Should you care if levothyroxine normalizes metabolic rate?

Image Credit: Photo by Jon Cellier on Unsplash 

 

Evidence-Based: Written by a Board-Certified Endocrinologist

A blog reader recently commented on one of my prior posts, Is TSH the Best Test?

So before the TSH test was developed, patients used the restoration of their metabolic rate to indicate adequate treatment of hypothyroidism with replacement hormone – however this was later determined to be overtreatment. Ok – I follow.

 

Can you explain why the adequate treatment of hypothyroidism with T4 monotherapy doesn’t restore metabolic rate? [HD: Bolding and italics are mine.]

 

Sincerely, a 5’9″ woman with hashimotos with a TSH of 2 who eats around 1200 calories a day to maintain 200 lb frame.

I love this question, because it’s a hard one and there isn’t a clear answer. But it does give us the chance to dive deeper into the issue and, hopefully, you’ll pick up a useful factoid or two.

Super-brief history of hypothyroidism diagnosis and treatment

I’ve covered this ground in the past, but because my blogging output has been (ahem) sluggish the past couple of years, let’s refresh:

In the mid 1910s, scientists figured out an easier way to measure basal metabolic rate (BMR). Recognizing that a low BMR was associated with hypothyroidism, physicians used the presence of a low BMR and other signs/symptoms of hypothyroidism to make the diagnosis. They also used BMR to titrate the dose of thyroid hormone.

By the 1940s, serum protein-bound iodine (PBI) emerged as both a diagnostic and therapeutic marker; this was the only way to quantitate thyroid hormone status at the time. Unfortunately, T4 monotherapy would often increase PBI above normal, while T3 monotherapy would normalize BMR but not increase PBI. Combination T4/T3 therapy, however, had the advantage of normalizing PBI. Thus, desiccated thyroid extract (DTE, or pig thyroid as I like to call it) continued to be the treatment of choice for hypothyroidism, as it had been since the 1890s.

By the mid 1960s to early ’70s, physicians and researchers began to sound the alarm that something just wasn’t right with DTE. Studies showed that DTE pills could have anywhere from 0-200% of their stated dose; they were inconsistent from bottle to bottle and batch to batch; and the shelf-life of these desiccated pills was greatly reduced if stored in humid conditions. At this point, DTE’s reputation was lousy.

Despite the fact that doctors were increasingly wary of pig thyroid, they were also worried that switching over to levothyroxine (T4 only) would result in T3 deficiency. But in 1970, the deiodinase enzymes that convert T4 to T3 were discovered, and over the next ten years, levothyroxine became widely adopted as the treatment of choice.

History of using BMR to diagnose and manage hypothyroidism

Remember the question my reader asked: why doesn’t T4 monotherapy (levothyroxine alone) restore the metabolic rate? If we assume that the premise of her question is sound – that T4 treatment does not restore BMR to normal – then the next thing we need to ask is, should it?

You might be tempted to say, of course it should! Not so fast.

It is true that, in the good-old days, thyroid hormone was often titrated to “normalization” of BMR. But how was “normal” determined? Did people have their BMRs measured at their yearly physicals, such that their doctor would always have a fairly up-to-date baseline measure of their metabolism, just in case they should develop hypothyroidism and need to know their own “normal?” Although I can’t know for sure whether a bunch of unscrupulous docs were up-charging their patients for a BMR test every year, I suspect the answer to this question is “no.”1

In fact – and this is something that doesn’t seem to be emphasized enough in modern thyroid literature – BMR testing in the early to mid-1900s was terribly inaccurate. Around that time, a couple of researchers named Roth and Buckingham noted:

…more than one authority has stated on the basis of extensive travel and observation, that as many as 70% of the basal metabolism reports made today by the average operator may not be worth the paper on which they are written.

I think I would have gotten along great with these guys, as their views on the movement of BMR testing from highly specialized laboratories to the offices of inexperienced clinicians mirrors my complaints about chiropractors and naturopaths advertising their services as “metabolic experts” after taking a weekend course at the local Sheraton:

…many of these technicians educated overnight merely to man the machine, lacked training and experience necessary to face the multiplicity of problems to be otherwise encountered…Their work and reports were generally unquestioned because there were few capable of checking and passing judgement.

