Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guidelineBMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l2006 (Published 14 May 2019) Cite this as: BMJ 2019;365:l2006
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We welcome the interest and rapid responses (e.g. 1-4) related to our recommendation and appraisal of supporting evidence. Colleagues and patients raised important issues, to which we would like to bring some elements of response. The BMJ Rapid Recommendations are clinical practice guidelines based on the best available evidence with a potential to change practice on a focused question. Our aim is to provide clinicians and patients with trustworthy guidance on how to use this evidence in daily practice.
We would like to re-iterate that our Rapid Recommendation refers only to adults with subclinical hypothyroidism, defined as a biochemical state with increased thyroid stimulating hormone (TSH) levels and normal T4, which is found in about 5% of the general population, and 10-20% of people >65 years old. Some people may experience symptoms, which are often non-specific and vary in severity, while more than one third experience no symptoms at all. Our guideline does not apply to women who are trying to become pregnant as such women were excluded from the studies that form the evidence base. It does also not apply to those with TSH values above 20mIU/L as these findings are suggestive of overt rather than subclinical hypothyroidism. In addition, the guideline may not apply to patients with severe symptoms and very young adults such as younger than 30 years, as only few of these patients were included in the studies.
The guideline panel recommends not to routinely offer levothyroxine in patients with newly diagnosed subclinical hypothyroidism within the scope defined in our guideline. We did not evaluate the effectiveness of other therapeutic strategies for subclinical hypothyroidism or other thyroid conditions. We are aware that other formulas of thyroid replacement therapy have been tried out, such as the combination of T4 (levothyroxine) and T3 (liothyronine), as raised by colleagues in their response. Some other groups aimed to summarize the evidence on the effectiveness of combination therapy for overt hypothyroidism, but there is no randomized evidence on patients with subclinical hypothyroidism.[8-10] Currently, there seems to be insufficient evidence to support the combination therapy for patients with subclinical hypothyroidism. Such alternative strategies would require further research and were not in the scope of our assessment and recommendation.
We acknowledge the worry about the applicability to younger adults, as expressed by the Society for Endocrinology and British Thyroid Association. The panel shared this concern, and therefore examined the age distributions of all randomized evidence, also producing a separate evidence summary excluding the large TRUST trial, which evaluated elderly only. The remaining evidence included in the systematic review applies to a broad age range of adults with subclinical hypothyroidism (mean 48 years, ranging from 32 to 74 years). Results consistently show no evidence of benefit. Following GRADE guidance, the panel rated down the quality of evidence for indirectness for several outcomes such as fatigue and mortality. Thus, although certainty in potential harms was low or very low, certainty in the consistent lack of benefits remained moderate to high across outcomes (see summary of findings in our infographic). Similarly, we found no evidence of any subgroup effect in randomized data across other available variables, such as TSH levels (e.g. higher vs. lower than 10mIU/L). Increased TSH levels can be prognostic of a progression to overt hypothyroidism, but no current randomized evidence supports the hypothesis, raised by observational data, that they can predict response to levothyroxine.
The Society for Endocrinology and British Thyroid Association  also stated that for a strong recommendation against levothyroxine, one would need compelling evidence that the drug does not work. We argue for a slightly different perspective, which is that we need clear evidence of benefits before considering prescribing a drug to such a large scale, as is currently the case worldwide. Indeed, the very high rates of levothyroxine utilization suggest an automatic prescription among physicians, which is at odds with the current body of evidence. If levothyroxine was a drug new on the market, current lack of benefits in randomized data would likely not be sufficient for its approval, even less so for a long-term (and often life-long) treatment with uncertain long-term harms for patients starting the drug at a young age.
Other responses suggested that the guideline minimizes clinical findings and symptoms.[1,2] This is not the case, and our recommendation should not be used to disregard patients’ symptoms. Although one third of patients with findings of subclinical hypothyroidism experience are asymptomatic, many patients may experience symptoms and distress, and their work-up and treatment remains challenging for patient and the clinician who look after them. For each patient, shared-decision making is important, to ensure decisions according to their own situation and aligned with their values and preferences. Shared decision-making is even more important in situations where our recommendation does not or may not apply, such as patients with severe symptoms. However, for mild symptoms, we found no benefit of thyroid hormones and the slight initial benefit was exactly the same under placebo. Shared decision-making may not only involve the decision to treat or not, but also additional diagnostic or follow-up strategies (e.g. frequency of clinical visits to monitor symptoms progression or resolution, or frequency of blood samples). When relevant, we advise patients to bring this recommendation and supporting evidence to their doctors to discuss how it can apply to their own situation. We thus hope our guideline and supporting decision aids can contribute to some of these complex discussions.
