Renowed researcher Dr. Wilmar Wiersinga, in the January 2014 issue of the medical journal Nature Reviews Endocrinology, has an interesting overview of some of the key paradigm shifts in thyroid hormone replacement therapy for hypothyroidism in recent years. I've summarized some of the most interesting aspects of the article.
THE FOUR PARADIGM SHIFTS
Dr. Wiersinga identifies four key paradigm shifts.
First Paradigm Shift: Hypothyroidism was untreatable until in 1891 in London, Dr. George Murray reversed severe hypothyroidism in a patient by giving an injection of sheep thyroid extract. Subsequently, ground or fried sheep thyroid or tablets of dried thyroid tissue began to be used as the first effective therapy for hypothyroidism.
Second Paradigm Shift: From 1960 to 1988, the use of natural desiccated thyroid drugs slowly declined, as use of levothyroxine increased. In 1978, the number of levothyroxine prescriptions exceeded natural desiccated prescriptions. By 1988, 84% of all patients were taking levothyroxine.
Third Paradigm Shift: Dr. Wiersinga describes how animal experiments from the 1990s have shown that euthyroidism -- achieving normal T4 and T3 levels in body tissues -- after surgical removal of the thyroid gland could not be achieved on levothyroxine only, but also required liothyronine (T3). Patients and practitioners have reported patients doing better with the addition of T3, or on natural desiccated thyroid, but most of the trials and research conducted during this time did not find conclusive that combination therapies were superior. Dr. Wiersinga suggests that there are genetic predispositions that make some patients more responsive to combination therapy - and says that "if further studies can identify this specific subgroup of hypothyroid patients, a third paradigm shift in the treatment of hypothyroidism might occur—perhaps heralding the use of personalized medicine in this setting."
Fourth Paradigm Shift: A 2012 research study described for the first time that functional thyroid tissue can be generated from embryonic stem cells. Dr. Wiersinga speculates that "this work could ultimately lead to a fourth paradigm shift, in which hypothyroid patients can be treated with thyroid-generating stem cells."
LEVOTHYROXINE-ONLY TREATMENTIn discussing the paradigm shifts, Dr. Wiersinga took a critical look at the use of levothyroxine (T4) only treatment. He pointed out that there are a number of studies that show that levothyroxine treatment is associated with a number of negatives for patients, including:
- increased psychological distress
- impaired well-being
- decreased health-related quality of life
- impairments in cognitive psychomotor speed, attention, learning and memory
- increased prevalence of anxiety
- poorer psychological function, working memory and motor learning
Dr. Wiersinga also reports on an interesting Scottish study that found that the risks of heart problems, arrythmias and bone density issues increased in patients with suppressed TSH levels (less than .03), and in patients with high TSH levels (above 4.0) but there was no increased risk associated with "low" TSH levels (.04 to .4).
Dr. Wiersinga presented research that demonstrates that "normal TSH levels consequently do not guarantee euthyroidism in all tissues that are targets of thyroid hormone." Simply put: levothyroxine-only treatment may not be the optimal treatment for patients with hypothyroidism. Instead, some addition of t3 may help normalize thyroid function in all tissues.
LEVOTHYROXINE PLUS LIOTHYROININE (T4 + T3)
A number of studies looking at levothyroxine-only therapy, versus the addition of T3 have shown that, according to Dr. Wiersinga, "a remarkably high proportion of patients (on average 48%) preferred the combination therapy...Differences in final serum TSH levels could not explain this patient preference."
(For an example of one of the more prominent ones, read New Study Shows that the Addition of T3 is Superior to Levothyroxine/T4-Only Thyroid Treatment for Hypothyroidism).
Dr. Wiersinga concludes that "a convincing argument can be made that combination therapy might have benefits if levothyroxine:liothyronine dose ratios are applied that result in normal serum TSH levels and free T4:free T3 concentration ratios" or when given to patients who have specific genetic issues that affect their ability to convert T4 to T3.
He also recommends that endocrinologists should be looking at options, including the addition of T3, to help hypothyroid patients who have persistent symptoms despite supposedly adequate levothyroxine doses.
According to Dr. Wiersinga, one option is to follow the European Thyroid Association's (ETA) guidelines for so-called "experimental" use of T4+T3 therapy, which involves a ratio of levothyroxine to liothyronine of about 17:1 According to the article, "for example, TSH-normalizing levothyroxine doses of 100 µg, 150 µg and 200 µg during monotherapy translate into combination therapy doses of 85 µg levothyroxine plus 5 µg liothyronine, 125 µg levothyroxine plus 7.5 µg liothyronine and 175 µg levothyroxine plus 10 µg liothyronine, respectively).
They also recommend splitting the daily T3 dose into two (a smaller dose given in the morning and a larger dose given at bedtime, the exact proportions depending on which of the locally available liothyronine preparations is used) to "help to mimic the circadian rhythm of free T3 levels, which reach their peak at 3 a.m."
The ETA also recommends a slow-release T3 preparation.
OTHER INTERESTING POINTSHere are a few other background points of interest from the article.
The treatment guidelines for hypothyroidism that were published in the 1980s and 1990s "unequivocally" recommend levothyroxine (synthetic T4) and don't really mention any other treatment options for patients. Interesting, all the hypothyroidism treatment guidelines published in the 2000s still recommend levothyroxine as the standard treatment, but also contain sections saying why combination levothyroxine and liothyronine (T4+T3) therapy consisting should not be used.
There is an increase in hypothyroidism treatment. In England, prescriptions of thyroid hormones have more than doubled between 1998 and 2007. In the Netherlands, the total number of people using thyroid hormone drugs increased by 53% between 2005–2011 -- the Dutch population increased only 2.1% during that time.
The proportion of patients who are on levothyroxine-only treatment has decreased slightly from 2005 to 2011 -- and there has been a slight increase in the number of patients on synthetic T4+T3 treatment.
Source: Wiersinga, Wilmar. "Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism." Nature Reviews Endocrinology (2014), Published online 14 January 2014