Further, the dominant method for checking BMR at the time tended to overestimate the values for “normal” subjects. Unfortunately, the direction of error for measuring BMR in patients suspected of having thyroid disease could be either positive or negative, due to the sheer number of variables that must be accounted for during BMR testing.

I’m frankly disappointed – though not surprised – that physicians at the time thought that BMR testing was quite helpful in the assessment of hypothyroidism. Despite the author of this 1933 paper acknowledging that errors of 10-20% or more would not only be possible but common, he maintained that a “certain comfort, however, is derived from following the effect of treatment with basal metabolic rates.”2 He goes on to say, in reference to BMR testing, at the end of his article:

Laboratory tests of function are valuable aids when given their proper place and importance. They have increased our knowledge of disease and have contributed to our clinical ability. It must be remembered, however, that they often represent single components of a complicated system of dependent variables. The danger not only in diseases of the thyroid, but in Medicine generally, is to become a slave to laboratory data and place too little reliance on good clinical judgment.

I don’t mean to pick on this one physician, but I do think this classically illustrates the truism that we think everyone else is more likely to be subject to bias or poor judgment than we are. Ever hear the survey results showing that 80% of people think they are “better than average” drivers?

When we dig deeper into the above author’s paper, he describes his clinical experience:

Thyroid gland should be given in amounts sufficient to bring the B.M.R. to within normal limits. Occasionally the result is spectacular and improvement is striking. In other cases without any change in the B.M.R. the patient may complain of accentuation of existing symptoms and no clinical benefit result. Still others with large doses of thyroid extract no beneficial change is observed in the clinical picture nor is there the expected rise in B.M.R.

Ummmmm…so, basically, anything can happen when you give thyroid hormone to somebody and measure their BMR? Listen, the guy had a machine, the machine spit out some results on paper, the paper looked official, and he derived comfort from those results – probably more comfort when the results confirmed his preconceived expectations and less when they didn’t – but I editorialize.

Hypothyroidism treatment in the modern era

Once the TSH blood test arrived on the scene in the early 1970s, BMR and PBI testing quickly fell out of favor. Studies clearly showed that people with hypothyroidism could be rendered clinically and biochemically indistinguishable from healthy controls, using a T4 dose just high enough to normalize the TSH. These T4 doses turned out to be 1/4 to 1/2 the prior doses used to normalize BMR and PBI, markers that were nowhere near as sensitive or specific as TSH.

Now, I guess I’ll have to address the widespread assertion that it was the replacement of BMR and PBI with TSH that led to our current “epidemic” of hypothyroidism under-treatment. Obviously, the doses of thyroid hormone used from the 1970s-on were dramatically lower than doses used in earlier decades. But in order to understand whether old-school doses were more appropriate than new-school doses, you have to look at clinical trials from the 1950s that attempted to assess efficacy, dose equivalency, and adverse effects among pig thyroid, levothyroxine (T4), and liothyronine (T3).

Those trials used big doses and treated to normalization of BMR or PBI; consequently, they were associated with higher rates (compared to today) of angina, heart failure, heart palpitations, psychosis, muscle stiffness, nervousness, sweating, and tremors.

Further, if we’re going to talk about whether people with hypothyroidism today have higher rates of under-treatment, we also have to talk about how people today are substantially more likely to be incorrectly diagnosed with hypothyroidism. While I have no data to back up this statement, I have many years of experience as an Endocrinologist, during which I have taken many dozens of people off of thyroid hormone. Upon retesting, the vast majority of these folks do not actually have hypothyroidism.3 Clearly, if someone has been incorrectly labeled hypothyroid, it should be unsurprising when many of their symptoms fail to improve with treatment.

BMR in the modern era

Although modern BMR testing using indirect calorimetry at a specialized lab is almost certainly more accurate than what they were doing back in the 1930s, it’s still going to suffer from the same fundamental flaw: it’s very difficult to know if a hypothyroid person’s current BMR is pathologically lower than it should be.4 The best we can do is compare you to a control standard which may or may not be extrapolable to your situation.

That said, the reader who inspired this post claimed that T4 monotherapy does not normalize BMR. There are some studies showing it does and others showing it doesn’t. I’m not interested in presenting those in great detail here, as you can easily get that discussion/information somewhere else. As regular readers know, I try to restrict my scope to commentary that I haven’t seen elsewhere.

