Tessnow agreed: "The sheer number of people who are doing fine on levothyroxine are going to cover up the potential benefit the combination would give those who are most symptomatic. We need to focus our studies on those patients".
In fact, this research gap was among the conclusions from an expert consensus statement published in March 2021, following a joint conference of the American Thyroid Association (ATA), the British Thyroid Association (BTA), and the European Thyroid Association (ETA). Bianco was one of the statement's authors.
This "acknowledges that the previous clinical trials were not adequately designed," says Bianco, adding, "there is a need for new clinical trials."
Many Patient Reports Document Dissatisfaction With LT4 Treatment
Numerous patient-generated publications have documented residual symptoms with LT4 treatment alone, including higher levels of symptoms on questionnaires, deficits in neurocognitive functioning, impact on psychological well-being, and "brain fog," as reported by Medscape Medical News and published in December 2021, and notably, a study from Bianco's group in 2018, which found "prominent dissatisfaction" with their treatment and their physicians.
"Some changed physicians five to ten times. We concluded there was a significant burden of unsuccessfully resolved symptoms among patients with hypothyroidism," Bianco said during his talk.
"Some say patient preference isn't a clinical outcome, but we have to consider it...To not listen to the patient in what they prefer is unfair and just gives them more reason to be mad at us," he added.
History and Physiology: Why LT4 Is Used But May Not Be Enough for Some
Treatment of hypothyroidism using implantation of a sheep's entire thyroid gland was first described in 1890, followed by subcutaneous injections of sheep's thyroid extract. A short time later, thyroid extract by mouth was introduced. In 1965, a study demonstrated efficacy of a 3.5:1 mixture of synthetic LT4 and LT3.
The shift to LT4 monotherapy happened in 1970, with a study published in the Journal of Clinical Investigation showing that T4 was converted to T3 in humans, "which all interpreted as 'no need to use thyroid extract,' then LT4 became the standard of care," Bianco said.
He then explained the physiologic basis for why some patients may not fare well with LT4 alone.
TSH in the normal range doesn't mean T3 and T4 are normal. "The thyroid is hardwired to preserve serum T3," he said.
But once the patient develops hypothyroidism, the thyroid no longer responds to TSH, and serum T3 is only maintained via conversion of T4 to T3. Although LT4 is used to normalize serum TSH levels, that occurs before serum T3 is normalized, resulting in lower serum T3 levels and relatively higher serum T4 levels.
The lower T3 level with normal serum TSH explains the residual symptoms, Bianco explained.
"Thus, by adding small amounts of LT3 to the regimen with LT4 we can normalize serum TSH but with normal serum T4 and T3 levels," he said.
So why do most patients report feeling fine with LT4 alone? "We do not have the answer to this question. Multiple factors could explain it, including genetics," he told Medscape Medical News.
How Can Combination Therapy Be Given Safely?
The 2012 guidance from the ETA provided specific information for how combination therapy should be prescribed by reducing LT4 and replacing a small amount with LT3 in order to keep TSH within normal range.
For example, if the patient is taking 100 µg/day of LT4, drop that to 87.5 µg/day and add 5 µg/day of LT3. Similarly, 200 µg/day of LT4 should be dropped to 175 µg/day and 10 µg/day of LT3 added.
Patients should undergo enhanced follow-up, with measurement of serum T3 at baseline and 3 hours after LT3.
This approach should be avoided in patients with cardiac conditions or concomitant use of other medications that could potentiate the effects.
Indeed, while there has been concern about cardiac effects of LT3, trials following nearly 1000 patients for as long as 1 year have shown that the addition of LT3 only minimally affects serum TSH, heart rate, or blood pressure. Bone turnover markers remained within normal range in two studies.
Another large study published in 2016 also showed no long-term effects of LT3 on cardiovascular disease outcomes or fractures, although there was increased use of antipsychotic medications.
"Given the new safety data, physicians could be more liberal with this form of therapy as they treat patients with residual symptoms," he concluded.
Bianco has reported receiving consulting fees from Abbott/AbbVie, Allergan, Synthonic. Tessnow has reported receiving consulting fees from Horizon.
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.
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...but why would doctors think there's a problem when they are taught that ypothyroidism is a really easy condition to treat? It's not until they get out into the real world of clinical practice that they suddenly find there's a portion of patients that are unhappy, who they then blame for their issues. 🤦♀️
Thyroid action is actually very complicated, and I would like to see doctors even GP's with a special interest in thyroid diagnosis and treatment. It's done in many other areas eg dermatology, eyes etc so I can't see why not for thyroid.
This is something I said just a few days ago. Most GP surgeries have a diabetic nurse or GP with an interest - why not thyroid dysfunction, after all, Levothyroxine prescriptions are higher than metformin/insulin.
Do you still believe that Bianco remains a believer in keeping TSH in range for all people on therapy Diogenes? Is that last long-held view still being held steadfastly?
