Levothyroxine Monotherapy - Cardiac Risk and Mortality

[jimh111]

Following on from my recent post on levothyroxine monotherapy and cancer

healthunlocked.com/thyroidu... this post is about levothyroxine monotherapy increasing the risk of cardiac events and an early death.

This is not about levothyroxine being ‘bad’ in any way, it looks at the effects of a high normal fT4 on the heart and life expectancy.

The studies listed below show that high normal fT4 levels (compared to low normal levels) are associated with cardiovascular disease, atrial fibrillation, and reduced life expectancy. These associations vary in strength, but they all point in the same direction and the risks increase with age.

A word of caution. Some of the studies claim a link to ‘thyroid function’ when in fact the study has measured fT4 and possibly TSH, not fT3. This is poor science as it is not known whether fT3 is above or below average.

Generally, the association with fT4 is much stronger than with TSH, suggesting fT3 has minor, if any effect on cardiac health (provided fT3 and fT4 are within reference intervals).

The studies show that people with an fT4 in the lowest tertile live three and a half years longer than those with fT4 in the highest tertile. Levothyroxine monotherapy (and guidance) generally requires a high normal fT4 in order to achieve average fT3 and resolution of symptoms. Thus, the one third of people who would have been in the low-risk group prior to becoming hypothyroid are shunted across into the high-risk group.

When treating hypothyroidism, we have two choices. Do we use levothyroxine monotherapy with high fT4 levels and accept the risks of cancer, cardiac disease, and a reduced lifespan? Or do we use combination therapy which is safer and gives an extra three and a half years of healthy life?

When treating or advising patients we must use evidence-based medicine and recommend treatments that are known to be safer and, in some cases, more efficacious. If we follow the evidence, it is very clear that for most patients the use of levothyroxine monotherapy is unethical.

Levothyroxine monotherapy exposes patients to the risk of serious illness and shortens lifespan. Consequently, levothyroxine monotherapy should not be routinely offered to patients.

Abbreviations

Atrial fibrillation (AF) odds ratio (OR) hazard ratio (HR) cardiovascular disease (CVD)

 

References

1. Gammage MD, Parle JV, Holder RL, et al. Association Between Serum Free Thyroxine Concentration and Atrial Fibrillation. Arch Intern Med. 2007;167(9):928–934. doi:10.1001/archinte.167.9.928 jamanetwork.com/journals/ja...

Subjects age > 65. A 5 pmol/L increase in fT4 gives an odds ratio of 1.47 for AF. No link between TSH and AF.

“It is possible that serum free T4 is a more sensitive index of cardiac “thyroid status” than TSH and that the present findings reflect particular sensitivity of the heart to T4.”

2. Heeringa J, Hoogendoorn EH, van der Deure WM, et al. High-Normal Thyroid Function and Risk of Atrial Fibrillation: The Rotterdam Study. Arch Intern Med. 2008;168(20):2219–2224. doi:10.1001/archinte.168.20.2219 doi.org/10.1001/archinte.16...

Average age 68.5. TSH lowest v highest quartile AF HR 1.94 fT4 highest v lowest quartile AF HR 1.62.

3. Anne R. Cappola, Alice M. Arnold, Kendra Wulczyn, Michelle Carlson, John Robbins, Bruce M. Psaty, Thyroid Function in the Euthyroid Range and Adverse Outcomes in Older Adults, The Journal of Clinical Endocrinology & Metabolism, Volume 100, Issue 3, 1 March 2015, Pages 1088–1096, doi.org/10.1210/jc.2014-3586

Age > 65, av. 74.5. fT4 associated with AF, heart failure & mortality (HRs 1.04, 1.04, 1.03). No association with tT3.

4. Bano A, Dhana K, Chaker L, Kavousi M, Ikram MA, Mattace-Raso FUS, Peeters RP, Franco OH. Association of Thyroid Function With Life Expectancy With and Without Cardiovascular Disease: The Rotterdam Study. JAMA Intern Med. 2017 Nov 1;177(11):1650-1657. doi: 10.1001/jamainternmed.2017.4836 doi.org/10.1001/jamainternm... . Erratum in: JAMA Intern Med. 2017 Nov;177(11):1703. PMID: 28975207; PMCID: PMC5710266.

Age 64.7. At age 50 life expectancy for TSH in highest tertile was 2.0(M), 1.4(F) years longer than lowest tertile. Lowest tertile of fT4 lived 3.2(M), 3.5(F) years longer than highest tertile. Lower TSH and higher fT4 tertile also suffered CVD for more years.

5. Bano A, Chaker L, Mattace-Raso FUS, van der Lugt A, Ikram MA, Franco OH, Peeters RP, Kavousi M. Thyroid Function and the Risk of Atherosclerotic Cardiovascular Morbidity and Mortality: The Rotterdam Study. Circ Res. 2017 Dec 8;121(12):1392-1400. doi.org/10.1161/CIRCRESAHA.... doi.org/10.1161/CIRCRESAHA.... . Epub 2017 Oct 31. PMID: 29089349.

Age 64.8. Higher fT4 (within reference interval) strongly associated with coronary artery calcification, atherosclerotic cardiovascular events (ASCV) and ASCV mortality.

 

6. Bano A, Chaker L, Mattace-Raso FUS, Terzikhan N, Kavousi M, Ikram MA, Peeters RP, Franco OH. Thyroid function and life expectancy with and without noncommunicable diseases: A population-based study. PLoS Med. 2019 Oct 25;16(10):e1002957. doi: 10.1371/journal.pmed.1002957 doi.org/10.1371/journal.pme... . PMID: 31652264; PMCID: PMC6814213.

Age 64.5. Highest TSH tertile life expectancy 1.5(M), 1.5(F) longer than lowest tertile. Lowest fT4 tertile life expectancy 3.7(M), 3.3(F) years longer than highest tertile.

