This is a reply to a group querying the validity of Bianco et al's paper on T4/T3 prefrence by some patients. I thought it nteresting to read the various arguments so I put it in full here, as it's behind a paywall.
Response to Letter to the Editor From Bonnema et al: “Comparative Effectiveness of Levothyroxine, Desiccated Thyroid Extract, and Levothyroxine + Liothyronine in Hypothyroidism”
Mohamed K. M. Shakir, 1,2 Daniel I. Brooks, 1 Elizabeth A. McAninch,3 Tatiana De Lourdes Fonseca, 3 Vinh Q. Mai, 1,2 Antonio C. Bianco, 4 and Thanh D. Hoang1,2
1 Walter Reed National Military Medical Center, Bethesda, Maryland 20889-5600, USA; 2 Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA; 3 Divsion of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois 60612, USA; and 4 Section of Adult and Pediatric Endocrinology, University of Chicago, Chicago, Illinois 60637, USA
Dear Editor,
We thank Bonnema et al (1) for giving us the opportunity to provide further details on our recent publication (2) while addressing their insightful questions.
In reference to the consequences of long-term treatment with liothyronine (LT3), we respectfully point out that there is now solid data that LT3 does not increase the frequency of adverse reactions if serum thyrotropin (TSH) levels are maintained within the normal range. For example, an observational study during 1997 to 2014 (3) compared nearly 34 000 patients taking only levothyroxine (LT4) with those using LT4 + LT3 (n = 327) or LT3 alone (n = 73) during a mean follow-up of 9.3 years (SD 5.6) and a maximum follow-up of 17.3 years. The study did not reveal higher mortality or morbidity risk due to cardiovascular disease, atrial fibrillation, or fractures. In addition, an analysis of 20 clinical trials that included almost 1000 patients observed for up to 1 year indicated that peaks of serum 3,5,3′-triiodothyronine observed after the LT3 tablets only minimally affected serum TSH, heart rate, and blood pressure; the frequency of adverse reactions was similar to patients taking LT4 (4). Bone turnover markers were studied in 2 trials, and they remained within normal range. This was confirmed in a recent meta-analysis by Millan-Alanis et al (5) in which 18 clinical trials comparing LT4 vs LT4 + LT3 therapy were evaluated found no differences in adverse events. In fact, we are unaware that combination therapy containing LT3 has ever been associated with increased occurrence of adverse reactions in patients maintaining normal TSH levels.
In reference to a potential placebo effect associated with “entering a trial,” we found that 20 patients comprised the subgroup with the worst outcomes while on LT4 therapy and these patients were randomly distributed across the 3 treatment arms. Seven patients received LT4 in arm 1 and 9 patients received LT4 in arm 2. Thus, it is unlikely that a placebo effect played a role.
Baseline values were considered in the analyses. As stated under “Materials and Methods,” differences between treatments were evaluated using mixed-effects models. The primary outcome model included a fixed effect for treatment and a random effect of subject. Models were run with and without the inclusion of baseline scores to isolate between treatment differences. In the subanalysis we also considered the baseline values but were not able to detect differences between baseline and the LT4-treated arm.
In reference to a subgroup analysis of patients on desiccated thyroid extract (DTE) or LT4 + LT3 before the trial, we found that there were 8 patients on DTE and 3 patients on LT4/LT3 at baseline. At the end of the study, out of these 11 patients, 6 preferred DTE and 5 preferred the LT4 + LT3 combination. This suggests that a placebo effect could not explain our findings. An appropriately powered study could address this point further. Of note, a preference for DTE had already been identified in our previous study(6). It has been our experience that most patients taking DTE show a strong preference for continuing on DTE rather than switching to LT4.
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diogenes
Remembering
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Thank you for posting this. Could you please tell us what was the “normal” range of TSH used in the study? I certainly always have a suppressed TSH result and I understood that this is usually the case when taking Liothyronine in addition to Levothyroxine. I was told that the TSH blood test was not created for patients on the combination T4/3. What is your opinion, please?
The normal range for TSH does not apply to athyreotic patients on T4, T4/T3 or T3 only
Unfortunately, I don't think doctors in the NHS got the memo on this. As a general observation from this forum they are still using standard reference ranges for TSH in patients without a thyroid or with a non-functioning thyroid.
The paper referred to by diogenes above can be found here (open access):
The first two columns after the parameter column show results for people in subgroup 1 (in which there were 58 people) with a TSH <= 0.03 μIU/mL at the beginning of the research (if I've understood it correctly).
So, surely the Before thyroidectomy column should have a TSH of <= 0.03 as well? But instead they show TSH as being 1.48 with (what I assume is) the standard deviation of 1.49?
Obviously I've misinterpreted this badly because it appears to make no sense. But I can't spot my mistake.
...
I've just worked it out - I think. The patients were put into subgroups after thyroidectomy, not before. The table makes more sense that way.
Thank you, but do our doctors know this? I have to fight my corner over this every so often when a different doctor reads my annual thyroid tests and panics about my suppressed TSH. Why is it not common knowledge? This is absolutely the first time I have heard it.
The idea that the same TSH range applies both to health and T4/3 therapy is at the moment as solid as the effigies of the Amrican Presidents on Mount Rushmore, The medics at all levels cling on to this for the obvious and embarrassing reason that if they change , this now would force on them the galling reality of having been wrong for 50 years. This destroys the the whole basis of diagnostic thyroidology that they have been preaching in guidelines and advice to GPs. It is as stark as that. So all they can do is pussyfoot around , trying to reconcile the ireconcilable. The idea will have to go eventually, but only over their dead (or retired) bodies.