No, he has references in articles now where thyroid hormones, particularly FT3 levels over ride TSH in terms of importance.
His book comes out soon so it will be interesting to assess how much his view points have swayed. For many patients the TSH will stay within range when optimally medicated so I think his sentiments cater for all now.
I'm afraid that the belief that "TSH" must be in the reference range for successful treatment" is not going to go without fearsome attempts to retain it. There is simply too much at stake to admit as they must that there has been 35 + years of diagnostic mismanagement which will sit unhappily on their con consciences. Combination therapy and T3-onl;y revisiting is fine and a first step but not the last.,
They should swallow their pride and make paramount their patients’ health and well being from now on. But humility probably isn’t part of their psychological make up.
I need to be catered for and with Central hypothyroidism (on diagnosis TSH 2.9 with below range T4 10, in range 12-22) and faulty DIO1 and DIO2 I do not get a TSH in range. These guidelines wouldn't work for me...😢
Agreed, you and many others need to be allowed to have low TSH. Those of us on only T3 therapy (because for a number of reasons T4 simply causes the return of symptoms) really cannot get TSH into range because of T3's highly suppressive effect on TSH.
So, the insistence of TSH being in range will indeed be an issue for many.
However, if it gets to a point where there is general acceptance of T3 being NEEDED in treatment for more patients than now. Plus this begins to happen without an immense fight by the patient themselves requiring multiple letters and references to NHS England Guidelines etc. etc., then T3 will once again become an acceptable thyroid medication. The door will then be AJAR, and it will be easier to push that door in order to get other aspects of treatment allowed in individual cases.
I think this is going to be a long game. It will be one of 'slowly slowly catchee monkey' not a massive all at once victory. I am still not sure I will be alive still to see a proper victory but I would like to be around long enough to see the clear path to one and to know it will happen. That's my personal hope.
I hope we both see it in our lifetime Paul though perhaps we may not be that lucky. I agree that if we can get T3 more widely accepted for the majority, minority groups with different needs will hopefully find it easier to have these adjustments accepted.
"For example, if the patient is taking 100 µg/day of LT4, drop that to 87.5 µg/day and add 5 µg/day of LT3. Similarly, 200 µg/day of LT4 should be dropped to 175 µg/day and 10 µg/day of LT3 added."
This is from 2012 ETA Hypothyroidism Guideline. This dosing is based on Pilo et al 1990, Wiersinga's first reference. Dr Tania Sona Smith has fulsomely refuted the Pilo findings back in 2019 on her Canadian patient thyroid groups. Pilo et al suggested that secretion of T4:T3 from the gland was at a ratio of 14:1. Dr Smith showed that only one person of 14 subjects in the trial had a T4:T3 ratio of near to 14:1. The lowest was 6:1 and the highest was 71:1. During each day, with each activity we have variable T4:T3 ratios. I'm really passionate that we should not allow this 14:1 erroneous T4:T3 ratio dogma to continue. The amount of secretion from the thyroid does not dictate how much of those thyroid hormones actually get into the cell, which may be totally different, and depends so much on what the deiodinases are capable of doing, the state of the various receptors, axis set points, the transporters, binding globulins, age, gender, state of health, corepressors and coactivators, and whether there's enough vits and minerals etc. to support the whole process.
The healthy thyroid subjects in the Pilo paper were overdosed with Lugol's solution.
I have done a bit of regression analysis on the '5-10%' i.e. the number of patients who do not get symptomatic relief with levothyroxine alone. This is noted in the first sentence of the 2012 ETA Guideline and is not referenced. Nowhere that I can find was this figure of 5-10% ever used before. Recently a children's hospital in Philadelphia (CHOP) stated approx. 15% of adults report persistent symptoms but again no reference. All of them are guessing! We need proper patient data on this figure. It would of course have been helpful if the NHS had continued with QoF (quality of framework) figures for THY001 and THY002, which give data for the number of patients with hypothyroidism per surgery, but collection of this data was discontinued in 2014. I have noted on at least one occasion that American thyroid figures are used by one UK based Endocrinologist.
They think of the thyroid like an identical preprogrammed pump in every individual blasting out exactly the same thyroid hormone ratio day and night regardless of environment and variable need - such a lack of understanding and a non existant imagination. I suspect they are lacking in any dynamism rather like their one thyroid one output model, the one size fits all brigade. They should try it with shoes 🙄
Thank you for this Diogenes. If TSH is to remain within the diagnostic regime (until such time it's accepted across the medical profession as being inadequate), is there a chance of the reference ranges being changed to reflect reality? Especially the upper limit, which is considered to be too high currently.
What about those whose TSH falls outside the upper reference and not considered hypothyroid until the value us over 10? In a sense this makes a mockery of having an upper limit, especially as many diagnosed with sub-hypothyroidism are symptomatic.