7. van Tienhoven-Wind LJN, Gruppen EG, Sluiter WJ, Bakker SJL, Dullaart RPF. Life expectancy is unaffected by thyroid function parameters in euthyroid subjects: The PREVEND cohort study. Eur J Intern Med. 2017 Dec;46:e36-e39. doi: 10.1016/j.ejim.2017.10.017 ejinme.com/article/S0953-62... . Epub 2017 Nov 6. PMID: 29122438. (Behind a paywall but available on SciHub).

Age 28-75, average age 46. This study found no link between TSH, fT4 and life expectancy in contrast to the next study which used an older subset of the same data.

8. Groothof, D., Flores-Guerrero, J.L., Nolte, I.M. et al. Thyroid function and risk of all-cause and cardiovascular mortality: a prospective population-based cohort study. Endocrine 71, 385–396 (2021). doi.org/10.1007/s12020-020-... doi.org/10.1161/CIRCRESAHA....

Using the same data as study 7 this study found (in the elderly, age > 70) that fT4 was associated with all-cause mortality (HR 1.18) and strongly associated with cardiovascular mortality (HR 1.61). Higher fT3 was associated with all-cause mortality in females only (HR 1.18) but not with cardiovascular mortality.

This study was the only one to measure fT3 and showed there was a weak tendency for fT3 to increase with fT4. Some of the hazard attributed to fT3 may be due to this correlation with fT4.

This study concludes that due to the phenomenon of regression dilution bias (variables assessed at one time point) the results will be underestimated.

[radd]

jimh111,

Strong words but so true. I hate when my FT4 is high as always makes my heart jump all over the place. When on T4 mono-therapy the bangs were so huge they would jolt me awake in the night and once during the day I nearly fell over on the pavement after a particular monstrous bang.

Adding T3 meds allowed me to reduce T4 dose and now my heart is fine 😊

[jimh111 in reply to radd]

Great news. I hope we can gradually get this known and then it will be difficult for doctors to deny T3, especially if they foresee future litigation.

[jgelliss in reply to radd]

Radd I would be very interested to know what dose T4 you where on before you lowered it and how much T3 did you add to your new dose T4? I had lots of palpitations after my TT when I was dosed with T4 sole. Years later I was finally given a script for 5 mcg T3 it helped . But still felt thumbing. Adding a bit more T3 with a lower dose T4 made a huge difference.

[radd in reply to jgelliss]

jgelliss,

Upon diagnosis I was prescribed 100mcg Levo resulting in vertigo, breathlessness, brain fog, etc, & the enormous heart bangs. Over the next four years my Levo dose was increased/reduced in random fashion between 75mcg - 150mcg now under the care of a NHS endo, whilst I became more unwell & accumulated further symptoms. I didn't know anything about T3 meds or FT3 labs at this stage.

Eventually through a member of this forum & the wonderful admin Clutter, I found a private endo & nutritionist who understood Hashi and my need for T3. I was prescribed 100mcg Levo + 20mcg T3 & my recovery started literally immediately.

After T3 meds were withdrawn twice I switched to self medicating NDT. I have found by addressing long standing gut issues and using liver supports I have been able to reduce thyroid meds dose. I presently medicate 1 grain Armour + 50mcg Levo during winter but Levo reduces to 25mcg during the summer.

If you understand a little about the deiodinases you will know how the presence of a little T3 up-regulates deiodinisation of T4 conversion. Therefore, we end up with more T3 than the amount we medicate. Also by meeting all essential cofactors the amount of T3 metabolic loss can be reduced and we gain more FT3 for successful utilisation.

I have no thyroid and have the DIO2 impairment.

[jgelliss in reply to radd]

Thank you so much for your very detailed response. It's so very helpful and useful. I'm so sorry that you too have no thyroid. I think that having no thyroids we most definitely benefit from both T3 and T4 meds. It makes me so much more appreciative of my once healthy thyroids that made all the adjustments that I was not ever aware of. Thank you so much for sharing your experiences.

Very helpful.

[smilingjane]

Hi jimh111

Thank you for posting this. It is a little complicated (for me atm) - to understand.

Is it saying that if those that have an underactive or no thyroid gland, need replacement hormones that it it is best to have Levothyroxin and Liothyronine as opposed to Levo only?

My recent blood test results 8 or so months ago were aporox' 10 (12-20) Levo and 6 (3.5 5.9)apprix' Lio.

Does this report state that my low Levo is okay because ny Lio is high?

🙄

[jimh111 in reply to smilingjane]

The studies show that an above average fT4 carries more risk than a low normal fT4. Thus, if someone needs thyroid hormone treatment it makes sense to give some T3 so that they don't have to have an above average fT4. In this respect hypothyroid patients would be advantaged because they can choose where their fT4 is whereas the healthy population are stuck with where their genetic makeup puts their fT4.

Your fT4 looks OK (I'm not a doctor) but your fT3 may be a bit high, it would depend on how long after taking your liothyronine you had the blood taken. It's difficult to measure fT3 when someone is taking T3.

[greygoose in reply to jimh111]

The studies show that an above average fT4 carries more risk than a low normal fT4.

What is an 'above average FT4'?

[jimh111 in reply to greygoose]

Some studies find the lower textile has less risk than the middle and upper textiles. Some find the bottom quartile has least risk and some find a progression of risk from low normal to high normal. They also find more risk when fT4 is above the upper limit but this has been known for a long time and is not the subject of my post.

I had in mind any fT4 that is above half way, this is a gut feeling on my behalf as I don’t think there is a precise cut off point. The mechanisms by which T4 causes cardiac problems hasn’t been identified.

[greygoose in reply to jimh111]

So, I imagine, it varies from person to person, like most things thyroid. Which is not in the least bit helpful because you won't know what your level is until it's too late.

So, now, the big question is: how does this get through to the millions of ignorant doctors that insist that levo is all everyone needs. It sounds like they're committing mass genocide!

[jimh111 in reply to greygoose]

The healthy population will take their chances just like all other risks linked to genetic makeup. When it comes to treating hypothyroidism it’s obvious that we should choose the safer option. Endocrinologists keep claiming liothyronine is harmful based on prejudice rather than evidence.

I will keep plugging the evidence and challenge patient support groups, all of whom claim to give evidence based advice. We just have to keep banging on at them until they adopt a true evidence based approach.

