RICHARD PLOTZKER, MD, Endocrinology, Metabolism, 10:21PM Jun 3, 2013
Management of primary hypothyroidism has become deceptively simple over decades, facilitated by increasingly sophisticated lab studies, from sensitive TSH measurements to direct Free T4 assays. It takes little professional skill to move the levothyroxine dose up or down to get the TSH to the right place, perhaps a little more experience to know where the right place is.
Not everyone needs to have a TSH within the full range of lab normal. Some people with thyroid cancer need their TSH suppressed during maintenance therapy but need it very much elevated at times of surveillance for residual tumor. Some pregnant patients have better outcomes if the TSH is kept toward the lower normal range while some people well advanced in years have better outcomes if the TSH is kept a little over the lab normal. But once it is established where the TSH should be, getting it there rarely poses a significant challenge in terms of prescription writing. Getting people to feel their best may be a little more elusive.
A study from a recent Journal of Clinical Endocrinology & Metabolism explored a question that has never been entirely resolved, whether advancement in available medications results in better relief of hypothyroid symptoms.
A group from the American military's medical service sought to answer this dilemma by comparing a variety of clinical parameters from neurocognitive function to weight to sense of well-being in a group of subjects with established hypothyroidism who took desiccated thyroid for four months and standard synthetic levothyroxine for four months, blinded to the patients and titrated by the prescribers to maintain a normal TSH. In order to understand the results, a review of the history of how hypothyroidism has been treated for the past century will add to the understanding.
While the diagnosis of hypothyroidism only became reliable with the development of the TSH assay in the 1970's, the overt clinical syndrome was well recognized in the 19th century. The first successful treatments began toward the final years of that century with a pill called desiccated thyroid or later Armour thyroid, both still available and the latter with many advocates for its use. The treatment was developed as a byproduct of the meat packing industry, thus the Armour Company's interest in it. Thyroid glands from hogs and cattle were dried in the field, and then ground into medication.
These original preparations contained thyroxine, tri-iodothyronine, some byproducts of endogenous thyroid hormone synthesis, thyroglobulin and a number of cellular elements. Patients ate these and got the active T4 and T3 that they needed for symptom reversal. Since the hypothyroidism being treated with these pills was quite overt, the clinical improvement could be assessed.
As the decades wore on, the pills were refined to include the active thyroid hormones or later in the case of Proloid, the thyroid hormones and thyroglobulin. All of these preparations contain a mixture of T4 and T3 in approximately the proportion that a cow or hog would make it, which is not a whole lot different from what we make.
Around 1960, with a better understanding of the chemistry and physiology of how the thyroid hormones worked, synthetic thyroxine first became available as the drug we know as Synthroid, or now generic levothyroxine produced by a number of competing manufacturers. Once TSH measurements became available maybe fifteen years later, it became apparent to prescribers that the synthetic thyroxine had a lot more predictability on the next office visit's TSH than did the mixtures, so most patients were converted to this and newly diagnosed patients were generally prescribed T4 alone rather than a T4/T3 mixture.
As the population was being converted over, there was a subset of patients who complained that they felt better on the older medicine than the new. Among the people newly diagnosed, a significant subset reported to their doctors that they wished they felt better, even though their lab numbers were normal.
Meanwhile, as antidepressant therapy improved over the same era, there were a number of patients who reached a plateau of efficacy with their tricyclics and later SSRI's. A psychiatric literature developed using thyroid hormone, most commonly T3, to boost daytime mood in partially treated depressives. As a result, a school of thought emerged that T3 released from the thyroid gland and circulated to the tissues had a benefit beyond what would be achieved by physiologic deiodination of T4 to T3 at the level of the target cell. This led to a number of attempts to compare therapy of hypothyroidism with thyroxine to therapy with T4/T3 mixtures.
Results were mixed, with one highly publicized study done in one of the Baltic States in the 1990's showing a benefit, but the benefit disappeared when other studies altered the patient populations to exclude individuals with depression. There was even a bit of self-promotion involved with a Dr. Wilson giving the eponym Wilson's Syndrome, making the talk radio show circuit trying to convince the public that they really needed some exogenous T3 to feel their best, even if their standard lab testing was normal.
So now back to the current study. Each subject received a course of each drug. Some patients lost enough weight to notice when they were on the mixture and had a clear improvement in their well-being scores. Patients were asked which medicine they preferred, with 48.6 preferring the four months on the mixture, 18.6% preferring pure levothyroxine and 32.9% not noticing any difference between the two courses of treatment.
Eight months of combined therapy is not enough time to assess whether these two preparations, one available for a century and the other for half a century, were of similar long-term safety, so it is premature to conclude that the medical community did the public a disservice from the population-wide shift by making people feel less well than they might to facilitate the simplicity and predictability of dosing.
Maybe what research should focus upon would be better identification of those who might benefit from the added T3 component. And more to the point, patients who do not feel as well as their lab work suggests need to have that reality accepted by their physician.