✅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.
By using this site and interacting in the Comments, you agree to abide by my Disclaimer. Please keep your comments respectful and refrain from ad hominem attacks. In the past, I’ve been permissive – no longer. The social and political discourse in our country has become so toxic that I cannot, in good conscience, allow my blog to provide a space for those who simply want to express outrage. If you disagree with something I’ve written, or something written by a fellow reader, fabulous. Make your argument in as dispassionate a way as you can, and we’ll all get along just fine.
- 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.
- 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.
- 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.
- 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.