[greygoose in reply to jimh111]

But the majority of hypos don't have a choice. I think the majority would choose T4+T3 if they did.

So, what advice are you suggesting we give people on forums, knowing that they rarely have a choice? Keep your FT4 low and suffer?

[jimh111 in reply to greygoose]

I’m suggesting that all patient support groups take an evidence based approach and advocate for combination therapy as the standard treatment. There will be some patients for whom levothyroxine monotherapy is appropriate, e.g. some of those with partial thyroid function. I know it will be difficult to achieve but we should push for combination therapy and suggest the evidence I’ve gathered is used.

As for individual patients they need to do what they can to get well and this may have to be levothyroxine monotherapy with a high or high normal fT4. In view of the risks it is even more important that we push as hard as we can for access to liothyronine.

[Hidden in reply to jimh111]

But have you not previously said that supra-physiological (above-range) levels of T4 are the problem…now, it seems that any levels above 50% are problematic…?

[jimh111 in reply to Hidden]

Yes I have. I have always felt that it was fine for patients with primary hypothyroidism who do well on levothyroxine monotherapy to have a high normal fT4. My recent studies on levothyroxine and cancer / cardiac disease reveals the evidence shows there are risks from a high normal or even above average fT4. Therefore, since there is a choice on whether to use levothyroxine monotherapy or combination therapy it is highly desirable to choose the safer option.

I’ve changed my view in the face of the evidence. We have to ask why the professionals, the endocrinologists, have ignored the evidence.

[Gilbo72 in reply to jimh111]

jimh111 , as you mentioned above it’s hard to know if these studies are basing it on High T4 alone or assuming high T4 means high T3 ? And or that wicked measurement of TSH getting in there?

Either way, I did feel uncomfortable as to feel anywhere near normal, my T4 levels had to be sky high on Levo alone. But if they weren’t I could not function. We are talking 28 to32 out of a range that finished at 22. This equated to my T4 in some cases being about 250-300% through range, whereas my T3 would be scraping along at 0-20% through range. I have been like that for about 10 years and for the last two my NHS endos have been collating evidence to finally give me a trial of combo with T3, so fingers crossed I keep it.

I did show them my sisters thyroid function tests as an example (she doesn’t have a thyroid problem) her TSH was a healthy 2, her T4 levels were 40% through range and her T3 was 80% through range, the complete opposite to me!

[jimh111 in reply to Gilbo72]

In my early days (around 2003) I was on similar levothyroxine doses to you and recovered a lot but it did nothing for my cognitive ability. I needed T3 to recover.

It's annoying that they keep refusing to measure fT3. Not only does it not help the patient but we end up with little data for future research.

If a high fT3 was strongly associated with a high fT4 then TSH would be very low. i.e. the link between cardiac / mortality risk and TSH would be far stronger than the link with fT4. The studies show the TSH link is weaker which indicates there is a lesser link between fT3 and these risks.

[Hidden in reply to smilingjane]

How can anyone who does not know you or your medical history know if your levels are ok? The advice given here is not supposed to replace medical advice. Nobody here can tell you that your `levo is ok because your lio is high`. Only your symptoms can tell you that. Besides, your FT4 is below range, so I would not automatically say that is ok unless you are on T3 only (in which case FT4 tends to be low). There are no saviours here to tell you what to do. All we can offer is patient-to-patient advice and support. You have to know your own body and learn to understand symptoms in order to find out what works for you.

[jimh111 in reply to Hidden]

There are two issues here. Genomic action, T3 binding to nuclear receptors which controls our metabolism and growth and determines how we are and feel. There are also non-genomic actions of T3 and T4 which often take place at the cell membrane. These non-genomic actions are associated with the cancer and cardiac risks and so how you feel has nothing to do with these risks.

You may find that the hormone levels that resolve your symptoms put you at risk. This is tough, until medicine advances and a fundamental cure is found such patients have to balance recovery with risks.

[smilingjane]

Thanks jimh111Is Ft3 measured with a blood test?

[jimh111 in reply to smilingjane]

Yes but the NHS is reluctant to do it even if a GP requests it.

[smilingjane in reply to jimh111]

I am booking my thyroid test bext week prior to seeing my endo. Is it worth getting an Ft3 if I stopped T3 a month ago? Would it be accurate?

😊

[radd in reply to smilingjane]

smilingjane,

Yes it would accurate, and it's always worth having FT3 tested because without measuring TSH + both thyroid hormones it is impossible to get a good picture of what is happening. These levels are then evaluated against symptoms for appropriate dose change.

Of course the right amounts of thyroid hormone in the blood doesn't guarantee wellness because there is still much that can go wrong with the transportation (free v bound) and regulation of thyroid hormone (activation/deactivation) which is controlled by many other factors, but getting thyroid hormone levels right for ourselves is the start.

[smilingjane in reply to radd]

I feel a right nit. Of course I realise the importance/relevence of FT3. Its just that I am used to seeing it as T3!

I was confusing FT3 wit RT3.

Wake up brain!!!

🙄

[radd in reply to smilingjane]

🤣 ... commonly known as thyroid-brain ache! We all get it.

[beaubeau1121]

Thank you so very much!!!

[bajmon]

So what are the recommended levels in digits?

[jimh111 in reply to bajmon]

We can only look at the evidence which shows that the risks increase as fT4 increases within its reference interval. For healthy people their levels are given and it is much too premature to suggest there should be any intervention on their behalf. For hypothyroid patients we have a theoretical choice as to what fT4 to aim at (provided doctors prescribe). In this case the evidence shows that if we keep fT4 in the lower third and keep fT3 normal we will get best outcome. There are some patients such as myself who need higher hormone levels, but most patients will recover with normal fT3 and fT4 levels.

[bajmon in reply to jimh111]

Sorry, this still doesn't answer my question really. I still don't know what are the normal and optimal levers in numbers.

