Apparently only elevated TSH gives significantly greater risk of OP, AF, heart disease and mortality.

[diogenes]

Another useful downloadable paper with some very interesting graphs. As we thought, lower TSH hasn't many adverse consequences

366:l4892 | doi: 10.1136/bmj.l48921RESEARCH

Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study

Rasiah Thayakaran, Nicola J Adderley, Christopher Sainsbury, Barbara Torlinska,Kristien Boelaert, Dana Šumilo, Malcolm Price, G Neil Thomas, Konstantinos A Toulis, Krishnarajah Nirantharakumar

Abstract

Objective: To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures.

Design Retrospective cohort study.setting The Health Improvement Network (THIN), a database of electronic patient records from UK primary care .Participants: Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017.to look at TSH concentration in patients with hypothyroidism.

Main Outcome Measure ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome.

Results 162369 patients with hypothyroidism and 863072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)).

Conclusions: In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.

NB (diogenes intromission): they didn't find low TSH gave significantly greater risks either but conveniently didn't mention it in the Abstract. Also the statement that TSH <0.1 gave higher mortality risk is contradicted by their own figures which show a similar hazard ratio for TSH <0.1 and 4-10.

[diogenes Remembering]

Another distortion they have applied that makes their data look better than it really is, is to use a TSH range 2-2.5 as their baseline hazard of 1. But the accepted reference range in health for TSH is 0.5-4.2 about. So why did they not set this range as hazard = 1 and compare the rest in that way. From the graph appearances I'd say the extra hazards at TSH < 0.5 compared with 0.5-4.2 would now be significantly smaller and indeed nonsignificant. The elevated TSH's would still have significant hazard. From this I conclude that their statement that their data uphold the guidelines as to extra hazard at low TSH is frankly misleading and unproven.

[waveylines in reply to diogenes]

Thanks Diogene -and for your explanation. Ive been diagnosed with Intermittant AF (consequence of aggressive necessary cancer treatment ) and an under a cardiologist presently. Being on ndt gives me a supressed TSH of 0.01 but thyroid hormones ft4 & Ft3 are in range..... Am worried the cardiologist may go on about my TSH so this piece of research will be useful if he does! Thanks!

[annnsandell in reply to waveylines]

Mine does.

[LindaC]

Thank you so much diogenes - much appreciated.

[fiftyone]

I find this study somewhat strange, measuring only TSH. Surely T3 should have been measured, too, to be sure it was the TSH level making a difference and not the T3, or that the TSH was a true reflection of the T3 level??

[diogenes Remembering in reply to fiftyone]

Simple answer is, they don't do T3 or FT3, relying totally on the TSH-is-all paradigm. FT3 might have told a subtly different story. And saying that the study vindicates the guidelines is a nonsense. What they should have said is that by and large, the guidelines were followed (though below normal TSH didn't give adverse results, in contrast to guideline advice). That conclusion is therefore unrearkable - it would only be remarkable if the guidelines hadn't been followed. And QoL wasn't mentioned at all - this is just another biochemical analysis without regard to patient outcome qualitatively.

[fiftyone in reply to diogenes]

thank you for those thoughts.

[annnsandell]

I feel I should immediately say RUBBISH but I will read the full detail and reflect calmly.

[Hidden]

Thanks for that, I found it very useful. I'm on T4/T3 combo with a TSH of around 0.03. the last locum endo I saw says he has no big concerns about that, but it's helpful to have some evidence in case my new endo is more risk averse.

Michael

[SarahJLD]

Good timing for me so thank you. Have been avoiding my annual GP review as last time he wanted to wean me off Levothyroxine as my TSH below 1 so he was convinced I was putting my heart at further risk following my delayed diagnosis of hypertrophic cardiomyopathy.

[diogenes Remembering]

I keep asking more questions about this study. Setting hazard at base 1 for TSH between 2 and 2.5 is not only arbitrary, it is false. There is no point on the graph in reality where hazard for a group is exactly 1 and no more or less. I mean that this area has its uncertainty region just like the others but this uncertainty has been arbitrarily buried and ignored, so that the false comparisons can be made with all the other regions of TSH. What should have been done is several comparisons using different groups set arbtrarily at hazard = 1 and comparing the rest in each case. Then putting all the results together you would get a proper hazard estimate (+ the uncertainty) for ALL regions of the TSH graph. Arbitrarily setting a group with no hazard and comparing everywhere else, without any evidence that the assumption is true is the wrong way to analyse the results. It exaggerates the hazard ratio elsewhere.

[kissemiss]

Thank you so much for sharing the article.

They researched the 'thyroid replacement therapy'

why did they only base it on the use of Levothyroxine when a mention of Liothyronine would have made the article more relevant and challenging.

[lynmynott Partner Thyroid UK]

Diogenes, have you thought about responding to the article with your thoughts or ask some questions? It would be interesting to see what they respond with.

[diogenes Remembering in reply to lynmynott]

I've broached this to Rudolf but haven't had a reply yet. He may be away at the moment.

[diogenes Remembering in reply to lynmynott]

I had this reply from Johannes Dietrich about the article:

Dear John,

Thanks. This is another one of many useless studies. Not surprisingly, the majority of the included subjects was treated with levothyroxine. Since most physicians use to titrate the L-T4 dose according to TSH concentrations, there is not a large variance in TSH to expect. Variance is, however, a precondition of covariance, and covariance defines correlation. Therefore, this study is systematically biased, since it lacks power due to a structural error.

The other stupidity is that they only examined TSH concentration as a possible predictor. Multiple trials, including the large Rotterdam studies, showed that FT4 and FT3 concentrations are much more important predictors of mortality and morbidity than TSH. Of course, the current policy of measuring TSH only makes it difficult to assess the effect of peripheral thyroid hormones based on electronic patient records.

It seems so that it is easier to publish stupid studies than intelligent ones.

Best,

Johannes

[lynmynott Partner Thyroid UK in reply to diogenes]

I agree. I'm been asked to help a researcher who is trying to do a study on pregnancy, fertility and mild hypothyroidism. I asked why they weren't checking FT3 and it's because they are using already existing data and, of course, there are not enough FT3 results within these. However, she agrees that future trials should include FT3. I'll keep in touch with her!

[jimh111]

Thanks for posting, an interesting study that confirms a similar earlier one academic.oup.com/jcem/artic... . Whilst it is regrettable that these studies only considered TSH they do neatly address the issue of what level of TSH is undesirable (I'm not advocating such an approach). Both studies show that a very low TSH (< 0.1 and <= 0.03) was associated with minor risks. On the other hand a mildly elevated TSH (>4.0 and 4.0-10.0) was associated with considerably increased risks, including mortality. On this basis I would expect a doctor to express a need for a little caution when a patient has a TSH below 0.04 and to recommend immediate treatment in patients with a TSH > 4.0 (in order to halve mortality rates at a cost of approx. £2 pcm). The term 'subclincal hypothyroidism' should not be used to describe an elevated TSH - surely 'elevated TSH' is a better term.

The study adjusted hazard ratios for a number of covariants. Adjustment for body mass index may not be fully appropriate since hypothyroidism and inadequate levothyroxine only therapy leads to weight gain. BMI is not a true covariant in hypothyroidism.

Most of the selected patients will have been diagnosed on the recommended basis of elevated TSH / low fT4. Patients suffering from resistance to thyroid hormone or with subnormal TSH secretion (e.g. a down-regulated axis arising from a period of thyrotoxicosis) will either need a supressed TSH or have a low TSH that ooes not reflect their hormone levels. These studies to not apply to such patient groups.