Separately, the proposed change in diagnostic criteria away from TSH to T4 and T3 will no doubt bring into the hypothyroid fold many people diagnosed with ME. Their symptoms are often identical to hypothyroidism but their TSH results are within 'normal' parameters despite T3 and T4 suggesting problems with the thyroid. Does Bianco et al consider this group of people I wonder?
The answer to that is simply as follows: in what conditions is TSH useful for diagnosis? The answer should be in diagnosing primary thyroid dysfunction and not thyroid treatment by hormones. There is, however, difficulty in primary diagnosis, because the spectrum of malfunction doesn't (taking the population as a whole) efficiently differentiate between sickness and health. There is overlap in values in health and disease especially for FT4 in hypothyroidism. And the controversial subclinical hypo class now gets in the way. For hyperthyroidism, there's scarcely any overlap so diagnosis is easy. In treatment with patients with no thyroid, T4-only does not restore the status quo, because the working thyroid produced its own T3, an action which now has to be shouldered by the body's deiodinases and which they cannot fully do, to the detriment of those who need more T3 to operate healthily. Given that, a TSH response by the pituituary no longer fulfils its purpose. It is thereby suspect as a diagnostic. So we ought to rely much more on FT3 as a diagnostic, taking into account other diseases which can affect its production.
Thank you for this. I think what I was trying to ask is: while TSH is still used in the short to medium term until it is (hopefully) phased out, is there any chance the reference intervals might be altered, especially the upper reference interval? Or maybe it's a non-question as it's highly unlikely the current medical regime will accept any change, whilst they are so wedded to using TSH and its current reference values.
The trouble with trying to rationalise TSH by expanding the range is that doing so brings truly hypothyroid patients into the healthy range. No test should be based on hard range frontiers. Especially in hypothyroidism there is a big overlap of SCH and true hypothyroidism meaning that though the medics have raised the cutoff to exclude true hypos, when they've actually failed in their objective.
when I was in my early 40’s my tsh was 9 and I was told borderline. Move on another 11 or 12 years and hey presto l was diagnosed but by that time my tsh was over 100. Not best pleased but back then I knew nothing about the thyroid. Jo xx
Tessnow agreed: "The sheer number of people who are doing fine on levothyroxine are going to cover up the potential benefit the combination would give those who are most symptomatic. We need to focus our studies on those patients".
So I know this post is from a few weeks ago but some anecdotal.
Hubby and I run a guesthouse. We have had a few hundred folk through this summer - several hypos. From reading lived experience etc for nearly two years now, I’m getting a bit of a dab hand at identifying people with hypothyroidism - I’m still a bit surprised by it, but there you are something must be sinking in.
People have a habit of reeling off symptoms over a cup of tea then I casually say “ oh I had that when I was under medicated for my hypothyroidism.” This neatly opens conversation.
Then the following issues are raised through those conversations. So far all about Levothyroxine.
People do not understand that they are on a necessary replacement therapy.
They do not realise they should not be missing doses 😱as they simply don’t understand what it is for.
Some have refused to be put on levothyroxine (for years) because they didn’t want to take any more ‘pills‘ not realising the gravity of the situation and being left ignorant of this fact. Yet having been successfully put on statins!
Being highly symptomatic, but thinking they are ok because this is the new normal.
So with regard to the study there will be a sizeable number of the sample who will not be complaining and not be well.
I have had a steady flow of overweight, thinning haired ladies (and men!) who are dragging themselves around utterly clueless- through no fault of their own. I received zero information from my local surgery when I was diagnosed - but I’m lucky I have a naturally enquiring mind. Also the science background gave me an incredible advantage.
All of the people who have come through our guesthouse would not question the treatment and this innocence will be massively skewing data.
Too many old people are frightened of hospital and over-respectful of doctors. Some of it is a hangover from when they were young and "going into hospital" was more of a death sentence. I can still remember the horrors of radium therapy for breast cancer in some women I knew. Antibiotics only appeared when I was about 10 years old. The remembrance of past times I think is part of it.
But some of the old people are my age and younger 😂. I’m 54 and I have been having many conversations with folk my age and younger - in fact one lass was (I doubt yet) in her thirties and a nurse and totally trusting. One has to say understandably, as doctors work on the premise the system has supplied them with sufficient information to treat their patients. So much faith in our medical profession- but the fault doesn’t sit with the doctors- real lack of training to critically think. On the last two telecons I had getting my last two dose increases, there was a distinct pause when I countered the “you are in range” with “yes but there is room in the range for another dose increase and I am still symptomatic”.
God bless them they obliged, but I had submitted hard copy reports a few days earlier that would have been hard for them to refute. 😉
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\"Rethinking Hypothyroidism\" - Antonio Bianco
U.S. Study Shows Combination Treatment Is Safe, Effective
Antonio Bianco's recommendation for T3 dosage
