New Study By Dr. Bianco on DIO2 Polymorphism

This gets a little technical but it is another step in knowledge about polymorphisms. Full free PDF is available. PR

"Hypothyroidism is found in about 4.6% of the U.S. population age 12 and older (1). The current standard

of care for these patients is treatment with daily tablets of the long-lived prothyroid hormone (TH), levothyroxine (L-T4). T4 is subsequently activated to T3 outside of the thyroid parenchyma via the deiodinases, ie, D1 and D2. Unfortunately therapy with L-T4 alone does not resolve symptoms in all hypothyroid patients, with approximately 12% of the patients remaining symptomatic despite normalization of serum TSH and TH levels (2, 3). Impaired cognition, fatigue and difficulty losing weight

are the main residual symptoms of these patients, for which we lack understanding and have no mechanistic explanation."

25 Replies

  • Bianco is a really good objective scientist in the States - a rare beast there I believe! Our own group have a deep respect for him and his work - though it is based really on cell biology and biochemistry in rats. We try to make a bridge between his approach and on-the-ground diagnostics and treatment, In this regard, we're now writing a less "ivory tower" paper which demonstrates the existence of various levels of T4-T3 conversion in panels of patients with hypothyroidism from various causes, the resulting failure of poor converters to achieve adequate FT3 by T4 dosage alone, the need for FT3 measurement to ensure proper response to medication in everyone, whether T4 alone or not, and the need for some people in the poor converter group to receive joint T3/T4 therapy. All this of course you all know anecdotally, but our study puts this into a controlled scientific context, which I'm afraid is the only way of confronting the present beliefs.

  • Diogenes, he has made some important contributions. The paper Rod posted on T4s effects on ubiquitination I think was a milestone. He actually didn't find what he was looking for in this study, at least that is how I read it.

    "Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected, i.e. the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated."

    I think it will take awhile before they clearly understand the polymorphisms' effects.

    I'm looking forward to your papers, I'm sure they will also be milestones on the road to understanding. Is Dr. Thienpont going to be successful in getting the FT3 test to a better and more uniform place of accuracy? PR

  • Diogenes, I am continually amazed at how little doctors actually understand about the Thyroid Function Tests. Both for diagnosis and treatment they literally think that a result within the reference range means the patient is normal and therefore no further discussion is allowed. They keep taking the reference range as the literal truth for a given patient. 'Normalizing the TSH' is a fools errand if there ever was one. If we could just educate them about 'the low index of individuality' it would improve treatment considerably. How can they be so ignorant of the science? PR

  • The other massive problem that I notice is that most doctors assume that TSH has a normal bell-shaped distribution within the reference range. There are plenty of people who say their doctor doesn't like their TSH being 1 or under, they want it nearer 2 or even over 2 i.e. mid-range.

    But TSH is highly skewed towards the lower end of the reference range. How can doctors be forced to face up to that particular nugget of information? :x

  • humanbean, yes, that is another problem, the TSH is not a normal shaped Gaussian curve, it has a front porch. The only thing you can say in regards to dosing with the TSH is that somewhere between complete suppression and about, say, 1.5 or 2.0, many people, not all, seem to do pretty well. And that a number of people, if they are on LT-4 monotherapy, never do very well. And that some people don't regain their health until they get on LT-3 monotherapy, which science is completely clueless about and doesn't recognize. Some days the frustration level exceeds my capacity to control it. Then there is the ridiculous number '10' which is only about 40 years out of date. The only profession which needlessly damages more people than the endos are the shrinks. PR

  • A reference range for any parameter is not like a football goal with two posts - if you put the ball between the posts it's a goal, if outside it isn't. A reference range is a statistical parameter. That is, first of all it has to exclude 5% of "normal" people (2.5% each end) and secondly, it is a probability function. In the middle of the range you are 99.99-----% likely to be normal (never 100%). As you approach the ends of the reference range the probability of being abnormal but within the reference range becomes steadily higher, until when you pass the arbitrary range limit, the probability of abnormality rapidly rises. This is why doctors should use a region close to the edges of the ref range but within it as a "grey area" for followup - the extent of the area depending on the doctor's willingness to accept and pay for larger numbers of false positives followed up - those who turn out to be normal. It is a balance between finding as many abnormals as possible for treatment and not wasting big sums on false positives.

