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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
See patient decision aids
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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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Find recommendations, evidence summaries and consultation decision aids for use in your practice
  1. G E Bekkering, guideline expert, methodologist1 2,
  2. T Agoritsas, doctor in general internal medicine, expert in shared decision making research3 4,
  3. L Lytvyn, patient partnership expert, methodologist4,
  4. A F Heen, general internist5,
  5. M Feller, general practitioner6 7,
  6. E Moutzouri, doctor in general internal medicine6 7,
  7. H Abdulazeem, patient partner8,
  8. B Aertgeerts, general practitioner1 2,
  9. D Beecher, patient partner9,
  10. J P Brito, endocrinologist10,
  11. P D Farhoumand, doctor in general internal medicine11,
  12. N Singh Ospina, endocrinologist12,
  13. N Rodondi, doctor in general internal medicine6 7,
  14. M van Driel, general practitioner13,
  15. E Wallace, general practitioner14,
  16. M Snel, endocrinologist15,
  17. P M Okwen, general practitioner16,
  18. R Siemieniuk, doctor in general internal medicine17,
  19. P O Vandvik, doctor in general internal medicine18 19 20,
  20. T Kuijpers, guideline expert, methodologist21,
  21. M Vermandere, general practitioner1
  1. 1Academic Centre for General Practice, Department of Public Health and Primary Care, KU Leuven, Belgium
  2. 2Belgian Centre for Evidence-Based Medicine, Cochrane Belgium
  3. 3Division of General Internal Medicine and Division of Clinical Epidemiology, University
  4. Hospitals of Geneva, Geneva, Switzerland
  5. 4Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada
  6. 5Department of Medicine, Innlandet Hospital Trust-division, Gjøvik, Norway
  7. 6Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
  8. 7Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
  9. 8Munich, Germany
  10. 9Milan, Italy
  11. 10Knowledge and Evaluation Research Unit in Endocrinology (KER_Endo), Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  12. 11Division General Internal Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland
  13. 12Department of Medicine, Division of Endocrinology, University of Florida, Gainesville, Florida, USA
  14. 13Primary Care Clinical Unit, Faculty of Medicine, University of Queensland, Brisbane Qld 4029, Australia
  15. 14HRB Centre for Primary Care Research and Department of General Practice, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland
  16. 15Department of Endocrinology/General Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
  17. 16Effective Basic Services (eBASE), Bamenda, Cameroon
  18. 17Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
  19. 18Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway
  20. 19Department of Medicine, Innlandet Hospital Trust-division, Gjøvik, Norway
  21. 20Norwegian Institute of Public Health, Oslo, Norway
  22. 21Dutch College of General Practitioners, Utrecht, Netherlands
  1. Correspondence to: G E Bekkering trudy.bekkering{at}kuleuven.be

Abstract

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.

Recommendation 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.

The evidence 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.

Footnotes

  • This BMJ Rapid Recommendation article is one of a series that provides clinicians with trustworthy recommendations for potentially practice changing evidence. BMJ Rapid Recommendations represent a collaborative effort between the MAGIC group (http://magicproject.org/) and The BMJ. A summary is offered here, and the full version including decision aids is on the MAGICapp (https://app.magicapp.org/public/guideline/nyqWPn), for all devices in multilayered formats. Those reading and using these recommendations should consider individual patient circumstances, and their values and preferences and may want to use consultation decision aids in MAGICapp to facilitate shared decision making with patients. There will no active dissemination of these results to patients. We encourage adaptation and contextualization of our recommendations to local or other contexts. Those considering use or adaptation of content may go to MAGICapp to link or extract its content or contact The BMJ for permission to reuse content in this article.

  • Competing interests: All authors have completed the BMJ Rapid Recommendations interests disclosure form and a detailed, contextualised description of all disclosures is reported in appendix 2 on bmj.com. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any relevant financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions. M Feller, M Snel, E Moutzouri, and N Rodondi participated in writing the systematic review that formed the evidence base for this guideline. JP Brito and N Singh Ospina wrote an editorial about the overuse of levothyroxine.

  • Funding: This guideline was not funded.

  • Transparency: G E Bekkering affirms that the manuscript is an honest, accurate, and transparent account of the recommendation being reported; that no important aspects of the recommendation have been omitted; and that any discrepancies from the recommendation as planned (and, if relevant, registered) have been explained.

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