[jimh111 in reply to bajmon]

A made up example. For someone with simple primary hypothyroidism on levothyroxine monotherapy they may feel well on 125 mcg levothyroxine with: -

TSH 1.5 (0.4 - 5.0) fT3 4.9 (3.5 - 6.5) fT4 18.5 (10.0 - 22.0)

By subsituting 10 mcg liothyronine for 25 mcg levothyroxine they might get: -

TSH 1.3 (0.4 - 5.0) fT3 5.1 (3.5 - 6.5) fT4 14.0 (10.0 - 22.0)

This would allow a reduction in fT4 and reduce cardiac, cancer and mortality risk. I know many patients on this forum will need higher doses but I'm just giving a fictional example.

[bajmon in reply to jimh111]

Thank you, i appreciate that as i only ever hear/read about TSH. I've been out on higher levo dose for 4 weeks and felt terrible so I'm back on 50/75 alternate days. I'll have years in 4 weeks as I've been in this dose for 2 weeks now. My fT3 never changes and is always 5 . Last tests 3weeks ago on higher dose showed that my TSH went crazy to 0.18 (February) from 2.94 (31/12/21), fT4 was 17.3(February) from 14.5 on 31/12/21 and fT3 5.5 from 5Neither those results made me feel well but Endo was happy each time with fT4

[Horsey07]

Posting this seems rather risky. Firstly, there is very little evidence regarding what healthy thyroid levels are as they only tend to be tested when people report symptoms. I accept that there have been tests on ‘healthy’ patients, but they are limited. Secondly, access to liothyronine on the NHS can be a postcode lottery and requires the support of an endocrinologist. Accessing the drug privately can be costly and beyond the reach of many so there is a risk of causing worry and distress to people unable to get the drug. NDT is not available on the NHS and private prescriptions are costly. Finally, there is a great deal of evidence from thyroid patients (myself included) that they only feel well when their ft4 and FT3 are in the upper 75% of their respective ranges. I imagine that many people will find having to choose between feeling well and having three extra years rather distressing. I’ve not had any significant heart symptoms on Levothyroxine and feel better than I have in years. This disease seems extremely varied with almost as many symptoms as there are patients, there simply doesn’t seem to be a ‘one size fits all’ treatment. Given that this is a forum for sharing patient experiences perhaps this was the wrong place to post this?

[Sparklyjenson in reply to Horsey07]

Hi horsey07. I don’t think it was risky and I’m pleased you posted as I’m sure other people will be thinking the same thing. It’s good that we have a forum where people can share their views and where we can be honest about our frustrations and worries.

I feel your pain re:frustrations about the fact treatment options are uncertain, not without risk and very varied around the country. However despite it being hard to read, I would much rather have access to all the available knowledge than have people censoring what I can read because of concerns that I can’t do much about it or it might upset me. I think a key benefit of this forum is a place to read the latest science and hear peoples views on it.

It’ll be many years before science really understands what is going on and how we can be treated best so I think that if a person’s treatment is working well they should take that as a win. Live life the best we can now. There are probably a million studies advocating choices that can knock a few years off us or give us a few more years. We would go crazy if we paid attention to them all. Didn’t they say a few months ago that daily light housework could give us an extra few years? I like life but I’d rather have a few years less than do more housework!

[bantam12 in reply to Horsey07]

I totally agree this info is likely to cause worry and even put some people off taking Levo at all and when there is either no or limited access to an alternative what purpose does this serve other than to tell people to reduce dose or suffer the consequences.I’m another one who needs high normal T4 and T3, my dose has been reduced in the past with dire outcome. I know that being prescribed T3 is not an option despite my late husband being prescribed it for many years. I do have cardiac problems but who’s to say it’s due to being on Levo ?!

There is also the issue of some people not tolerating T3 or NDT so I’m not sure suggesting these are the only sensible treatments is helpful.

By the way my late husband was on combo T4 and T3 but it didn’t stop him getting heart problems and the T3 was a significant reason for his death.

[jimh111 in reply to bantam12]

I understand this post will cause worry, the intention is to inform not alarm. Your case is much alike mine where we both need above normal hormone doses. My view is that we should be aware of the risks, stay on a dose that is no more than needed to get well and do what we can to mitigate such risks. It also underlines the need for urgency in investigating why some people need abnormally high hormone levels to survive, to solve the underlying cause.

I'm very much against a cavalier attitude to L-T3 or NDT treatment. I often upset people by challenging assertions that e.g. fT3 and fT4 should be in the upper quartile (for a few people yes) or that when using NDT you should ignore blood tests. Many of us are in a very difficult position where we have to accept some risk to lead a reasonably normal life.

This particular post is specifically about people who are well on normal doses of levothyroxine, how their lives would be healthier and longer with a just a little liothyronine.

[bantam12 in reply to jimh111]

So the question is how do those of us already on the lowest possible dose of Levo and who already have cardiac disease manage this ? I don’t think my dodgy heart could tolerate adding T3 even if it were possible to get it ! Seems to be a no win situation.

[jimh111 in reply to bantam12]

So true. Information is supposed to be power but sometimes we are powerless. Hopefully by educating the doctors we can get more research and better treatment in time.

[tattybogle in reply to bantam12]

How are we supposed to manage this ? If we are already on the lowest possible dose of Levo needed for us to function adequately then we already are managing it .

If we didn't have this information to consider then we might be inclined to ignore higher T4 levels from a higher dose , but with this information perhaps we wouldn't.. that's all there is to it.

[TSH110 in reply to bantam12]

I think three years less life in the grand scheme of things is better than suddenly stopping Levothyroxine and croaking very much sooner than that because of a misunderstanding of what this post is saying. I can’t believe people could ditch their Levothyroxine on reading this - it simply doesn’t make any sense to do that.

[bantam12 in reply to TSH110]

I haven’t misunderstood the post at all, I merely said that some people already anxious about taking Levo could worry even more.I have no intention of altering my dose or stopping it, I have no thyroid so I’m well aware of the consequences!

And in reply to your other reply I know T3 isn’t a magic cure, my husband took it and died of heart problems, in fact T3 was a factor in causing his death.

[jimh111 in reply to bantam12]

I appreciate it can increase anxiety, unfortunately the alternative is blissful ignorance. I feel it puts an onus on all of us to raise awareness and lobby for better treatment.