1. Jenkins, E. Lab results taking precedence over clinical judgement (Letter to the Editor).
2. Sanday, L. Letter to the Editor.
3. Forsyth, L. Statement from the Society for Endocrinology and British Thyroid Association (letter to the Editor).
4. Sharvill, N. Letter to the Editor.
5. Siemieniuk RA, Agoritsas T, Macdonald H et al. Introduction to BMJ Rapid Recommendations. BMJ 2016; 354: i5191. doi: 10.1136/bmj.i5191
6. Bekkering GE, Agoritsas T, Lytvyn L et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline BMJ 2019; 365 : l2006 . doi: https://doi.org/10.1136/bmj.l2006
7. Canaris GJ, Manowitz NR, Mayor G et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526-34.
8. Guglielmi R, Frasoldati A, Zini M et al. Italian association of clinical endocrinologists statement-Replacement therapy for primary hypothyroidism: A brief guide for clinical practice. Endocr Pract. 2016 Nov;22:1319-1326. doi: 10.4158/EP161308.OR
9. Hennessey JV, Espaillat R. Current evidence for the treatment of hypothyroidism with levothyroxine/levotriiodothyronine combination therapy versus levothyroxine monotherapy. Int J Clin Pract. 2018 Feb;72(2). doi: 10.1111/ijcp.13062.
10. Wiersinga WM. Therapy of endocrine disease: T4 + T3 combination therapy: is there a true effect? Eur J Endocrinol. 2017 Dec;177(6):R287-R296. doi: 10.1530/EJE-17-0645.
11. Feller M, Snel M, Moutzouri E, et al. Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis. JAMA 2018;320(13):1349-59. doi: 10.1001/jama.2018.13770.
Competing interests: No competing interests
Only the US guideline mentions the presence of anti-thyroid antibodies as an indication for treatment. I wonder how often anti-thyroid antibodies are measured in the UK and if data on treatment of "subclinical hypothyroidism" is coloured by a lack of testing for autoimmune thyroid disease under NHS guidelines.
Competing interests: No competing interests
Lab results taking precedence over clinical judgement
This interesting guideline does bring into question physicians’ reliance on lab results and the notion of ‘normal’ blood tests. Greater weight should be given to clinical findings rather than absolute values for thyroid function. The guideline advises against thyroid treatment in SCH but I suggest we should consider physicians reliance on absolute blood results in general. The guideline suggests that the notion of ‘normal’ blood results is leading to the unnecessary treatment in the SCH group. Statistically, there are also individuals who have ‘normal’ T4 and TSH levels, yet symptoms of hypothyroidism responsive to thyroxine, who are also being let down by the reliance on biochemistry results.
We know that reference ranges only represent 95% of the population; just as this means people may have values outside of the reference ranges and be asymptomatic, there are also individuals with blood results in the ‘normal range’ who are symptomatic. My worry is that the headlines generated by this guideline will overall lead to more conservative management of hypothyroidism, when in fact a more individualised approach is required, with pharmacological management of the disease titrated to symptoms, not blood results, perhaps a skill that is being lost with the reliance on investigations in clinical practice.
Competing interests: No competing interests
The guideline needs to be clearer on who it applies to. The vast majority of patients with hypothyroidism in my practice have Hashimoto's disease. The high prevalence of Hashimoto's may have something to do with falling population vitamin D levels.
People with Hashimoto's disease have positive anti-thyroid antibodies, and hence are excluded from the guideline, according the the "exceptions" in the text. The major question is whether people with Hashimoto's disease and a plethora of vague symptoms can be considered "subclinical" and if they might benefit from thyroid hormone supplementation. The guideline doesn't clarify the situation for a majority of my patients.
