderate GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Mean score: 0-100 (Low better)

No important difference Thyroid-related symptoms High More 16.7 16.4

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone has little or no effect on thyroid-related symptoms High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

No important difference Fatigue / tiredness Moderate More 28.6 29.0

Minimum clinically important difference is 9 points 9 CID Risk of Bias No serious concerns Imprecision No serious concerns Indirectness Serious Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone probably has little or no effect on fatigue / tiredness Moderate GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Mean score: 0-21 (Low better)

3.6 Depressive symptoms High More No important difference 3.3

Risk of Bias No serious concerns Imprecision No serious concerns Indirectness No serious concerns Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone has little or no effect on depressive symptoms High GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Mean score: 0-infinity (High better) After 1.5 years

No important difference Cognitive function Low More 27.1 29.7

Risk of Bias No serious concerns Imprecision Serious Indirectness Serious Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone may have little or no effect on cognitive function Low GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Events per 1000 people After 2 years

27 Mortality Very low More 14 No important difference

Risk of Bias No serious concerns Imprecision Very serious Indirectness Serious Inconsistency No serious concerns Publication bias No serious concerns We are uncertain whether thyroid hormone increases or decreases mortality Very Low GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low

48 Cardiovascular events Very low More 54 No important difference

Risk of Bias No serious concerns Imprecision Very serious Indirectness Serious Inconsistency No serious concerns Publication bias No serious concerns We are uncertain whether thyroid hormone increases or decreases cardiovascular events Very Low GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
Mean score: 0-100 (Low better)

10.9 Side effects Low More No important difference 10.3

Risk of Bias No serious concerns Imprecision Serious Indirectness Serious Inconsistency No serious concerns Publication bias No serious concerns Thyroid hormone may have little or no effect on side effects Hyperthyroidism due to overdosing Low GRADE score, because of: GRADE certainty ratings The authors have a lot of confidence that the true effect is similar to the estimated effect The authors believe that the true effect is probably close to the estimated effect High The true effect might be markedly different from the estimated effect The true effect is probably markedly different from the estimated effect Moderate Low Very low
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Daily oral medication, normally tablets, often long-term treatment Overdosage can lead to hyperthyroidism symptoms Should be taken 4 hours apart from any products containing calcium or iron Long-term regular visits and blood samples to monitor hormone levels Regular visits and blood samples to monitor progression or resolution The panel expects little variability in how patients weigh the lack of benefit against the possible harms Potential harms, and in particular risk of dying, may be valued differently by patients depending on their age, quality of life and comorbidities Values and preferences TSH levels may vary with stress, transient disease or with age. Elevated levels thus often revert to normal without treatment There is no clear evidence on how to reliably attribute symptoms to subclinical hypothyroidism TSH levels and symptoms Key practical issues NO THYROID HORMONES THYROID HORMONES

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Re: Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline

Dear members of the panel,

As a member of the lay public I found this clinical practice guideline a fascinating read. I have lived with a long term sufferer of subclinical hypothyroidism over a 10 year period and I have completed a significant amount of reading around the subject. The recommendations presented in the meta-study are well received in the case of Levothyroxine having low efficacy in a situation where levels of T4 are normal. However I was surprised to see Levothyroxine referred to in the abstract (and throughout the body) as the totality of 'thyroid hormones', as the panel is clearly aware that Levothyroxine is a singular synthetic hormone (T4) and that there are a number of other thyroid hormones produced in the body.

When Free T4 levels are normal but an elevated level of TSH is detected it is presumed that there is instead a decreased level of T3 which is triggering the negative feedback loop which leads the pituitary to over produce TSH. It is not clear if an absence of Free T3 is considered, and if so how this affects the guideline's opening hypothesis "[When] the free T4 (thyroxine) level is normal [...] it is reasonable to ask whether treatment with thyroid hormones might help symptoms."

Moreover it is surprising that the well known alternative thyroid hormone treatment, 'desiccated thyroid', is not mentioned any where in the guideline. In fact there is a notable absence of significant comparative studies between levothyroxine and desiccated thyroid except for the 2013 study 'Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomised, double-blind, crossover study' (Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK, 2013). This is significant because this alternative contains T3 as well as T4 and therefore negates the hypothesis that taking thyroid hormones is pointless when Free T4 is measured as normal.

The use of the term 'thyroid hormones' in stead of being specific about T4 may seem like a necessary simplification for the public but it led to headlines in the press such as 'Thyroid drug "offers no benefit"', which seems fundamentally dangerous when this condition may affect as many as 20% of the population who may be discouraged from seeking any treatment and thereby progress into a much more severe state of hypothyroidism.

I hope the panel considers appending a note on the possibility of other treatments that are not exclusively T4 to the guidelines as well as considering future research into the efficacy of desiccated thyroid hormone.

Kind Regards,
Lindsay MacVean

Competing interests: No competing interests

15 May 2019
Lindsay J. MacVean
Software Engineer
Woking