Our letter on SCH

[diogenes]

This published letter is our take on SCH. Given in full as behind a paywall

Letter to the Editor EJE

Treatment options for subclinical hypothyroidism

Rudolf Hoermann1 , John E M Midgley2 , Rolf Larisch 1 and Johannes W Dietrich3,4

1 Department for Nuclear Medicine, Klinikum Lüdenscheid, Paulmannshöherstr. 14, 58515 Lüdenscheid, Germany.

2 North Lakes Clinical, 20 Wheatley Avenue, Ilkley LS29 8PT, UK

3 Medical Department I, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Buerkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany

4 Ruhr Center for Rare Diseases (CeSER), Ruhr University of Bochum and Witten/Herdecke University, Alexandrinenstr. 5, D-44791 Bochum, Germany

Short Title: Subclinical hypothyroidism

We read with great interest the current debate on the controversial issues that have long surrounded the treatment of subclinical hypothyroidism (1). The fact that the two discussants disagreed so strongly in their approach to a prevalent problem, routinely faced by clinicians around the globe, may indicate severe shortcomings in the current approach. Although this controversy has started many year ago, it remains unresolved. Unlike in many other diseases, thyroid diagnosis has evolved through definition by exclusive reliance on a single biochemical measure, as opposed to symptomatic presentation of the disease.

In our opinion, the problem begins with the term and very definition of “subclinical hypothyroidism”. What is subclinical hypothyroidism? Is it a true disease or a mere laboratory constellation? According to current guidelines, the diagnosis of subclinical hypothyroidism is made when a confirmed TSH measurement has been obtained that exceeds the upper reference range of the pituitary hormone while the concentrations of thyroid hormones still remain within their reference range (2). Adding to the confusion, therapeutic targets have been separated from diagnostic criteria of the disease by recent guidelines (2). LT4 substitution has been recommended to be withheld in patients with diagnosed subclinical hypothyroidism unless their TSH concentration exceeds a much higher threshold (of 10 mIU/L or even up to 20 mIU/L) than he diagnostic threshold (of approx. 4 mIU/L) (2,3). This disease understanding has left clinicians with a conundrum to explain to many patients why they suffer from a disease, yet would not require any therapeutic intervention. This may be particularly difficult to accept for patients presenting with symptoms which are in their opinion suggestive of a thyroid condition,

Perhaps, it is time to consider a different approach, potentially more satisfying to clinicians. As implied in the original term “subclinical” the new strategy should re-focus on the clinical manifestation rather than the biochemistry. In recent year, the over-reliance on a TSHcentred diagnostic strategy has been strongly challenged (4,5). The apparent deficiencies of this approach and its lack of diagnostic specificity and reliability have been reviewed elsewhere (6). The problem is deeply rooted in the guiding principles of HPT regulation (7).

In patients with subclinical hypothyroidism due to autoimmune thyroiditis and sufficient intact thyroid tissue, thyroid regulation importantly includes, in addition to the classical feedback of circulating thyroid hormones onto pituitary TSH secretion, the feedforward control of TSH over preferential thyroidal triiodothyronine (T3) secretion (8). The system is designed to take pro-active action in anticipation rather than reactive to the event of a shortage of thyroid hormone supply to the body. The manifestation of a clinical disease is determined either by the success or failure of the central attempt at compensation. Measurement of a slightly elevated TSH in subclinical hypothyroidism, cannot reliably discriminate between the two outcomes. It must therefore be regarded as an ambiguous signal, unless all thyroid hormones and clinical endpoints are taken into account.

Subclinical hypothyroidism, as a laboratory constellation, has been implicated to increase the risk of cardiovascular mortality (9). This conclusion may also be premature, because slightly elevated TSH levels together with "normal" thyroid hormone concentrations may not necessarily indicate early thyroid failure (10). Alternatively, this may reflect an increase in the homeostatic set point of the hypothalamus-pituitary-thyroid axis (10). Set point adjustments frequently occur in association with chronic psychosocial stress or allostati

load type 2 (10). The latter, in turn, is a well-recognized cardiovascular risk factor. The high individual variability in the expression of the hypothalamic-pituitary-thyroid set point is further augmented by genetic traits.