Completely agree. Let's hope the new cohort of endocrinologists are able to think for themselves before they get indoctrinated in the TSH centric dosing ideology.
But why can’t they just hold up their hands and say we were wrong? Life is a journey of learning and current ideas on all sorts of things may change over time - this is reality as it is lived what is the matter with these people still hanging on to what is clearly incorrect in light of what we know now. There’s nothing wrong in admitting you were wrong but there’s a lot wrong with carrying on a nonsensical pretence of the discredited being still credible. What’s the point of chopping down the trees if you’re in the wrong forest in the first place🙄 better to relocate to the right forest and get coppicing there…..
Simple answer… ego. They’re the infallible “experts” who have been spouting this nonsense for most, if not all, their careers and to backpedal now would be an humiliation too far!
But I’d have huge respect for any backpedalers it takes some courage to say I was wrong, but some individuals do have that courage, sadly there’s no evidence of it from that lot.
Medicine generally works by groupthink. Mavericks are silenced or hunted out of the discipline. The whole history of medicine has plenty of examples stretching many years. For example, when medicine stopped bleeding people with fevers, did anyone or a group openly denounce this. No, by some mysterous process it suddenly stopped over a short period. Thyroidology is merely one example of the stranglehold groupthink has on medical practice, and like all previous examples it will mysteriously change without anyone k knowing exactly how.
en.wikipedia.org/wiki/Semme... ...Leary provided the following polemical definition of the SEMMELWEIS REFLEX: "Mob behavior found among primates and larval hominids on undeveloped planets, in which a discovery of important scientific fact is punished".
'if serum thyrotropin (TSH) levels are maintained within the normal range'
i suppose (to be fair to him) in this comment he is talking about "this is what the current evidence from studies has proved" .. he doesn't say "i believe TSH must always be kept in range"
But i agree with you , the lack of any comment 'about resolution of symptoms' is not encouraging.
I'm hoping (maybe nievely) that if they can first get T3 into accepted use using the available studies done based on the accepted 'TSH normal theory' .. someone will later be able to do other studies which allow TSH below normal, .. studies which could then prove that 'below normal' on T3 isn't dangerous.
But at the moment i assume there is just not enough research data on 'Long term TSH below normal on T3' because allowing TSH to be below normal hasn't thus far been included in the design of most studies done.. because they still think it's 'risky' .. so unethical to deliberately allow it in research to date ?
Pity there aren’t some older studies with NDT there was a very long period of it’s sole use, perhaps because it actually worked reasonably well no studies were needed. I wonder how much of a real problem it’s quality really was.
yes .. i bet it wasn't that much of a problem at all..... and even of it was .. to be honest ,i'd much prefer to take my chances with some highly variable strength/quality NDT and a 1930's doctor who looked at me and felt my pulse and asked intelligent questions occasionally ... than i would dealing with todays very consistent Levo (consistently lacking any T3 !) and an utterly TSH centric GP ,with one hand tied behind his back by guidelines ,and with no time to practice any observation skills ,and without enough knowledge of the effects of thyroid hormone on various organs to know 'a symptom' even if one jumped up and bit him on the backside ......
I agree and I despair of ever being free of the constraints of the dreaded TSH blood test. Why cannot doctors think for themselves and ask sensible questions about symptoms, instead of relying obsessively on a few meaningless figures on a piece of paper?
Studies so far have been restricted to keeping TSH within its reference interval. It seems to me that the most common reason for people needing T3 therapy is that they have a subnormal TSH, their TSH is lower than expected for their hormone levels. This results in impaired deiodinase, especially D2 which takes place within, and regulates T3 levels within tissues such as the brain and skeletal muscles. Putting normal T3 levels in the blood via liothyronine or NDT is not sufficient to compensate for this loss of cellular T3.
In this respect a low TSH is undesirable (and unavoidable), it results in low cellular T3 levels.
As regards safety. The evidence is clear, levothyroxine monotherapy is unsafe. As shown in my recent posts levothyroxine monotherapy is associated with increased cardiac and cancer risks and a reduced lifespan. Regardless of whether it makes patients feel better combination therapy is safer.
It's a nightmare that doctors are still trying to keep those of us on some form of supplementary T3 in within the standard reference range, but it's not really surprising, because it's what the NICE guidance says to aim for. It's a huge get out clause for them.
My Endo is concerned because my TSH is 0.01. This is hardly surprising because on diagnosis nearly 14 years ago, my T4 was below the range of 12-24 at 10.9, yet my TSH was within an 'acceptable' range at 2.9.
I despair!!
It's all the more worrying that I have faulty gene DIO2 (and faulty DIO1 and DIO3), and the Endo is saying my T3 level is too high at 4.9 in the range 3.1-6.8!
I have told him that my TSH is useless at responding to my need to maintain good thyroid levels and that just because I have a result of 4.9 for T3, does not indicate how much T3 is getting into my cells.
I had asked for a small increase of T3 of 5-10 mcg because I had a return of some hypo symptoms. I don't think the Endo's listening to me, as he wants me to undergo a further full hormone panel of tests. He mentioned in passing that it's his job to sort out my hormonal issues, but if the tests don't show anything then he will refer me back to my GP for her to investigate further.
Again, I despair! It took me many years to get my T3 on the NHS.... I hope it doesn't take as many years to get an Endo who knows as much (or more) about my condition than I do
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