Competing interests: No competing interests
To the BMJ Editor
This report, as previous Guidelines, places more importance on biochemical thyroid function testing, than on how each hypothyroid patient experiences hypothyroidism, whether subclinical or overt, which skews many potentially meaningful conversations between Dr and patient.
Patients want symptoms resolved. Symptoms are distressing. In any other disease/condition where there is more than one medication, patients would be subjected to medications in rotation, to find one that clears up their symptoms; they would not be left to suffer for years waiting for the right biochemical levels to turn up. Hypothyroidism is a one-medication hormone deficiency, apparently. Levothyroxine is ‘always right’ so it's the symptoms that are ‘not right’, or the patient is somehow wrong. And because hypothyroidism mainly affects females, very quickly old ‘hysteria’ dogmas or ‘other conditions’ surface to contest the lack of medication on offer.
The Authors concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones. ‘Hormones’ plural. The Guideline only mentions one hormone, strangely, Levothyroxine. At no point in this recommendation is Liothyronine, T3, even acknowledged as being necessary to test, yet it is the hormone our cells need. All eukaryotic cells rely upon T3 to power every cell in their body, so why not include Ft3 testing in tft’s? Why isn’t it deemed important enough? Why was ft3 testing and associated paradigm not included in this report?
Where thyroid function tests are limited to TSH/Ft4 they fail to identify where the critical Ft3 level is in the reference range, and if there is poor or no conversion of T4 to T3, the patient suffers. I eventually found hypothyroidism symptom relief with Liothyronine at the age of 64, despite having gorged on levothyroxine for several decades, still in possession of most, if not all, of my original symptoms.
Patient symptoms in this report are disregarded even further by stating -
“the relation between symptoms and biochemical TSH levels remains unclear”.
“Many of these symptoms are not specific to hypothyroidism”.
Individually, each symptom could be attributed to other conditions as suggested by the Authors, but as a collection of 12, hypothyroidism patients would recognise them all. The over-reliance by clinicians on biochemically testing just TSH and Ft4, and interpreting results as ‘normal’ and believing them to indicate a euthyroid state anywhere within test ranges, totally disregards even clearly distressing symptoms expressed by the patient. This can only exacerbate an already deeply unsatisfactory situation for the patient and creates a wider gulf of hypothyroidism understanding between primary physician and patient. This is the point where many patients lose faith in the healthcare system. I had 14 years of clearly distressing symptoms before initiating levothyroxine medication, but all were ignored because my TSH was not raised. Only much later did someone look at my other (lacking) pituitary hormones.
The shortsightedness of downgrading patient symptoms in favour of biochemical testing in this Report, also ignores the increasing forward cost burden, to state and individual, as evidenced by the number of thyroid support groups currently on social media with patients requiring help from each other in dealing with their untreated and debilitating symptoms.
Competing interests: No competing interests
Statement from the Society for Endocrinology and British Thyroid Association
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.
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)
Competing interests: No competing interests
We refer to the recent BMJ article - Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline (1). We appreciate that the article has shed more light onto the need for a better understanding of treating subclinical hypothyroidism. It reinforces the recent literature that symptom relief and improvement in quality of life (QOL) is minimal with LT4 treatment in subclinical hypothyroidism (2,3).
The clinical practice guideline is based on a recent systematic review (3). In most of the studies analysed in this systematic review, the TSH of the subclinical hypothyroid patients was <10mU/L. The studies in the systemic review also excluded patients already treated with LT4, as any recent LT4 treatment can affect TSH levels. Other studies (4) concur with the systematic review that there is no difference between placebo and LT4 treatment in symptom relief for subclinical hypothyroidism.
Subclinical hypothyroidism has been shown to resolve spontaneously in about half of patients with mild TSH elevations with TPOAb negativity, while progression to overt hypothyroidism was only associated in those with TSH >10mU/L (5). In another prospective follow-up study (6), many patients on existing LT4 treatment based on borderline TSH values was deemed unnecessary and many of them remain euthyroid after withdrawal of their existing LT4 treatment. The study suggested that the treatment strategy for a mildly abnormal TSH is to re-test after 2-4 months and then consider LT4 treatment if TSH is repeatedly abnormal. This strategy is also supported by others (7,8) that encourage a repeat thyroid function test 2-3 months later before LT4 treatment in subclinical hypothyroidism to exclude transient causes of raised TSH (e.g. recovery from non-thyroidal illness and subacute thyroiditis).