Given the inherent ambiguity arising from TSH being a controlling parameter, its nonergodic behaviour and complex relationship with both thyroid hormones and clinical endpoints results obtained in clinical studies require careful consideration of their design, statistical analysis (risk of collider stratification bias) and interpretation (risk of confounding between set point elevation and thyroid failure). Consequently, we suggest that a disease defining role should be assigned to thyroid hormones, derived structural thyroid parameters (estimated functional thyroid capacity, set point reconstruction) and markers of tissue response to develop a clinically useful algorithm to be verified in clinical trials.

Recent advances in our understanding of system regulation may help put the role of TSH into a better clinical perspective. The debate should encourage further efforts to address unresolved issues and find a more clinically inclusive definition for subclinical thyroid disease, more deserving of this name.

References

1. Peeters RP, Brito JP 2020 Subclinical hypothyroidism: To treat or not to treat. Eur J Endocrinol 83: D15-D24. doi:10.1530/EJE-20-0621

2. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, Cooper DS, Kim BW, Peeters RP, Rosenthal MS, Sawka AM 2014 Guidelines for the treatment of hypothyroidism: Prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid 24: 1670-1751. doi:10.1089/thy.2014.0028

3. Bekkering GE, Agoritsas T, Lytvyn L, Heen AF, Feller M, Moutzouri E, Abdulazeem H, Aertgeerts B, Beecher D, Brito JP, Farhoumand PD, Singh Ospina N, Rodondi N, Van Driel M, Wallace E, Snel M, Okwen PM, Siemieniuk R, Vandvik PO, Kuijpers T, Vermandere M 2019 Thyroid hormones treatment for subclinical hypothyroidism: A clinical practice guideline. BMJ 365: l2006. doi:10.1136/bmj.l2006

4. Chaker L, Korevaar TIM, Rizopoulos D, Collet TH, Völzke H, Hofman A, Rodondi N, Cappola AR, Peeters RP, Franco OH 2017 Defining optimal health range for thyroid function based on the risk of cardiovascular disease. J Clin Endocrinol Metab. 102: 2853-2861. doi:10.1210/jc.2017-00410

5. Fitzgerald SP, Bean NG, Falhammar H, Tuke J 2020 Clinical parameters are more likely to be associated with thyroid hormone levels than with thyrotropin levels: A systematic review and meta-analysis. Thyroid doi:10.1089/thy.2019.0535

6. Hoermann R, Midgley JEM, Larisch R, Dietrich JW 2017 Recent advances in thyroid hormone regulation: Toward a new paradigm for optimal diagnosis and treatment. Front Endocrinol (Lausanne). 8: 364. doi:10.3389/fendo.2017.0036

7. Hoermann R, Midgley JEM, Larisch R, Dietrich JW 2015 Homeostatic control of the thyroid-pituitary axis: Perspectives for diagnosis and treatment. Front Endocrinol (Lausanne). 6: 177. doi:10.3389/fendo.2015.00177

8. Hoermann R, Pekker MJ, Midgley JEM, Larisch R, Dietrich JW 2020 Triiodothyronine secretion in early thyroid failure: The adaptive response of central feedforward control. Eur J Clin Invest. 50: e13192. doi:10.1111/eci.13192

9. Inoue K, Ritz B, Brent GA, Ebrahimi R, Rhee CM, Leung AM. 2020 Association of subclinical hypothyroidism and cardiovascular disease with mortality. JAMA Network Open 3: e1920745. doi:10.1001/jamanetworkopen.2019.20745

10. Dietrich JW, Hoermann R, Midgley JE, Bergen F, Müller P 2020 The two faces of Janus: Why thyrotropin as a cardiovascular risk factor may be an ambiguous target. Front Endocrinol. 11: 829. doi:10.3389/fendo.2020.542710

[helvella Administrator]

Only one problem - will "they" read and understand?

Some of what you have written is inherently obvious to patients who are suffering. (Some takes multiple readings to understand. )

And please let us know of replies to your response. They could be interesting.

[Gingernut44]

Thanks for posting - it would be nice to think that those with the power to change things would read and inwardly digest.

[Musicmonkey]

Great! diogenes I love how you have positioned this noting how the very description 'subclinical hypothyroidism' should at least mean some clinical discerning is taking place! Also, by referring to the HPT axis and the importance of assessing all three measures, including the two thyroid hormones. Not forgetting the risks of untreated subclinical hypothyroidism and pointing out the nonsense of confirming a diagnosis, yet not treating it, because of an arbitrary threshold.