We also need more decisive and rapid diagnosis of hypothyroidism. Many hypothyroid patients are left on inadequate treatment for years with consequent damage to their health, especially cardiovascular decline. Sadly by time it is recognised they need combination therapy they are in no state to tolerate adequate thyroid care.

My post is very much about getting patients, support groups and doctors to look at the evidence and change attitudes.

[StitchFairy in reply to bantam12]

Can you please say more about why you're claiming T3 to be a factor in causing your husband's death? Was he taking too much perhaps?

[bantam12 in reply to StitchFairy]

No he wasn’t taking to much, I can’t give exact details as we are still waiting for the inquest but in brief each dose of T3 caused massive cardiac problems while he was in ITU post surgery, if he had been on Levo alone he would have had a better chance of surviving.

[StitchFairy in reply to bantam12]

Oh gosh, I'm so sorry, didn't realise this was so recent. Thank you for replying.

[bantam12 in reply to StitchFairy]

He died 2 years ago but it’s taken time for the formal investigations (for other reasons) to be completed and the coroners questions over T3 being a significant factor has raised concerns hence the inquest.

[jimh111 in reply to bantam12]

I'm so sorry, especially as it was recent. During heart attacks, or any serious illness, there can be 'low T3 syndrome'. This appears to be a protective measure where the body converts T4 to rT3 instead of T3 and so slows the metabolism - often locally at the site of trauma. In the case of cardiac problems doctors just don't know whether this low T3 is protective or pathogenic, i.e. whether it helps or hinders recovery. There is little research into this as there are a whole host of ethical problems. In your husband's case it seems clear that T3 was causing problems and perhaps with a pragmatic approach his thyroid treatment would have been changed.

This is a general point regarding thyroid treatment. Some of us require above normal doses to just survive, this doesn't come without a cost. It is very important to monitor and look out for hyperthyroid signs. There is then the difficult decision whether to reduce the dose and suffer debilitating symptoms.

[TSH110 in reply to bantam12]

But you’ve got to die of something eventually. Half my family have died of heart failure but they didn’t have any thyroid problem you can’t expect T3 to grant us immortality or cure everything.

[jimh111 in reply to Horsey07]

There have been lots of studies on healthy thyroid levels, the studies I cite in this post each have several thousand subjects. Also, remember that when reference intervals are determined for blood tests it involves testing hundreds of presumed healthy subjects to find the 'normal' levels. There have also been a number of recent studies to see whether the reference intervals should be changed, these involved more rigorous selection of people who had no signs or symptoms of thyroid disease.

I agree it is very difficult to get liothyronine or NDT. That's not a reason for ignoring the evidence, for collaborating with the 'enemy' as it were. I know it will worry some patients but it is right that the evidence is presented and not pushed to the side.

My post is primarily about the bulk of patients with primary hypothyroidism who on the whole (85%) do well on levothyroxine monotherapy. The evidence shows that this strategy is not as safe as combination therapy. Most of these patients will not be on the forum as they've never experienced problems after being put on levothyroxine. Nonetheless their treatment should be changed. By raisng awareness of what is a huge loss of life (assume 2% of UK population is hypothyroid) we will increase the pressure for liothyronine prescriptions which will benefit all patients.

Many of us need higher doses of thyroid hormone, I used to need 120 mcg L-T3 and now just about get by on 50 mcg L-T4 + 30 mcg L-T3. This is a bit too much and carries cardiac risks. I know this but have no choice. if we need above normal levels of hormone (especially T4) it carries risk, we can either be aware of these risks or not. Given I have this cardiac risk I stay on my lowest effective dose and try to take lots of exercise. Getting liothyronine for all will help those of us who need more of it.

[Horsey07 in reply to jimh111]

Thank you for your reply. Perhaps along with the studies you quote you wouldn’t mind posting your medical qualifications as I couldn’t see them on your profile. I don’t see how one can take as gospel that the thyroid levels of ‘presumed’ healthy individuals are in fact accurate any more than one can presume that 3% of mono therapy patients who suffer from cardiac disease would not have done so in any event.

[jimh111 in reply to Horsey07]

I'll update my profile to point out I am not a doctor. This is a patient forum and as far as I know there are no medical practitioners on the forum.

There have been a very large number of studies to establish population thyroid hormone reference intervals pubmed.ncbi.nlm.nih.gov/?te... .

The reserch I cited shows that high normal fT4 carries more cardiac risk than a low normal fT4. Levothyroxine monotherapy usually requires a high or high normal fT4 to achieve an average fT3 and make the patient better. I make an assumption that this need for a higher fT4 carries the same risk as a naturally occuring fT4. This seems a reasonable assumption and an appropriate degree of caution unless and until it can be shown that there is no such risk.

Bear in mind that the non-genomic actions of T4 take place as a result of the presence of this T4, regardless of where it comes from.

For an individual person we don't know whether their cardiac disease was caused by their T4 levels or something else. The name of the game is to avoid unnecessary risk.

[RedSonja in reply to jimh111]

But I wonder how much it ultimately matters.

Are you asserting that if a hypothyroid paitient has a mid range or under T4 level that there aren't as many, if not more risks to their health as having a normal high T4 level?

If a person has a lowish T4 and a lower cancer risk, but cannot even walk around the block, has low gut motility, slow mental function, high cholesterol etc they're in a very unhealthy state and I'm guessing would rather take have a high T4 level and be able to exercise and think faster and have a life.

I'd happily exchange the risks of a slightly shorter lifespan for a life now. All medicines have certain risks. You can't eliminate all risk entirely.

Some of us in this forum already know mono-therspy is less than desirable and some of us are extremely ill (often you could argue, because they didn't receive mono-therapy early enough and were left untreated for far too long, or undertreated for too long)

Some of us cannot work. We are extremely financially challenged and cannot afford NDT or T3. Some of us live in fear of not being able to continue affording it. Skyrocketing gas prices and energy increases will probably force many barely affording it to not being able to anymore.