To that end, I do want to mention a randomized, double-blind, crossover study of levothyroxine vs liothyronine. When treated to equivalent TSHs, the authors did find that the T3-only group lost a small but statistically significant greater amount of weight than the T4-only group. Interestingly, there was no detectable difference in BMR between the groups, making it unclear what exactly accounted for the weight loss. Though the authors of this study (and at least one other study I read while researching this topic) think the most likely explanation is that the BMR test itself simply isn’t sensitive enough to detect the difference. While that’s certainly possible, I think we need to be careful about being too comfortable with the idea that the proposed mechanism is correct, but we just can’t prove it. 

The point is, if a T3-only vs T4-only trial has a tough time proving that there’s a significant difference in BMR attributable to the use of T3, then the typical real-life scenario of adding in a small, physiologic dose of liothyronine to levothyroxine would probably not result in a detectable jump in BMR (should one choose to measure it before and after adding in the liothyronine).

What do we really care about when we say BMR?

I would assume that most people with hypothyroidism aren’t as interested in the numerous metabolic processes that collectively make up BMR, as they are in the issue of whether or not they can achieve and maintain a weight with which they are satisfied. When it comes to treating hypothyroidism and the effect on weight, the trials are all over the map. We can’t clearly say that taking some (or a lot of) T3 is clearly superior to taking only T4.

My take: if you take levothyroxine and have many residual signs and symptoms of hypothyroidism, despite “perfect” labs, it’s reasonable to broach the idea of T3 add-on therapy with your doctor. In my experience, the fewer residual signs and symptoms you have, the less likely it is that T3 therapy will help with weight loss. And, when difficulty losing weight is the only issue you have, with perfect thyroid labs, the chance of T3 add-on therapy resulting in weight loss is miniscule.

All told, I do think that the subject of BMR and hypothyroidism is important, but I am skeptical that we’ll soon be getting any firm answers that lead to dramatic changes in my proposed treatment strategy.

 

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  1. An analogous situation would be the contemporary primary care doctor who owns the vascular testing lab where – for example – carotid ultrasounds and exercise stress tests are performed. While that can be a convenience for the patients who need it, it also provides a financial incentive to order testing for asymptomatic patients. Sadly, I’ve occasionally seen such doctors order “yearly testing” for their elderly, asymptomatic patients who don’t need it. []
  2. If you decide to read the paper, keep in mind that historical standards for publication in medical journals were significantly different from modern standards. That’s all I’m going to say about that. []
  3. In my experience, naturopaths account for at least 9 out of every 10 healthcare practitioners who overdiagnose hypothyroidism. Hey, when the only tool you have is a hammer, everything looks like a nail. []
  4. Obviously, the lower the BMR in reference to a standard, the more likely it is to be abnormally low. But the closer it is to the standard, the harder it would be to tell if the BMR is truly abnormal. []

10 Replies to “Should you care if levothyroxine normalizes metabolic rate?”

  1. So happy to read a new post by you :). Thanks!

    Love this: “Listen, the guy had a machine, the machine spit out some results on paper, the paper looked official, and he derived comfort from those results” LOL. THIS is exactly why I pretty much never go to any doctor anymore. The fine art of practicing medicine is lost due to “paper spitting numbers = diagnosis and treatment.” I had papillary thyroid cancer four years ago. I have 1/2 of my thyroid left (thank god I dirted the surgeon that wanted to take it all) but even still, I listened to the paper spitter who told me my metabolism would now tank with just 1/2 of a thyroid gland. I went through over a year of unsuccessful “pill” treatment (T4, T4/T3) with crazy (and I mean crazy) anxiety, palps, etc. In fact, when on “pills” with “normal” labs I was actually GAINING weight!

    When I left my body to it’s own devices, my thyroid actually started doing just fine with nothing (this also made me realize for all the years prior I did not even need to be taking 50mcg’s of T4 at all!!). My TSH ranges from 5-7 (FT4 always fine). This throws my doc into a tizzy as I calmly tell them my pituit simply squirts out a bit more TSH due to my unique gland situation. This is MY normal.

