The Joint British Thyroid Association/Society has updated its guidelines, suggesting that liothyronine (LT3) could be beneficial when used alongside standard levothyroxine (LT4) in treating hypothyroidism. This recommendation applies to a small subset of patients who continue to experience symptoms despite undergoing standard treatment.
Rupa Ahluwalia, MBBS, MD, of Norfolk and Norwich University Hospitals NHS Trust, UK, and colleagues recently published this consensus statement in Clinical Endocrinology.
LT3/LT4 Combination Therapy: A Contentious Issue
The application of LT3/LT4 combination therapy has been a subject of dispute for over two decades. Despite 16 randomized controlled trials and four meta-analyses failing to demonstrate any significant benefits of the combined regimen over LT4 monotherapy, the debate continues. Many patients still report experiencing benefits from the combination therapy.
Wilmar M. Wiersinga, MD, Ph.D., an emeritus professor of endocrinology at the University of Amsterdam, acknowledges the divide within the scientific community regarding the value of LT4/LT3 combination therapy. However, he welcomes the joint statement as it provides valuable guidance on this controversial issue.
The Quest for Alternative Treatments Amid Persistent Symptoms
Thyroxine, also known as T4, is a hormone produced in the body, with its pharmaceutical replacement product being levothyroxine (LT4). Triiodothyronine, or T3, is another hormone produced in the body, with liothyronine (LT3) being its pharmaceutical replacement.
Despite the normalization of biochemical levels following LT4 treatment, a significant proportion of hypothyroid patients continue to experience symptoms such as fatigue, sleepiness, memory problems, cognitive issues (brain fog), and weight gain. This persistence of symptoms has driven the exploration of alternative treatments, including LT3/LT4 combination therapy and the use of desiccated thyroid extract (DTE).
Guidelines for Considering LT3/LT4 Combination Therapy
Both the European Thyroid Association (ETA) and American Thyroid Association (ATA) have previously accepted the practice of prescribing combination therapy. The new joint statement from the British Thyroid Association/Society echoes this sentiment but emphasizes that most hypothyroid patients should primarily be treated with levothyroxine alone.
However, the guidelines do outline certain conditions under which LT3/LT4 combination therapy may be considered. These include:
- Diagnosed overt hypothyroidism (documented TSH ≥ 10 mU/L and/or low FT4 pretreatment with thyroid replacement hormones).
- LT4 dosage optimization to a TSH target range of 0.3-2.0 mU/L for 3 to 6 months before considering LT3.
- LT3/LT4 combination therapy trial may be warranted if symptoms persist despite LT4 treatment and other comorbidities have been ruled out.
- Healthcare practitioners should not feel obligated to start or continue LT3 medication if they believe it’s not in the patient’s best interest.
- A minimum of 3 to 6 months on the combination therapy should be considered before assessing the response to the trial.
- Patients should be informed about the risks of arrhythmias, accelerated bone loss, and stroke associated with iatrogenic hyperthyroidism and the need for long-term monitoring.
- Due to LT3’s short half-life, splitting doses across 24 hours is recommended for many people.
The joint association does not recommend the use of desiccated thyroid extract (DTE), an old medication used to treat hypothyroidism, made from the dried thyroid glands of animals.
Reasons for Persistent Symptoms Are Murky; Don’t Forget Menopause
One of the key factors complicating hypothyroidism diagnosis and treatment is the similarity of symptoms with other conditions, such as menopausal syndrome. This overlap can lead to misdiagnosis and inappropriate treatment with levothyroxine (LT4), contributing to its rise as the third most frequently prescribed medication in the UK.
The Conundrum of Subclinical Hypothyroidism
The authors of the recent consensus statement stress the importance of confirming overt hypothyroidism before considering combination therapy. Unfortunately, many patients with subclinical hypothyroidism [TSH 5-10 mU/L] are being treated with LT4 despite lacking a clear diagnosis of hypothyroidism.
Instead of pharmaceutical intervention, these patients could benefit from lifestyle modifications and exercise routines which have proven benefits. However, this advice is often overlooked in favor of prescribing medication.
The Menopause Factor
Anthony Bianco, MD, a past president of the ATA, identifies menopausal syndrome as a significant confounding factor in diagnosing and treating hypothyroidism. “In my experience, the most confusing factor [in treatment decisions] is menopausal syndrome,” he said.
Symptoms of menopause and hypothyroidism can be strikingly similar, leading to potential misdiagnoses. Bianco suggests that estrogen replacement therapy could be an option for some women experiencing these symptoms and recommends consulting with specialists to ensure a correct diagnosis.
Other possible causes of persistent symptoms include anemia, iron deficiency, other autoimmune diseases, and diabetes. Bianco’s advice is clear: “Exclude everything that you know. Use your common sense.”
Maintaining Clinical Judgment Amid Pressure
Wilmar M. Wiersinga, an endocrinologist from the Netherlands, appreciates the new consensus statement for its reinforcement of clinical judgment. Amid pressure from patients and patient associations to try combination therapy, doctors must stand by their expertise and not feel obliged to prescribe any medication that they believe is not in the patient’s best interest.
This includes no obligation to continue prescriptions for LT3 or desiccated thyroid extract started by other healthcare practitioners or accessed without medical advice if they deem it not to be in the patient’s best interest.
He further commends the recommendation for involving an endocrinologist when considering a trial of T3, recognizing the potential scenario of patients seeking general practitioners if denied LT3 by a specialist.
An international consensus statement published by members of the ATA, ETA, and British Thyroid Association in 2021 set forth recommendations for future trials of LT3/LT4 combination therapy, aiming to establish more conclusive guidance in this contentious area of endocrinology.