Other factors can also impact the over-reliance on TSH results. TSH increases with age (9), with up to 14.5% of subjects over 80 years old having TSH >4.5mU/L; the TSH spread is even wider in some other studies (10). This suggests that in older individuals a slightly high TSH could be tolerated without LT4 intervention. Besides, there is no strong evidence for the use of age-specific TSH reference ranges (11). Smoking, non-thyroidal illness, and pregnancy can cause transient decreases in TSH, whereas obesity and diabetes can elevate baseline TSH (10,12). For patients with normal FT4 values, the TSH levels are slightly higher in men than women (10,13). Another confounding issue is the variability between TSH assays due to a lack of assay standardization; discrepancies between different assays persist despite attempts at harmonization (14). Besides the absolute TSH value, it is important to consider the patient’s clinical picture and other factors before commencing LT4 treatment.
This article needs to be considered in perspective. Firstly, this article is more applicable to patients with milder subclinical hypothyroidism (TSH<10mU/L) and not generalized to the more severe forms of subclinical hypothyroidism (TSH >10mU/L) or overt hypothyroidism. While the impact of LT4 treatment in subclinical hypothyroidism on QOL, thyroid-related symptoms, depression and cognitive symptoms is well known, the effect of LT4 treatment on cardiovascular outcomes and mortality in these patients are less clear. This is due to the paucity of studies in this regard. Increased risk of cardiovascular disease in patients with TSH >10mU/L has been reported (15). Another factor that has not been considered in this study is the influence of TPO on TSH as individuals with TPO positivity have a higher serum TSH than those patients with TPO negativity (16). Separation of subclinical hypothyroidism by TPO-Ab status might identify subjects with higher risk who warrant LT4 therapy.
We agree that treatment of patients with mild subclinical hypothyroidism (TSH<10mU/L) with LT4 is probably not indicated except in those with symptoms, are pregnant or trying to conceive. Patients with mild TSH elevations in subclinical hypothyroidism should be observed and retested to confirm a persistent elevation of TSH before considering LT4 prescription. Physicians must interpret the TSH values in conjunction with the entire clinical picture of the patient.
1 Bekkering GE, Agoritsas T, Lytvyn L, Moutzouri E, Beecher D, Singh Ospina N, et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ 2019; 365: l2006.
2 CS Lau, TC Aw. Thyroid function testing – Why, What and When. J Otolaryngol: Res 2019; 2: 128.
3 Feller M, Snel M, Moutzouri E, Bauer DC, de Montmollin M, Aujesky D. Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis. JAMA 2018; 320: 1349-1359.
4 Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijart SP, et al. for the TRUST Study Group. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med 2017; 376: 2534-2544.
5 Somwaru LL, Rariy CM, Arnold AM, Cappola AR. The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study. J Clin Endocrinol Metab 2012; 97: 1962-1969.
6 Livadas S, Bothou C, Androulakis I, Boniakos A, Angelopoulos N, Duntas L. Levothyroxine Replacement Therapy and Overuse: A Timely Diagnostic Approach. Thyroid 2018; doi: 10.1089/thy.2018.0014.
7 Peeters RP. Subclinical hypothyroidism. N Engl J Med 2017; 376: 2556-2565.
8 Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 2014; 24: 1670-1751.
9 Surks MI, Hollowell JG. Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism. J Clin Endocrinol Metab 2007; 92: 4575-4582.
10 Vadiveloo T, Donnan PT, Murphy MJ, Leese GP. Age- and gender-specific TSH reference intervals in people with no obvious thyroid disease in Tayside, Scotland: the Thyroid Epidemiology, Audit, and Research Study (TEARS). J Clin Endocrinol Metab 2013; 98: 1147-1153.
11 Kahapola-Arachchige KM, HadlowN, Wardrop R, Lim EM, Walsh JP. Age-specific TSH reference ranges have minimal impact on the diagnosis of thyroid dysfunction. Clin Endocrinol (Oxf) 2012; 77: 773-779.