If such people read this I imagine they will be extremely anxious. It's a claim that doesn't take into account other factors

You are comparing a healthy population with an unhealthy one who may have underlying T3 resistance for a start, and in which the mechanism for conversion may be hampered by inherited polymorphisms or bad gut absorption.

I don't see a conclusion of inference from one population to another as natural at all.

[jimh111 in reply to RedSonja]

First this post addresses the majority of patients who do reasonably well on levothyroxine monotherapy. It may work for them but combination therapy may work a little better and would be much safer.

There is a tacit assumption / assertion from the endocrine community that combination therapy is more dangerous than levothyroxine monotherapy. This misinformation is put forward with no evidence whatsoever. We need to challenge this with evidence. These false claims of greater risk with combination therapy underlie the inability to get liothyronine prescribed.

I always point out that the risks associated with clinical hypothyroidism outweigh the potential risks of higher hormone levels. Being unable to function normally leads to many illnesses, we need to be able to move and excercise, to have enough hormone to avoid elevated cholesterol etc.

This post will cause concern for some patients, this is unavoidable. The alternative is to bury the evidence. Resistance to thyroid hormone and conversion issues do not affect many of these risks as the actions are non-genomic, i.e. they are not caused by T3 acting on nuclear thyroid hormone receptors.

Like many illnesses we have to balance conflicting risks, many medications carry substantial harmful side effects. In the case of hypothyroidism combination therapy is safer than levothyroxine monotherapy. This is the essential point to get across.

[TSH110 in reply to RedSonja]

If you don’t mind dying three years earlier than someone on a better treatment regimen, it doesn’t really matter at all I suppose. But I can’t imagine anyone opting for it when alternatives do exist but are being denied us.

[RedSonja in reply to TSH110]

Thanks for your reply. However that is not what I said.

[Horsey07 in reply to jimh111]

I think that would be very sensible. Your post sounds extremely scholarly and many reading it would assume medical expertise. CVD can be caused be many factors, amongst which are inactivity and high cholesterol. High cholesterol is a symptom of hypothyroidism and the intense fatigue many experience leads to diminished activity. Does your study take those risk factors into account? According to the bmj approximately 3% of the population has CVD, which matches what you say is an increase in risk for patients on Levothyroxine only.

[jimh111 in reply to Horsey07]

I've amended my profile to state that I am not a doctor.

If I may be flippant I object to the presumption that a doctor or endocrinologist will have more knowledge than a thyroid patient! This has not been my experience.

The studies compare cardiac risk and overall mortality against TSH and fT4 finding higher fT4 levels confer extra risk. If a patient has some of their L-T4 replaced by an equivalent dose of L-T3 their cholesterol will change little but their risk will be reduced.

[Horsey07 in reply to jimh111]

Yet you don’t see the irony in taking this medical study as gospel whilst refuting that t4 alone does, indeed, suit a lot of people (patient experts) and offers no more risk than that of the general population.

[jimh111 in reply to Horsey07]

I'm sorry, I don't understand what you are saying. I searched PubMed for e.g. studies that looked at T3, T4, TSH and mortality and came across the studies I cited. I took care to avoid any bias, to treat TSH, fT3 and fT4 equally when looking at heart disease and mortality. I don't take any study as 'gospel', I summarised the results and give the reference so you can study the methods and the results.

Levothyroxine monotherapy does indeed suit a lot of people. I have been criticised a lot in the past for asserting that it does! I've always been in favour of it when it works for people. However, in view of my recent research into the SAFETY of levothyroxine monotherapy I feel it should not be routinely used.

In the general population the studies conclude that around 1/3rd of the population who have lower normal fT4 levels have fewer cardiac events and longer lives than the other 2/3rd. Current policy, levothyroxine monotherapy, assigns most primary hypothyroid patients to the higher risk 2/3rds group - even though 1 in 3 of these patients would have originally been in the lower risk group.

I'm advocating that we should switch to combination therapy because this will put primary hypothyroid patients into the lower risk group. The 1/3 who lost out will be restored to their lower risk profile and the other 2/3 will be better off. Given a choice should we not adopt the safer strategy?

Bear in mind that levothyroxine monotherapy involves a higher combined fT3, fT4 than is seen in the general population. fT4 needs to be near or above the upper limit to achieve normal fT3 and resolution of symptoms.

Levothyroxine monotherapy does carry higher risks than in the general population because it requires a high normal fT4 whereas in the general population fT4 clusters around the mid-point of the interval doi.org/10.1515/labmed-2014... .

[TSH110 in reply to Horsey07]

And what exactly are yours?

[Hidden in reply to TSH110]

I think that Horsey07 `s question is justified; it is Jim making medical claims, not Horsey07.

[jimh111 in reply to Hidden]

The question is valid. We should ask 'where is the evidence'. I provide the evidence in my post, I appreciate some of the studies are a bit heavy and difficult to follow.

When endocrinologists or guidelines promote levothyroxine monotherapy we should ask for the evidence that it is safe as combination therapy - and be prepared for bluster or a long wait.

[Hidden in reply to jimh111]

and now just about get by on 50 mcg L-T4 + 30 mcg L-T3. This is a bit too much and carries cardiac risks. I know this but have no choice.

Too much for whom??? I hope you mean for your individual needs, and are not making a general statement.

[jimh111 in reply to Hidden]

It equates to 140 mcg levothyroxine which is a bit high for me (72 kg) and most people but not everyone. I would be better off on a slightly lower dose but can't manage. It's the sort of risk / benefit choice that has to be made in many illnesses. There would also be risks in being a little clincally hypothyroid so I am probably close to the minimum risk I can achieve as well as feeling relatively well.

These harmful effects of T4 on the heart are non-genomic so they can take place even if there is insufficient T3 action on the cells.

[TSH110 in reply to Horsey07]

So we ignore the evidence based science that jimh111 has gone to great trouble to research and discussed here, because of one person’s results and opinion and so we don’t upset people who are being given treatment that is not as safe for them as combination therapy, yet that therapy exists. What sort of argument is that? Just because it is hard to get combination therapy now does not mean we should keep the truth from people just to spare them worry and let them go on blissfully unaware of the risks they are being made to take. We need to face up to reality and do everything we can to get this situation changed not hush it up in the mistaken belief it is better people are kept in the dark.