[Kitten44]

Excellent letter, thank you so very much for your continued efforts to raise awareness for better clinical understanding of thyroid conditions and their treatment!

[tattybogle]

slowly, slowly, knocky TSH off it's perchy

[Localhero]

Thank you so much for this. I so appreciate what you are doing here.

[jimh111]

Thanks to your team. I avoid using the term 'subclinical hypothyroidism', it's playing their game.

It's interesting that the experts who played a major role in the development of TSH assays (yourself and Robert D Utiger) caution against its misuse. Utiger points out that when TSH production is low due to insufficient TRH the TSH molecules have reduced bioactivity mayoclinicproceedings.org/a... .

Reduced feedforward produces TSH with reduced bioactivity, the TSH assay counts molecules, it doesn't tell us if they are any use. In general patients on this forum with 'subclinical hypothyroidism' have more severe and difficult to treat hypothyroidism than those with primary hypothyroidism that is biochemically obvious.

A failing thyroid which fails to secrete enough hormone is a problem, a failing thyroid + subnormal TSH secretion is more difficult to diagnose and treat and incorrectly referred to as 'subclinical hypothyroidism'.

This is my favourite paper on the subject of 'subclinical hypothyroidism', the full paper can be obtained from Sci Hub. pubmed.ncbi.nlm.nih.gov/210... .

[NieuwOndaatje]

Many thanks Diogenes! Congratulations, once again, for highlighting the issues and challenges thyroid patients face every day in getting adequate treatment for our conditions. All too often we are all typically treated as the “standard” thyroid patient as described in most medical journals based on a standardised TSH range, irrespective of symptoms, presentation and pathology. There may be some “standard” patients who may respond adequately to standard protocols and titration of Levothyroxine treatments based on standard blood tests but there are also large cohorts of thyroid warriors for whom it just doesn’t work. The drip feed of more recent journal articles that are questioning the current status quo and asking for more nuanced, tailored and individualistic treatments based on both symptomatic and/or atypical blood work is a welcome break from the current dogma in most thyroid treatment. I have a sense that the tide may be changing and long may it continue! There are many other Central Hypothyroid patients that have suffered from the vagaries of the typical diagnostic tests available and failure to investigate the evident anomalies in patients with many of the classic signs of hypothyroidism but a low TSH - in the absence of fT4 and fT3 testing who remain under the diagnostic radar for far too long as sub clinical when it is actually the hypothalamus or pituitary or the HPT axis that is struggling to regulate the thyroid and related hormones. Ca suffit!

[Musicmonkey in reply to NieuwOndaatje]

No clinician has agreed that I have Central hypothyroidism, but on diagnosis, my TSH. was 2.9 with a below range T4, i.e. 10 (12-22). Surely that's a low/normal TSH? I have only found relief from symptoms with Combination therapy. Levo mono didn't help.I also have faulty DIO2. jimh111 you might have an answer for me?

[jimh111 in reply to Musicmonkey]

I mustn’t hijack this thread. I call this ‘subnormal TSH secretion’ as it’s not quite central hypothyroidism, or at least not normally associated with pituitary damage. Since TSH also stimulates T4 to T3 conversion subnormal levels of TSH lead to lower intracellular T3 and in my personal experience this means we need serum levels of T3 that are a bit above normal to recover. As we are in danger of drifting off topic please raise a separate post if you want to discuss further.

[Musicmonkey in reply to jimh111]

Understood. Thanks jimh111

[Adam10]

May I request that someone put the findings of this paper in layman’s language.

I read it but cannot understand it. (I never knew medical-speak could be so unfathomable).

My last endo said I probably have a failing thyroid with lack of TSH secretion by the pituitary gland - is this called secondary hypothyroidism?

[diogenes Remembering in reply to Adam10]

Briefly, SCH is a syndrome that may in some cases have roots in a nonthyroidal issue (where the situation will resolve over time). Others with similar TSH may go on to overt hypothyroidism - you can't tell which is which from TSH alone.TSH in this case cannot be used as sole diagnostic test and to get the whole picture, FT4, FT3 and TSH are needed as tests. We suggest therefore that patient presentation is dominant over blood test results because a purely mechanical diagnosis based on thyroid hormone levels may be misleading. Thus if there are two possibilities that can't be distinguished one from another it is useless to try to resolve the problem with TSH alone. Thus presentation of patient is more important.

[Charlie-Farley]

Just brilliant.