T3 in Hypothyroidism Gets Extra Recommendation, With Caveats

New recommendations from the Joint British Thyroid Association/Society add to the increasingly general consensus that liothyronine (LT3) may be useful in combination with standard levothyroxine (LT4) in the treatment of hypothyroidism in some patients whose symptoms persist after standard treatment, despite a lack of evidence of benefit in clinical trials.

"Most patients with primary hypothyroidism respond well to levothyroxine replacement therapy," recommends the joint association in the consensus statement, by Rupa Ahluwalia, MBBS, MD, of Norfolk and Norwich University Hospitals NHS Trust, UK, and colleagues, recently published in Clinical Endocrinology.

"For the small minority of patients who remain symptomatic despite adequate biochemical replacement with levothyroxine, a trial of liothyronine/levothyroxine combination therapy under specialist supervision may be appropriate," they write.

The ongoing debate over the use of LT3/LT4 combination therapy has persisted for more than two decades, with at least 16 randomized controlled trials and four meta-analyses failing to show any significant benefit of the combined regimen in key quality of life and cognitive function outcomes compared with LT4 monotherapy. However, many patients continue to report benefits with combination therapy, so the issue has not been laid to rest.

Wilmar M. Wiersinga, MD, PhD, an emeritus professor of endocrinology at the University of Amsterdam, the Netherlands, told Medscape Medical News: "The scientific community is divided as to whether or not the LT4/LT3 combination therapy has any value whatsoever, whereas the pressure from individual patients and patient associations on physicians — both general practitioners and specialists/endocrinologists — can be very high [in terms of] demanding prescriptions for the combination therapy."

"I welcome this joint statement very much because it provides guidance, especially for clinicians, on a hotly debated issue," he said.

Persistent Symptoms Drive Pursuit of Alternatives

T4 refers to the hormone thyroxine made in the body, and LT4 to the pharmaceutical replacement product for that hormone, levothyroxine. Similarly, T3 refers to the hormone triiodothyronine, made in the body, and LT3 refers to its pharmaceutical replacement, liothyronine.

Driving the continued demand from some patients with hypothyroidism and interest among clinicians is the relatively high proportion of patients who continue to experience symptoms even after the normalization of biochemical levels after treatment with LT4, which resolves symptoms in most patients within weeks of therapy.

Those who don't improve report common ongoing symptoms including fatigue, sleepiness, memory problems, cognitive difficulties (brain fog), and weight gain.

However, with 60% of people commonly having one or more of the same symptoms even when their thyroid levels are normal, pinpointing the actual causes is a challenge, the societies report.

In the absence of other diagnoses, clinicians often turn to alternative treatment strategies, which, as well as addition of LT3 to LT4, also include the use of desiccated thyroid extract (DTE).

DTE was the medication first used to treat hypothyroidism years ago, originally made from pig glands. There are now several prescription medications made from the desiccated (dried) thyroid glands of animals, including brands such as Armour Thyroid, NP Thyroid, and WP Thyroid.

The practice of prescribing combination therapy has already been deemed acceptable by both the European Thyroid Association (ETA) and American Thyroid Association (ATA). The latter recommended in their 2014 guidelines that the combination of LT3/LT4 therapy may be trialed in exceptional circumstances or among patients who fail to improve with LT4 alone.

In following suit, the new Joint British Thyroid Association/Society consensus statement cautions that, first and foremost, "most patients with hypothyroidism should be treated with levothyroxine alone."

However, combination LT3/LT4 therapy may be considered an option under key important conditions, including:

When a diagnosis of overt hypothyroidism (documented TSH ≥ 10 mU/L and/or low FT4 pretreatment with thyroid replacement hormones) is established. If overt hypothyroidism cannot be confirmed, patients are recommended to first have a trial without LT4 and a repeat serum TSH after 6 weeks.
For patients with overt hypothyroidism, prior to consideration of LT3, the dose of LT4 should be optimized to a TSH in the target range of 0.3-2.0 mU/L for 3 to 6 months. In some patients, it may be acceptable to have serum TSH below reference range (eg, 0.1-0.3 mU/L), but not fully suppressed in the long term, instead of starting LT3.
A trial of combination therapy may be warranted with confirmed overt hypothyroidism and persistent symptoms despite LT4 treatment and the exclusion of other comorbidities.
Clinicians should not feel obliged to start LT3 or continue LT3 medication provided by other healthcare practitioners or accessed without medical advice if they judge this not to be in the patient's best interest.
When opting for LT3, a minimum of 3 to 6 months on the combination therapy should be considered before determining response to the trial, and for assessment, monitoring with serum TSH only is recommended.
Patients should be counseled regarding the risk of arrhythmias, accelerated bone loss, and stroke associated with iatrogenic hyperthyroidism and the need for long-term monitoring.
Given the short half-life of LT3, splitting doses across 24 hours is recommended for many people.
The joint association does not recommend the use of desiccated thyroid extract (which appears to be surprisingly on the rise, as recently reported).

Reasons for Persistent Symptoms Are Murky; Don't Forget Menopause

The key reason for the emphasis on making sure patients have overt hypothyroidism before trying LT3 is that patients are often treated with LT4 despite not even having hypothyroidism to begin with.

"In reality, many patients with subclinical hypothyroidism [TSH 5-10 mU/L] are now treated with levothyroxine, fueling a rise in its use, such that it is now the third most frequently prescribed medication in the United Kingdom," the authors explain.

"In contrast, few patients are advised to seek lifestyle and exercise changes, despite the fact that there is positive evidence to support their benefits," they continue.

In a recent Medscape podcast, Anthony Bianco, MD, a past president of the ATA, underscores another important factor complicating the ability to make conclusive hypothyroidism diagnoses in women — menopause.

"In my experience, the most confusing factor [in treatment decisions] is menopausal syndrome," he said.

"The symptoms are very similar. Most patients with hypothyroidism are women. Are we getting close to menopause? Are we dealing with this? Is estrogen replacement therapy an option for this woman? Should we consult a colleague?" Bianco explained.

And there are other possibilities, including anemia, iron deficiency, other autoimmune diseases, and diabetes, he added.

"Exclude everything that you know," Bianco said. "Use your common sense."

Although the new statement echoes other guidelines, the recommendations are helpful amid the ever-present debate, said Wiersinga, the endocrinologist from the Netherlands.

Because of the pressure to try combination therapy, from patients and patient associations, the statement's position that doctors must stand by their clinical judgment is important, he noted.

"I think many doctors would welcome the recommendation that doctors are not obliged to prescribe any medication that they believe is not in the patient's best interest, and, in particular, that 'doctors have no obligation to continue to provide prescriptions for LT3 or desiccated thyroid extract that have been started by other healthcare practitioners or accessed without medical advice if they judge this not to be in the patient's best interest,'" he asserted.

"Also, the recommendation that an endocrinologist should be involved when a trial of T3 is considered is very valuable," he added, noting the potential scenario of patients going to a general practitioner if turned down by a specialist for LT3.

An international consensus statement published by members of the ATA, ETA, and British Thyroid Association in 2021, further set forth recommendations for the development of future trials of LT3/LT4 combination therapy to establish more conclusive guidance.

Senior author Simon H. Pearce has reported receiving speaker fees from IBSA, Merck, Quidel, Berlin-Chemie, and consulting for Apitope/Worg and Immunovant/Roivant on issues unrelated to T3. The other authors of the consensus statement have reported no relevant financial relationships. Wiersinga has reporting consulting for Prolevi Bio.

Clin Endocrinol. Published online June 5, 2023. Full text

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