12 Jonklaas J, Razvi S. Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers. Lancet Diabetes Endocrinol 2019; doi: https://doi.org/10.1016/S2213-8587(18)30371-1.
13 Hadlow NC, Rothacker KM, Wardrop R, Brown SJ, Lim EM, Walsh JP. The relationship between TSH and free T(4) in a large population is complex and nonlinear and differs by age and sex. J Clin Endocrinol Metab 2013; 98: 2936-2943.
14 Thienpont LM, van Uytfanghe K, Beastall G, Faix JD, Ieiri T, Miller WG, et al. Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 1: thyroid-stimulating hormone. Clin Chem 2010; 56: 902-911.
15 Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010; 304: 1365-74.
16 Chaker L, Korevaar TI, Medici M, Uitterlinden AG, Hofman A, Dehghan A, et al. Thyroid function characteristics and determinants: the Rotterdam Study. Thyroid 2016; 26: 1195-1204.
Competing interests: No competing interests
Bekkering GE, Vermandere M, Lytvyn L, Brito JB, Singh Ospina N, Rodondi N, Abdulazeem H, Wallace E, Darbellay-Farhoumand P, B Aertgeerts, Kuijpers T, Agoritsas T.
On behalf of the panel for the Rapid Recommendation ‘Thyroid hormones treatment for subclinical hypothyroidism’
We welcome the interest and discussions related to our Rapid Recommendation and supporting evidence. The BMJ Rapid Recommendations are clinical practice guidelines based on the best available evidence with a potential to change practice on a focused question.(1) Our aim is to provide clinicians and patients with trustworthy guidance on how to use this evidence in daily practice.
We would like to re-iterate that our Rapid Recommendation refers only to patients with subclinical hypothyroidism, a biochemical state with increased TSH levels and normal T4,(2) which is found in about 5% of the general population, and 10-20% of people >65 years old. Some people may experience symptoms, which are often non-specific and vary in severity, while more than one third experience no symptoms at all.(3) This guideline does not apply to women who are trying to become pregnant as such women were excluded from the studies that form the evidence base. It does also not apply to those with TSH values above 20mIU/L as these findings are suggestive of overt hypothyroidism. In addition, the guideline may not apply to patients with severe symptoms and very young adults as only few of these patients were included in the studies.(2)
The guideline panel recommends not to routinely offer levothyroxine in patients with newly diagnosed subclinical hypothyroidism within the scope of our guideline. We did not evaluate the effectiveness of other therapeutic strategies for subclinical hypothyroidism or other thyroid conditions. We are aware that other formulas of thyroid replacement therapy have been tried out, such as the combination of T4 (levothyroxine) and T3 (liothyronine). Some other groups aimed to summarize the evidence on the effectiveness of combination therapy for overt hypothyroidism, but not on patients with subclinical hypothyroidism.(4-6) Currently, there seems to be insufficient evidence to support the combination therapy for patients with subclinical hypothyroidism. Such alternative strategies may require further research, and were not in the scope of our assessment and recommendation.
In all cases, we emphasize that shared decision-making with each individual patient is central, and even more so in situations where our recommendation does not or may not apply. When relevant, we advise patients to bring this recommendation and supporting evidence to their doctors to discuss how it can apply to their own situation, and ensure treatment and follow-up decisions are aligned with their values and preferences.
1. Siemieniuk RA, Agoritsas T, Macdonald H et al. Introduction to BMJ Rapid Recommendations. BMJ 2016; 354: i5191. doi: 10.1136/bmj.i5191
2. Bekkering GE, Agoritsas T, Lytvyn L et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline BMJ 2019; 365 : l2006 . doi: https://doi.org/10.1136/bmj.l2006
3. Canaris GJ, Manowitz NR, Mayor G et al. The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160:526-34.
4. Guglielmi R, Frasoldati A, Zini M et al. Italian association of clinical endocrinologists statement-Replacement therapy for primary hypothyroidism: A brief guide for clinical practice. Endocr Pract. 2016 Nov;22:1319-1326. doi: 10.4158/EP161308.OR
5. Hennessey JV, Espaillat R. Current evidence for the treatment of hypothyroidism with levothyroxine/levotriiodothyronine combination therapy versus levothyroxine monotherapy. Int J Clin Pract. 2018 Feb;72(2). doi: 10.1111/ijcp.13062.