I don’t want the dark, I want the light.

[Hidden in reply to TSH110]

I don’t want the dark, I want the light.

So you mean Jim says: `let there be light!`???

[TSH110 in reply to Hidden]

His post is enlightening. I have long wondered if t4 monotherapy may not be ideal even for those better suited to it, as it is not what a functioning thyroid provides which is a balance of the two hormones (T3 and T4) as needed, and after seeing Dr Tania Smith’s post about related health conditions in those with hypothyroidism on t4 therapy, this seemed to confirm my suspicions. This post further adds to evidence to suggest a combined therapy is safer and gives better long term health results than T4 alone. I personally find it blindingly obvious that this should be the case given it is what we had before becoming ill. But the evidence is stacking up towards this being the case. To ignore it seems to be perpetuating the darkness in treatment of thyroid disorder.

I am not claiming jhm111 is god just someone trying to elucidate a complex matter using the evidence we have.

[Hidden in reply to TSH110]

But this is not about combo treatment in general, but for a very specific reason: Jim claims to have evidence that T4 monotherapy increases the risk of cancer and cardiac disease. But why is that not generally known and accepted by the medical community if the evidence is there for everyone to see?

[jimh111 in reply to Hidden]

Why indeed. I think we know the answer - dogma. Endocrinologists jump on a bandwagon and no amount of evidence will persuade them. I cite around 30 studies elucidating the links between higher T4 levels and cancer, cardiac disease and mortality.

‘A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.’ Max Planck

[tattybogle in reply to Hidden]

PurpleCat71 "But why is that not generally known and accepted by the medical community if the evidence is there for everyone to see?"

The medical community don't generally have time or interest to look at 'research' They go by guidelines and accept what is written in guidelines as 'evidence based'. Guidelines take years to be made and then years more to be updated and revised , Guidelines are made by committees who are duty bound to only include evidence that is already considered very solid , such as that from large randomised double blind placebo controlled studies ,... therefore , much of the 'latest' research that comes into the 'that's interesting but we cant prove it yet' category does not even get past the entry requirements for making guidelines. .....It might get a mention in 10 yrs time under 'recommendations for further research'.

This is exactly the same situation we are used to dealing with re.T3 /NDT ....'we' all know T3 and NDT has a safe and legitimate place in hormone replacement, but the guidelines still say T3 is not routinely recommended, and NDT is not to be recommended at all.

And the case for T3 is already many years old. But it will still be a long time before it's 'generally known and accepted' by the medical community.

The issues discussed in the studies Jim has given links to such as T4 's observed effect on the integrin b receptor thingy that has a non genomic action that relates to cancer cells, are relatively newly discovered ... it will be decades before anyone in the mainstream medical community even get's to hear about them ,let alone design and fund major studies which can provide evidence' of the kind that that the medical community will feel is strong enough to accept and act on.

This sort of discussion and the sharing of interesting research as soon we become aware of it, is necessary if we want to keep one step in front of what the GP /Endo can tell us .... if we accept that WE need to interpret the findings of obscure studies on the subject of T3 /NDT then we should be equally accepting of our need to be open minded when we consider the initial findings of various studies re. cancer and other diseases that may relate to our use of thyroid hormone .

Any one who only wants to go by 'evidence that is generally known and accepted by the medical community' is frankly ,unlikely to stay one the forum for long anyway because much of what they find here say's "Your Doctor won't know , and even if he does, he's not allowed to prescribe it".... so if intelligent open discussion about increased potential for cancer risks and heart risks is going to scare them off, does it really make much difference ?

I think you are in danger of 'shooting the messenger' ..... i too would rather i hadn't come across studies apparently finding increased risks associated with higher T4 levels , because i have very high T4 levels myself , so they are uncomfortable studies for me to consider ... but these studies exist ... Jim didn't 'do' them , he hasn't misrepresented the findings they reported ... so what is the problem with a post that informs us they exist and lets us know the findings might be something we all might want to consider ?

If you look at all the studies and then decide the methods/ subjects used , render their findings of no concern to you , then that s fine, you and anyone else can decide to ignore them and wait for the medical community to tell you what to do , but whats the problem with one person telling some other people that these these studies exist, and trying to help them understand what the findings could mean ?

[jimh111 in reply to tattybogle]

As regards guidelines it's important to note that the people who write up the guidelines are handpicked to get the desired results. For example, the NICE guidelines have a clear majority of people opposed to anything other than levothyroxine monotherapy restrict to patients who present with a (very) high TSH.

[Hidden in reply to Horsey07]

Thank you for all sensible posts!

[Sparklyjenson]

Thank you for posting. I really appreciate this forum for access to the latest evidence about thyroid and the views that people share about potential implications for our treatment.

[tcpace]

Thanks for your interesting posting. Any idea how this applies to those people who are T3 only (and a virtually zero T4 serum level)?

[jimh111 in reply to tcpace]

No! I'm more or less in this situation. Research shows that high thyroid hormone levels are associated with cardiac problems such as atrial fibrillation. Liothyronine is about 3x as potent as levothyroxine so for example 40 mcg L-T3 would be equivalent to 120 mcg L-T4 which is a pretty normal dose for an average weight person. I'd guess (I do mean guess) this would be OK. Essentially the higher the dose the more the risk. Bear in mind that if someone is so hypo that they can hardly move they are likely to be at much greater risk due to their enforced lifestyle. In life we often have to balance risks.

[jimh111]

For clarification this post primarily addresses the risk factors for patients on the recommended (by NICE etc.) levothyroxine monotherapy which typically gives a high normal fT4, an average fT3 and a normal TSH. Most guidelines give the impression this is a safe option and that combination therapy with is dangerous. This is not true. The evidence shows that combination therapy is the safer route.

Bear in mind that the figures in the studies represent relative risk, a Hazard Ratio of e.g. 1.2 indicates someone is 20% more likely to suffer an adverse outcome. We also have to look at absolute risk (how many people are actually affected each year) and the age at which these risks occur. This doesn't remove the risk but perhaps puts it into perspective.