  • Diogenes, as always a clear explanation but a different aspect from the 'low index of individuality', as I understand it. Please bear with me, I would really like to know if my understanding is correct. The 'low index of individuality' has to do with the fact that we each have our own unique reference range and set point. There are at least six studies on this that I know of. Anderson et al. is the one that is usually quoted. The 15 subjects in his study had unique TSH reference ranges that varied from 0.32 mIU/L wide to 2.35 mIU/L wide. The average width was 1.13 mIU/L wide. Set points are unique to the individual and vary from person to person. So any single result within the reference range is incapable of accurately telling you whether that person is at their 'normal' set point or if they have moved off their 'normal' set point. Dr. Anderson thought a move of 0.75 would be significant but science doesn't really know and I suspect a smaller move could be significant given how tightly the body tries to control T3 levels. (Dr. Bianco and his, "The biological imperative is to defend serum T3.") Unfortunately Dr. Anderson used a vertical graph to display the results, most people think horizontally in regards to reference ranges. So the TSH test is incapable of telling you anything until an extreme change for many people. So any result you get within the reference range has a high degree of correlation with the full range but a low degree with the individuals own set point and range. This is normally talked about in regard to intra-individual versus inter-individual.

    As Dr. Anderson said, "Our data indicate that within an individual thyroid hormone

    concentrations are maintained within relatively narrow limits. In addition, we found large variations among individuals and thus a low index of individuality for all

    thyroid function tests. This demonstrates that conventional population-based reference intervals for thyroid function tests may be unable to detect abnormal test results that are considerably outside the normal range for the individual being tested. These findings are consistent with previous observations (18–20)."

    So the TFTs, quite often, do not show a problem until an extreme change for many individuals and are in fact incapable of showing what is optimum for any given individual unless you've already established a baseline, which rarely happens.

    Is my understanding incorrect? PR

  • Yes this is quite true. Eg for TSH the individual's spread of values over the day is far smaller than the population range for normality even given the spread over the diurnal rhythm. . Contact Louise Warvill at TUK for my latest paper on setting TSH ranges - there is a graph there that tells it all. What maybe normal for one person is pathogenic for another even within the reference range.

  • Diogenes, checking Dr. Anderson's references I found a study I had missed from 1980, the earliest I've found so far relating to this subject. There are five studies from 1986 forward. This is from the 1980 study, "In general, a low ratio (below approximately 0.6) means that the usual population based reference interval is an insensitive index of abnormality in the individual patient." It just amazes me that the science has been ignored for 35 years and it certainly shatters the myth of Evidence Based Medicine. PR

  • Diogenes, I keep coming back to this paragraph because it is the clearest explanation of a reference range that I have read. I did not fully understand the 'probability function' aspect before. As a rule I regard conversations on here as private but in this case I would like to ask your permission to quote your explanation of a reference range if and/or when I write about testing in other situations. This is going to post several entries below your paragraph explanation of a reference range. PR

  • OK, that's fine - it applies to EVERYTHING measured in the human body, don't forget! When healthy, the solutions to health at the biochemical level are many and widespread. This is latent Darwinism. That is, the human race has to be so adaptive and different, so that with radically changed natural environments (like an Ice Age) there will be some who are able to adapt when most can't. Just an example, but the basic reason as to why we are all different. We're waiting to take advantage of those circumstances which promote our survival. BTW you are going to be pleased with further work we're doing and submitting, which links "T4-OK" with "T4-not OK" subjects and indicates what to test and how to diagnose to distinguish the various modalities.

  • Diogenes, thank you, I appreciate it. I always look forward to the work you and your collaborators produce, you are some of the few doing something to stop all the needless damage that occurs every day to thyroid patients. We simply have to stop destroying so many lives, society cannot afford to lose the productivity nor bear the costs involved. PR

  • Just as a matter of interest, you might like to see what Rudolf Hoermann has concluded from our series of papers published and upcoming. It tells you something of the history ad how things have changed over the years and why.

    I am quite happy with our latest findings.

    I think we reached a level of differentiation that is very realistic

    some have no problem with T4

    other need a higher dose

    and others require a combination.

    That makes sense. 20 years ago we had approx. 10-20% on combination.

    The guidelines then discouraged the use of T3/T4. Not that I didN’t use it any more at all, but more reluctantly.

    If someone suffers a heart attack, which may happen in the elderly as you know, and happen to be on T3

    they might blame the T3 and the prescribing doctor. And if guidelines were violated the doctor is in trouble.

    T3 is also interesting. The lower T3 which I did observe from time to time was mostly dismissed as assay variation.

    As we do not repeat any measurement with our own assay for reason of cost savings FT3 is difficult to judge unless clear cut.

    After finishing other business, we could address this and do some quality simulations.