6. Wiersinga WM. Therapy of endocrine disease: T4 + T3 combination therapy: is there a true effect? Eur J Endocrinol. 2017 Dec;177(6):R287-R296. doi: 10.1530/EJE-17-0645.
Competing interests: No competing interests
Re: Consideration of severity of TSH elevation in decision-making about thyroid hormone treatment for subclinical hypothyroidism
The biochemical definition of subclinical hypothyroidism (SCH) is elevation of thyroid stimulating hormone (TSH) concentration above a 95% population reference range, with normal free thyroid hormone measurements. However, in elderly individuals without thyroid disease, the upper 97.5% conﬁdence interval of TSH is 7.5 mIU/L (1). In this age group mild TSH elevations above the general population reference range may be considered normal.
The biochemical severity of SCH has traditionally been defined by the TSH cut-point of 10.0 mIU/L (2), characterizing mild and severe elevations, below and above this value, respectively. This distinction has important prognostic implications as large epidemiologic studies have shown significantly increased age- and sex-adjusted risk for coronary heart disease events (3), coronary heart disease mortality (3) and heart failure events (4) for TSH values ≥ 10.0 mIU/L, but not necessarily for mild TSH elevations.
In this BMJ Rapid Recommendation, Bekkering et al. strongly recommend against the use of thyroid hormones in adults with SCH, with the exception of women who are pregnant or trying to become pregnant, patients with severe symptoms, patients with serum TSH values > 20 mIU/L, or young adults (≤ 30 years of age). This recommendation is based on a systematic review and meta-analysis of data from relatively short-term randomized controlled trials (3 to 18 months in duration), which demonstrated lack of treatment benefit for a variety of outcomes. Although increased harms of treatment were not demonstrated in the review, the guideline panel expressed concerns about the “burden of lifelong management” and “uncertainty on potential harms”, regarding thyroid hormone treatment. Although not specifically reported as a harm by the authors of the guideline, progression to overt hypothyroidism (TSH elevation > 20 mIU/L or low free thyroid hormone levels), would be a risk in untreated patients. Overt hypothyroidism is associated with increased risk of symptoms (5) and morbidity.
We are in agreement that routine levothyroxine treatment of mild TSH elevation in asymptomatic adults is not indicated. The topic of pregnancy or pregnancy consideration is beyond the scope of this review. However, the inferred biochemical treatment threshold of serum TSH > 20 mIU/L reported by Bekkering et al. is substantially higher than the 10 mIU/L threshold recommended in current clinical practice guidelines on SCH (2,6,7). We have the following comments related to the recommended TSH threshold for levothyroxine treatment of SCH reported in this guideline:
1) There is underrepresentation of individuals with TSH ≥ 10 mIU/L in the trials informing this guideline
In the systematic review and meta-analysis of RCTs informing this guideline, Feller et. al. (8) reported that “the findings may not be generalizable to people with subclinical hypothyroidism and a thyrotropin level higher than 10 mIU/L”, given the paucity of individuals with severe TSH elevations included in the meta-analysis. The guideline authors have reported the range of mean TSH values from included trials, but the variance of individual trial TSH values does not appear to be considered. As such, we have conducted random effects meta-analyses of mean baseline TSH values from the trials included in this review and determined that the upper limit of the 95% confidence interval was < 10 mIU/L for the populations in all outcome analyses. Given the underrepresentation of individuals with TSH values ≥ 10 mIU/L in these trials and lack of long-term follow-up, there is substantial uncertainty with respect to long-term treatment impact (including cardiovascular event risk) in this group.
