REVIEW: Ineffectiveness of L-T4 monotherapy in subclinical hypothyroidism

A new study published October 2018 has reviewed prior research on levothyroxine monotherapy in cases of “subclinical hypothyroidism” and has found it to be ineffective in improving quality of life and thyroid-related symptoms in patients.

Studies like these could logically be used to launch a staunch critique against the presumed effectiveness of normalizing TSH via L-T4 monotherapy. They ought to inspire clinical studies of T3-based therapies that could be more effective for patients.

Believe it or not, they come to completely different conclusions!

Instead, studies like these are being used to reinforce the current paradigm of therapy AND prevent all “subclinically hypothyroid” patients from receiving any thyroid therapy whatsoever!

Source

Feller, M., Snel, M., Moutzouri, E., Bauer, D. C., Montmollin, M. de, Aujesky, D., … Dekkers, O. M. (2018). Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis. JAMA, 320(13), 1349–1359.  LINK: https://jamanetwork.com/journals/jama/article-abstract/2705188

Two major flaws in the research

Alas, studies like these are defective in two major ways:

1. They generalize about “thyroid hormone therapy” in their title and throughout — this is a term which ought to apply to therapy with ALL thyroid hormone medications including T3 / Liothyronine and desiccated thyroid. But when you look into the articles, “thyroid hormone therapy” really means T4-monotherapy (levothyroxine). Of course, this is only one type of thyroid hormone therapy! Therfore, you must realize that their review is ONLY about the incapacity of levothyroxine monotherapy to improve this particular subclass of patients’ symptoms and quality of life despite normalizing TSH. But the authors’ wording implies the findings to apply to ALL thyroid hormone therapy, which is a big mistake.
2. The articles they reviewed did not correlate any significant changes in FREE T3 levels with symptoms or quality of life. Instead, they make the false assumption that normalizing thyrotropin (TSH) alone, or even merely raising T4 levels, should be sufficient to “fix” the patient’s thyroid hormone biochemistry including the most active thyroid hormone, T3. This is illogical thinking. It directly contradicts scientific results of other studies that show a TSH-T3 disjoint and a radically different T3:T4 ratio in LT4 thyroid therapy. Each patient may metabolize T4 differently, and the same level of TSH and FT4 will yield different levels of Free T3 in different patients.

Dangerous conclusions

The danger is that articles like this can persuade medical systems to adopt a hands-off approach — it makes it look like no thyroid therapy at all is going to make a difference whenever TSH is moderately above reference and FT4 is _anywhere_ in normal range.

The conclusion clearly states “These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.”

Thyroid status is NOT defined by TSH and FT4

It is sad that clinical research in thyroid therapy does not think it relevant to measure where in range these patients’ FT3 falls at baseline nor after therapy, taking it on blind faith that “normal” T4 and TSH should be all that matters.

Why don’t these researchers realize that there’s no biological basis for the assumption that changes in blood TSH and FT4 levels can _directly_ alter health, much less symptoms?

• We know TSH does not enter thyroid hormone receptors — TSH enters TSH receptors in the thyroid gland and throughout the body.
• T4 molecules have very weak affinity for thyroid hormone receptors and have no known genomic activity there — T4’s actions are primarily limited to its non-genomic effects and its ability to modify pituitary TSH secretion.

TSH and T4 hormones are therefore only indirectly related to true thyroid hormone sufficiency.

Thyroid hormone sufficiency, from the perspective of organs and tissues, is defined as T3 sufficiency rather than TSH normalization.

TSH and T4 primarily have their power by means of influencing T3 production from healthy thyroid gland tissue and T4-T3 conversion rates within bloodstream and peripheral tissues.

