The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review+meta-analysis

[helvella]

Not one single mention of T3 (in what is accessible).

Comes across as having the potential to increase shoe-horning of individuals into population ranges. diogenes

And with that list of names, its implementation will very likely be a fait accompli.

The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Yanning Xu, MD

Arash Derakhshan, MD

Ola Hysaj, MSc

Lea Wildisen, PhD

Till Ittermann, PhD

Alessandro Pingitore, MD

Nazanin Abolhassani, PhD

Marco Medici, MD

Prof Lambertus A L M Kiemeney, PhD

Prof Niels P Riksen, MD

Robin P F Dullaart, MD

Stella Trompet, PhD

Prof Marcus Dörr, MD

Suzanne J Brown, BSc

Prof Börge Schmidt, PhD

Prof Dagmar Führer-Sakel, MD

Mark P J Vanderpump, MD

Axel Muendlein, PhD

Prof Heinz Drexel, MD

Prof Howard A Fink, MD

Prof M Kamran Ikram, MD

Maryam Kavousi, MD

Connie M Rhee, MD

Prof Isabela M Bensenor, MD

Prof Fereidoun Azizi, MD

Prof Graeme J Hankey, MD

Prof Massimo Iacoviello, MD

Misa Imaizumi, PhD

Prof Graziano Ceresini, MD

Luigi Ferrucci, PhD

José A Sgarbi, MD

Prof Douglas C Bauer, MD

Prof Nick Wareham, MD

Prof Kristien Boelaert, MD

Prof Stephan J L Bakker, MD

Prof J Wouter Jukema, MD

Bert Vaes, MD

Prof Giorgio Iervasi, MD

Prof Bu B Yeap, PhD

Prof Rudi G J Westendorp, MD

Tim I M Korevaar, MD

Prof Henry Völzke, MD

Salman Razvi, MD

Prof Jacobijn Gussekloo, MD

Prof John P Walsh, PhD

Prof Anne R Cappola, MD

Prof Nicolas Rodondi, MD

Prof Robin P Peeters, MD

Layal Chaker, MD

for the Thyroid Studies Collaboration

Published:September 08, 2023

DOI: doi.org/10.1016/S2213-8587(...

Summary

Background

Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are statistically defined by the 2·5–97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT4 based on the risk of cardiovascular disease and mortality.

Methods

This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT4, and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT4, thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576.

Findings

We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18–106) at baseline. There was a J-shaped association of FT4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2–13·9]) to 40th percentiles (median 14·8 pmol/L [12·3–15·0]) conveying the lowest risk. Compared with the 20–40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT4 in the 80–100th percentiles was 1·20 (95% CI 1·11–1·31) for the composite outcome, 1·34 (1·20–1·49) for all-cause mortality, 1·57 (1·31–1·89) for cardiovascular disease mortality, and 1·22 (1·11–1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0–18·3]), and men with FT4 greater than the 75th percentile (16·7 pmol/L [14·0–17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68–2·25]) to 80th percentiles (2·90 mIU/L [2·41–3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60–80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0–20th percentiles was 1·07 (95% CI 1·02–1·12) for the composite outcome, 1·09 (1·05–1·14) for all-cause mortality, and 1·07 (0·99–1·16) for cardiovascular disease mortality.

Interpretation

There was a J-shaped association of FT4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20–40th percentiles of FT4 and the 60–80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes.

Funding

None.

Summary (as above) only - rest behind paywall:

thelancet.com/journals/land...

[tattybogle]

they excluded individuals with overt thyroid disease ..

not sure exactly what they mean by that in this context.

if they aren't looking at patients taking thyroid hormone , then the findings shouldn't apply to those who are , because taking thyroid hormone alters the relationship of TSH : fT4 : fT3.

[Zephyrbear]

As you say… “not a single mention of T3”.

How on earth can they be expected to be taken seriously if they exclude the ‘active’ hormone in favour of the ‘pre-hormone’?

And yet, to the detriment of actual patients, these people’s opinions will be listened to…

I despair… 🤬

[thyreoidea]

When people post these scientific studies which are enlightening for some with the relevant backgrounds, would it be possible for the poster or someone else to explain the conclusion in terms that the average person can understand please.

[helvella Administrator Thyroid UK in reply to thyreoidea]

The big problem is that much of the paper is behind a paywall.

In this case, the sheer number of endocrinologists listed is such that this paper will have an impact. But the paper's own Findings and Interpretation need to be read in conjunction with the graphs/diagrams/illustrations of the paper - to which we have no access.

I feel that it is better to post exactly what the paper says rather than attempt a more accessible form without access.

We quite often find that, in time, one or more members gains access and adds their replies.

And, yes, I agree that it is far from easy to appreciate as it stands.

[thyreoidea]

Thank you for your explanation which I can understand.

[helvella Administrator Thyroid UK in reply to thyreoidea]

Even when I feel able to add some interpretation of a paper, I sometimes do so as a reply. That seems to help separate the factual "this papers exists" from the possibly speculative "that paper could mean this".

[Fifteen]

All statistical. That's the problem. They do not seem to link the numbers to the lived experience of us - real people.

[LindaC in reply to Fifteen]

And there often lies the problem - many medics do not understand, methodology and stats. A colleague and me were going to write a book for students, using personal life [not ours!] experience to illustrate which statistical tests to apply to a range of circumstances, thereby highlighting - in everyday terms - what the #s mean.

She died. I got caught up in... Still think it would be really helpful.

[asidist]

Ugh. Sounds full of generalizations and largely lacking in nuance.