    Yes, I eat well, exercise alot (w/ proper body loading and alignment), get my spine adjusted regularly, bla bla, etc. I have noticed with this tremendous metabolic improvement (gotta get those big muscles and the CNS working right). Not downplaying the severity that Hashi’s can wreak; I know many people whom struggle with it and I definitely do not think one should just “go off” their thyroid meds! I do encourage those struggling to look for an endo with more of this blogs mindset. You must keep looking and finding answers that will work for YOU. YOU are the captain of your fleshy space suit and no one really cares about it or knows it but YOU!

  2. Thanks doc for the info. Always love reading your posts. For folks who “just don’t feel normal” on T4, are there are new treatments on the horizon ?

    1. Thanks, Dave. I don’t think there is anything imminent. Haven’t heard much lately about the timeline for FDA approval of extended-release/sustained-release T3, but that’ll probably be one of the more interesting treatments once it gets to market. As you know, I do not trust compounding pharmacies to make a true, sustained-release, well-standardized product.

      1. My Man, last year was the clinical trial for the sustained release t3, the results are beautiful, and the comparative pharmacokinetics of both regular t3 and sr- t3 looks good

        That’s a good idea for a short post, about what do you expect from the first study

        https://pubmed.ncbi.nlm.nih.gov/34641706/

        Hope things are going your way doc !

        1. This is a phase 1 trial, so I guess I won’t hold my breath on this one. I try not to predict much based on this kind of thing, despite really wanting to see a good sustained-release T3 product come to market.

  3. Is it possible that taking Potassium Iodide could have a similar effect to taking T3? I assume this would only be a possibility if you were actually iodine deficient.

    I started taking potassium iodide 3 months ago as I had never actually tested a hunch that my winter depression and sometimes putting on weight and then just going into reverse and losing it without trying could be thyroid related. I never did it before as the only real symptom of hypothyroidism I could claim to have was 3/4 length eyebrows.

    I have lost weight dramatically but feel fine – I lost weight so easily that if I felt bad I would check for illness. I am using other things that could cause this – specifically androgens: Mesterolone and Oxandrolone, but i was using them before I tried Potassium Iodide without dramatic effect on weight. Dumping white rice and switching to boiled ‘al dente’ [to slow absorbtion] black rice is likely a factor, but my weight would increase and decrease on white rice. I have lost craving for carbs though. Historically the supermarket shelf where they keep the Belgian chocolate seashells would start it’s siren call around 11 am in winter, but I could walk past it like it wasn’t there in summer.

    The main thing is I am functioning beyond the second week of November when I just shut down – many years I would have had real problems concentrating enough to structure even these few paragraphs – the level of limbic arousal is normally low by now.

    In my early 20’s I went to see a Doctor because I was just so non functioning and this has been a recurrent thing over the following 35+ years. I was told that “everything is within normal ranges” and Thyroid hormones were specifically mentioned. A few years ago my TSH, thyroglobulin (?) and T3/T4 were found to be in normal ranges and the Doctor said I was “not struggling”. Thailand is known to have iodine deficient soils and I eat eggs and Tuna for Iodine. I very happily gave up munching unhappily on seaweed after your blog post pointing out it won’t do anything. I asked the doctor if OK T3/T4 levels meant I was getting enough Iodine and she said it was not possible to extrapolate backwards like that.

    I have T4 untouched in the house and could buy T3 to further experiment, but that is quite a leap.

    1. While I can’t speak to your situation, I can say that taking potassium iodide should not have a T3-like effect in people. And, unless one is iodine-deficient, taking higher than multivitamin levels of potassium iodide (>100-150 micrograms) has the potential to suppress thyroid function, at least for a time. It also has the potential to induce hyperthyroidism in susceptible people.

  4. Hi HD
    Good to see you are back at least once a year, I hope you are doing well

    There is a couple of brothers (both MD) (Endo and obesity field) who have a podcast about busting medicine myths and keeping it real. Karl and Spencer Nadolsky are pretty cool guys, and one of them, years ago (the Endo) shared your post about thyroid diets. That’s the one reason I got to this place

    They like the idea of having you on an episode, if you are interested I can talk to them again

    https://anchor.fm/docswholift

    Don’t forget about the patreon idea, the world needs you in this fake info post modernism

    Bye, take care

    1. Hey Erick, yes, I’m familiar with Karl and Spencer, even though I don’t know them personally. I’d be happy to talk to them about doing a podcast episode, if they’re still interested in talking to a non-prolific blogger. If I ever ramp up my production of material, maybe I’ll take your advice and set up a Patreon…

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