2) The risk of disease progression of untreated SCH is insufficiently addressed
The risk of disease progression in untreated SCH is not sufficiently addressed in the BMJ guideline. Multiple long-term prospective observational studies, including a broad spectrum of severity of SCH, have reported that the risk of progression to overt hypothyroidism (defined by low free thyroid hormone levels or TSH values > 20 mIU/L) increases significantly according to the degree of the baseline TSH elevation (8-10). Of direct relevance to the BMJ guideline recommendation, Diez et al., reported on 107 individuals with SCH who were followed every 6 months and not treated with thyroid hormone unless the TSH value was > 20 mIU/L or the free thyroid hormone level was low (9). After a mean follow-up period of 32 months, overt hypothyroidism occurred in 66.7% (24/36) of patients with TSH values of 10 to 19.9 mIU/L, which was substantially higher than the rate of 5.6% (4/71) in patients with TSH values of 5 - 9.9 mIU/L (9). The severity of TSH elevation independently and significantly predicted the risk of progression to overt hypothyroidism, after adjustment for sex, age, symptoms, goiter, and presence of thyroid peroxidase antibodies (9). Thus, we believe it is important to appropriately counsel patients about the risks of biochemical disease progression, according to severity of baseline TSH elevation, in order to facilitate fully informed treatment decision-making and guide the appropriate intensity of disease surveillance.
In conclusion, there are important uncertainties (relating to indirectness of evidence and unrecognized harms), that limit confidence in a strong recommendation against offering thyroid hormone treatment to patients with subclinical hypothyroidism with TSH ≥ 10 mIU/L. These evidence uncertainties need to be addressed in the language and strength of recommendations relating to this subgroup, as well as other relevant explanatory sections of the guideline.
Although the main focus of this commentary is consideration of severity of TSH elevation in decision-making about levothyroxine treatment of SCH, it is important to treat the patient, not just the biochemical abnormality (12). Thus, healthcare practitioners and patients need to consider other relevant factors such as symptoms, comorbidities, safety/feasibility issues, and patients’ values/preferences in deciding about management of SCH.
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8) Feller M, Snel M, Moutzouri E, et al. Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: a systematic review and meta-analysis. JAMA 2018;320:1349-59. 10.1001/jama.2018.13770. pmid:30285179.
9) Díez JJ, Iglesias P. Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure. J Clin Endocrinol Metab. 2004;89(10):4890-7.
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12) Jonklaas J, Razvi S. Reference intervals in the diagnosis of thyroid dysfunction: treating patients not numbers. Lancet Diabetes Endocrinol. 2019;7(6):473-483.
Competing interests: The authors have previously participated in development of clinical practice guidelines on thyroid-related topics. The views expressed are that of the authors, and not made on behalf of any professional organization.
Thank you for the comprehensive review of subclinical hypothyroidism. With respect to pregnant women and women planning pregnancy, there are a number of important published studies and guidelines which were not referenced in the review, but support an opposing view..
The authors refer to a meta analysis of observational data of SCH in pregnancy, but do not include the 2 large, high quality RCTs which did not show a difference in outcome for women or babies when women with SCH were treated during pregnancy with thyroxine (1, 2). They refer to one practice guideline from ATA, but do not include the clinical practice guidelines from ACOG and RANZCOG which do not support treating pregnant women with SCH (3, 4).
Thyroxine treatment for women with thyroid autoantibodies planning pregnancy has also been shown not to be effective in improving pregnancy rates in 2 large RCTs (5, 6).
Over all, high quality evidence does not support thyroxine treatment of pregnant women or women planning pregnancy with SCH to improve obstetric outcomes.
1. Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, et al. Treatment of Subclinical Hypothyroidism or Hypothyroxinemia in Pregnancy. N Engl J Med. 2017;376(9):815-25.
2. Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, et al. Antenatal thyroid screening and childhood cognitive function. N Engl J Med. 2012;366(6):493-501.
3. American College of Obstetrics and Gynecologists. Practice Bulletin No. 148: Thyroid disease in pregnancy. Obstetrics and gynecology. 2015;125(4):996-1005.
4. Royal Australian and New Zealand College of Obstetrics and Gynecologists. Subclinical hypothyroidism and hypothyroidism in pregnancy. 2018.
5. Wang H, Gao H, Chi H, Zeng L, Xiao W, Wang Y, et al. Effect of Levothyroxine on Miscarriage Among Women With Normal Thyroid Function and Thyroid Autoimmunity Undergoing In Vitro Fertilization and Embryo Transfer: A Randomized Clinical Trial. JAMA. 2017;318(22):2190-8.
6. Dhillon-Smith RK, Middleton LJ, Sunner KK, Cheed V, Baker K, Farrell-Carver S, et al. Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception. N Engl J Med. 2019;380(14):1316-25.
Competing interests: No competing interests