The indirect influence of TSH and FT4 upon T3 sufficiency rely on too many factors and can break down:

• One cannot assume that a patient has sufficient thyroid tissue to be stimulated by TSH to produce relatively more T3 — a mechanism that is now called the “TSH-T3 shunt” (Berberich et al, 2018)
• Some patients have “thyroid hormone resistance” and require a higher than normal level of T3 hormone to activate thyroid hormone receptors.
• Some patients may have TSH receptor blocking antibodies, and these may overstimulate TSH production by blocking the TSH receptors on the pituitary gland and interfere with the pituitary gland’s ultrashort feedback loop.
• Some patients have inherited defects in thyroid hormone metabolism, such as polymorphisms in the DIO1 or DIO2 gene or a partial SBP2 deficiency — and this will yield abnormally low T3 levels in blood and/or tissues despite a normal FT4.
• The claimed “rarity” of an extremely low T3:T4 ratio is underestimated due to the rarity of testing Free T3 and inability of most clinicians and researchers to interpret TSH, T4 and T3 levels as a three-way relationship.

On the other hand, there is other research showing that alterations in blood FT3 levels — even within the reference range — DO make a difference to T3 levels in organs, such as liver.

The huge gap in thyroid research and therapy

The blindness to Free T3 has caused a huge gap in thyroid research and therapy and has the potential to harm many patients who have low, or low-normal, Free T3 levels.

Other studies have shown that levothyroxine monotherapy actually yields LOWER than average Free T3 levels at the same TSH and T4, so the patients may gain some T4 but lose some T3 — and that tradeoff is likely why there’s no overall QoL benefit to merely normalizing TSH via T4 monotherapy.

If only researchers would test Free T3 and target T3 in therapy, as well as optimize a patient’s thyroid hormone levels within the reference range by attending to symptoms and other measurable signs of T3 sufficiency like cholesterol levels and ankle reflex — I bet they would see different results.

Subclinical hypothyroidism: A controversial area

Another problem with such articles is that “Subclinical” hypothyroidism is defined as “a thyrotropin (TSH) level above the reference range in combination with a free thyroxine (FT4) level within the reference range.”

This is a category of diagnosis that relies solely on TSH and T4 levels to the exclusion of Free T3 levels. It also relies on population-wide statistical reference ranges to interpret the significance of hormone levels.

Hoermann et al (2015) point out that this category is misleading because it includes people who are euthyroid and people who are hypothyroid:

Consequently, subclinically hypothyroid patients therefore comprise a heterogeneous population of truly dysfunctional and truly euthyroid subjects.

Hence, current definitions of subclinical hypothyroidism or hyperthyroidism cannot serve as a satisfactory and consistent aid to an accurate disease classification in itself.

Emerging integrated and personalized diagnostic concepts need to be evaluated and appropriate new markers of tissue euthyroidism must be developed.

This category primarily applies to the early stages of thyroid gland failure in autoimmune thyroid disease when higher levels of TSH stimulate the thyroid gland in order to maintain the body’s Free T3 levels as Free T4 secretion decreases.  It is known that higher levels of TSH stimulate the thyroid gland to increase its production of T3 hormone, and higher TSH in the presence of lower T4 levels also stimulates Deiodinase Type 2 to convert more T4 to T3.

However, low levels of Free T3 even within the reference range can result in hypothyroidism in organs that depend on T3 from bloodstream, such as the liver and the cardiovascular system.

As the thyroid gland fails, there is a point at which TSH can no longer stimulate sufficient Free T3 production from a failing thyroid gland and cannot encourage enough T3 to convert from a decreased supply of Free T4.

But because the definition of subclinical hypothyroidism does not rely on Free T3 measurement, it includes patients who have past this point and are truly hypothyroid and in need of therapy.

Another danger arises from the unfortunately too common mistake of generalizing “subclinical hypothyroidism” to apply to any patient, post-diagnosis and on thyroid hormone therapy, whose TSH and Free T4 fall into this pattern. This error in thinking can result in incorrectly presuming that a patient with this pattern of lab test results does not need further dose or therapy adjustments — The dangers of this misapplication of “subclinical hypothyroidism” is seen in this study of a patient who ended up in Myxedema Coma due to her low FT3 levels.