  • Diogenes, quite interesting reading. It looks as though you will be busy for awhile yet, more studies to do. I'm curious to understand more about just exactly how Dr. Hoermann views T3. It is interesting that he is apparently one of the few that have used combo therapy for some time.

    The last couple of years I have been trying to focus more on understanding the problem from the doctors' point of view. It is difficult because they don't really talk to us, well actually, they talk to us but do not talk with us, a conversation is difficult, they don't have the time or the inclination. Modern doctors practice in a very complicated situation, I think it detracts from their ability to be doctors.

    It would be fun to spend an afternoon with you and Dr. Hoermann discussing Endocrinology and Biochemical testing.

    I probably shouldn't be greedy, it is a rare enough gift that you participate on this forum. I have learned a lot from our conversations. PR

  • Diogenes, what I have a hard time getting a grasp of is, why is it that some doctors, a minority unfortunately, see the human being standing in front of them, treat that human being and look for results in that human being, and other doctors don't, they treat the test. Dr. Hoermann was aware of the danger of the guidelines but he still treated the person in front of him. Is it fear, is it ignorance, it is lack of understanding or training?

    It is very apparent that the professional endocrinology associations have chosen to ignore the science of just what exactly a population reference range is and the limitations of the low index of individuality associated with thyroid population reference ranges. Intellectual laziness? The magic number '10' is sheer dogma, how they possibly hold on to it. What is it that they gain by doing this except make themselves look like fools? In reality, as the patient population becomes educated, the endocrinologists end up becoming more and more irrelevant, they become a joke. Is somatoform disorder actually running rampant in allopathic medicine? Surely denial of reality would qualify as a symptom.

    I just find it such a curious situation, there is no sense or logic in it. PR

  • It's now 4.6% of US population? (always thought the epidemic was comparable to diabetes). Just seen a UK quote of 3%!

    ...and are they taking notice of the 'recommended' TSH range reduction to 3? (other US folk i've spoken to say this is rubbish & has NOT been implemented - levels remain the same as UK, often over 5 or per "testing equipment manufacturer".

    I've just read a Dr Briffa doc - if TSH had been reduced to realistic level there would be a 4 fold increase in diagnoses. (apologies, cannot remember exact words - this happens a lot lately for me!)

    Why don't docs know the TSH is inaccurate? (afraid of non-evidence medicine, I suspect). JD

  • Sparerib, the TSH top of 3.0 never took hold in the US. After the suggestion was made there was a whole lot of fighting about it. The top is generally between 4.0-6.0, roughly, pretty much what I've seen on here of UK ranges. The 4.6% is primary hypothyroidism, I would guess if you included all forms of hypo problems it would be in the 30-40% range. One reason the 3.0 never took hold was it would have doubled the number of people with hypo problems in the US and their egos couldn't live with that thought. (Oh we couldn't have possibly been so wrong for so long.)

    As for your last question, there is plenty of science that shows the limitations, why it has been ignored is something I would love to know. The emperor has no clothes. PR

  • There are plenty of examples of good science being ignored - if I wasn't so hypo I would give you a myriad examples starting with the world is flat ....."...........

  • UK figures for 2014:

    Country Indicator Numerator Denominator Ratio

    Wales THY001 125380 3266906 3.8%

    Scotland THY001 187030 4937786 3.8%

    Northern Ireland THY001 143438 3842430 3.7%

    UK THY001 2283812 68091208 3.4%

    NHS England THY001 1827964 56044086 3.3%

    Interesting how much higher in Wales, Scotland and Northern Ireland. Or is that lower in England? :-)


  • It is interesting to speculate exactly what happens to people who were on levothyroxine, but then:

    Are prescribed desiccated thyroid;

    Are prescribed T3 (as in, T3 without any levothyroxine);

    Go private;

    Go off and get their own and stop getting levothyroxine prescriptions.

    I guess they drop out of these statistics.

  • Rod, I would think the numbers are vastly understated. In the US for primary the low is about 4-5% and the high around 9-10% and yet the UK is low to high 3 something? Also do you happen to know the difference between UK THY001 and NHS England THY001? other than about 12 million people. And as you mention how many people may not be on the rolls. PR

  • Yes - I do. UK THY001 is simply the sum of the others!

  • So Scotland is only about 1/10th the size of England, I didn't realize that. One Scottish doctor I read somewhere commented on the fact that the Scots also had lots of famines and he thought that was the reason he saw so many hypos in Scotland, epigenetics. I can't help but thinking the numbers are either vastly under reported or under detected. PR

  • ...or lack of sunshine and VitD... :-)

  • Marz, Scotland definitely lacks in that aspect. PR

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