The essential message from the evidence is that combination therapy is safer than monotherapy (for equivalent doses). This is the opposite of what we are being told. When a doctor implies combination therapy is dangerous we should ask "where is the evidence".

[radd in reply to jimh111]

Great informative and well explained post jimh111,

Thank you 😊

[Lovecake]

Thank you for the post.I am grateful for any information which supports T4/T3 combo treatment.

I think the medical profession needs to be more aware of these issues and be open to helping us more.

I understand there are people who might worry about such a post, but for those of us who are fighting to keep our treatment it is a good thing.

And surely it is good for others on mono therapy too? At some point they will (I’m a positive person) get offered more treatment which could help them to have a better QoL too?

Please keep the info coming - I don’t understand all of it - but the comments usually iron out the bits that befuddle me 🤪

[diogenes Remembering]

I've become rather suspicious of large studies like those quoted. One reason that raises my doubts is the finding that NDT or T3 combination has, in a large unselected patient group, no apparent benefit over T4 dosage alone . This was due to a significant minority of patients who do approve combination therapy being statistically swamped out by the uncaring T4 mono therapy majority. All the studies quoted assume that the group is a homogenous whole where it might not actually be so. We then get into the difficulty of asking whether there are subgroups whose response to higher FT4 is to cause AF, and a majority who don't fit this. And this leads on to the individual patient who may or may not be in the majority, regardless of the actual FT4 values. Cause and effect are uneasy bedfellows I think.

[jimh111 in reply to diogenes]

Your point is perfectly valid. We, certainly not me, don't know the underlying mechanisms that cause the risk between T4 and cardiac / mortality issues and so cannot identify those who are affected. So, we end up playing the odds.

In the general population these studies suggest that about 1/3 rd live a little over three years longer because their fT4 is in the lower tertile, at least at the time of the study. For hypothyroid patients there is a choice: -

1. Do we use levothyroxine monotherapy and put everyone in the higher risk group? This will disadvantage the 1/3 who would have fallen in the lower risk category.

2. Do we use combination therapy with a little liothyronine to keep fT4 in the lower tertile? The 2/3rds who would have been in the higher risk group are now advantaged, they become lower risk. For once thyroid patients have some good news.

The debate is about safety - regardless of whether the patients show any improvement on combination therapy. Up until now endocrinologists have promulgated the idea that a little liothyronine may carry grave risks, without supplying any evidence. Guidelines even require doctors to fully explain the 'risks' of T3, claimed risks that are not backed up by any evidence. Of course, supra-physiological doses of thyroid hormone do carry significant risks but this topic is about restoring normal hormone levels for a large number of patients.

Regarding the therapeutic benefit of combination therapy my experience and comments on the forum suggest that the patients who benefit greatly from liothyronine (or NDT) tend to have a down-regulated axis or in some cases peripheral resistance to thyroid hormone. These patients do not have an elevated TSH. Since all the combination studies so far have selected subjects on the basis of an elevated TSH they have neatly excluded the patients who need T3. Even if more care is taken to identify suitable subjects studies will continue to show little benefit as long as those with a 'normal' TSH are excluded from the trials, especially if L-T3 doses are restricted to maintaining normal thyroid profiles.

The trials assume (mandate) that patients recover with normal TSH, fT3, fT4 levels. This is unscientific, we should determine the doses needed for various cohorts and then seek the underlying cause of their hypothyroid signs and symptoms.

The point of my research is to show that combination therapy is safer than levothyroxine monotherapy for the majority of patients with primary hypothyroidism. To dispel the lie that combination therapy based on an equivalent dose is dangerous.

[Poniesrfun]

From another research nerd – this is an excellent post with good interpretation, even if some may not agree with Jim's perspectives. IMO it's important that thyroid patients (my focus is regarding thyroid cancer patients) need to become educated about thyroid function, thyroid hormones (all of them), how their thyroid disease affects their overall health and what they must do to maintain or regain their health. It's complex but not rocket science. My primary provider (a nurse practitioner) happens to know more about all of this than many endocrinologists I've met. That's partly because she, like Jimh, stays abreast of current research and understands where and how to apply it.

I'm saddened when I see patients being treated poorly by physicians who practice boiler plate medicine, either because of outdated beliefs or algorithmic constraints placed by their employer.

We'd probably be better off if levothyroxine, liothyronine and NDT were available over the counter. While sure, some would abuse it, but they are probably much safer than other substances easily and legally available, and patients wouldn't be driven to unmonitored and possibly non-standardized, unstable or unsafe sources. Testing should be readily available and affordable. Patients should not be held hostage by a practitioner who gaslights their patients.

Every patient who cares to can access, read and interpret the research and draw their own conclusions. But having someone who understands how to interpret the research and turn it into readable information (such as Jimh and others here and thyroidpatients.ca) can give you the tools to figure out how to get what you need.

Patti in AZ

[RedApple]

The relationship between thyroid and the heart is, it seems, complicated enough for a whole book to be written about it. First edition published 2008, 2nd edition published 2020.

Thyroid and Heart: A Comprehensive Translational Essay smile.amazon.co.uk/Thyroid-...

Thyroid and Heart Book Cover

[jimh111 in reply to RedApple]

I think I've seen this before and might have a similar book lost somewhere. I assume the secornd edition is updated which would be useful. Would be interesting to see if it also covers non-genomic actions of thyroid hormone. I'll look to see if it's in the British Library sometime as it's expensive.

[DeeD123]

I have always been one that needed high ft4 to bring my ft3 up to halfway, tsh was normally in range but at lowest end. My ft3 dropped to the bottom last year ,even though I have asked for reasons and blood tests from my endocrinologist I have been ignored and no answers given. In Aug I was diagnosed with bowel cancer, my ft3 is still bottom of the range even though I often go above range with the ft4, still no answers sadly and my GPs have kindly taken over my tests including ft3 reading, but I’m wondering if the slowing down of metabolism you mentioned could be in operation. It’s intriguing me. Thanks for the post by the way. I have a bit of reading to do I think