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Prof Bianco wrote: The authors are concerned with the increasing utilization of LT3 in the treatment of hypothyroidism" Title: "Limiting the use and misuse of liothyronine in hypothyroidism"
Note: Bianco doesn't personally comment on it. There is no online access to it at the moment, but I've been sent it as a PDF. I'll paste below; apologies for the length. Take a deep breath.
Limiting the use and misuse of liothyronine in hypothyroidism
Authors: Laszlo Hegedüs, Endre Vezekenyi Nagy, Enrico Papini & Petros Perros
Liothyronine treatment for some patients with hypothyroidism has preoccupied academics, clinicians and patients for decades, and is a controversial topic in thyroidology. Persistent symptoms are at the heart of this discourse and, contrary to scientific evidence, liothyronine use is increasingly common. Aetiologies and interventions beyond thyroid dysregulation and pharmacological approaches must be pursued.
Over the past 20 years, prescriptions for thyroid hormones, including liothyronine, have increased (1), which mirrors a downward trend in the threshold of thyroid-stimulating hormone (TSH) levels at which thyroid hormone therapy is commenced (2). The majority of people being treated for hypothyroidism either have mild (subclinical) hypothyroidism or were euthyroid before starting treatment. One of several reasons for the inclination to treat people who are euthyroid is the misconception that symptoms that are compatible with hypothyroidism are more reliable than thyroid function biochemistry in the diagnosis of hypothyroidism (2). If symptom relief is the goal, then therapeutic failure and disappointment is assured for this group of patients.
Drivers for these increases in diagnoses and treatment include misinformation (especially internet-enabled misinformation) about symptom attribution and ‘direct-to-consumer’ thyroid function tests, which circumvent professional clinical assessment and facilitate indiscriminate biochemical screening for thyroid dysfunction. Physician-related contributors include a lack of appreciation that common hypothyroid-like symptoms (such as fatigue, brain fog, mood swings and weight gain) are associated with a low pretest probability of detecting overt hypothyroidism, pressure from patients to perform unnecessary tests and to be treated with thyroid hormones, and a willingness to prescribe levothyroxine for people who are euthyroid for non-evidence based-indications (2). Unexplained persistent symptoms are at the centre of diagnostic and therapeutic inflation.
The suggestion that combination treatment (levothyroxine and liothyronine) might be an antidote to persistent symptoms comes from evidence extrapolated from some elegant rodent experiments. This low tissue tri-iodothyronine (T3) hypothesis has been tested in patients with hypothyroidism in a large number (n = 19) of randomized controlled trials(1). Systematic reviews and a meta-analysis have concluded that combination treatment is not better than levothyroxine monotherapy in alleviating patient symptoms and impaired quality of life (1). Yet, liothyronine is still prescribed and its advocates justify it by citing real-life experiences.
Individual testimonies from patients who are treated with liothyronine contrast with findings from randomized controlled trials. Transformative recoveries following treatment with liothyronine are regularly reported(3). However, these reports need to be interpreted with caution. Surveys have shown that a large proportion of people who are treated with liothyronine continue to be symptomatic and to have a poor quality of life(1). Those with good responses might represent true examples of low tissue T3, adequately addressed by liothyronine. In our experience, many patients receiving liothyronine are overtreated and might experience an enhanced sense of wellbeing as a result of overuse and misuse of liothyronine (4) Patients treated with liothyronine have usually been repeatedly denied it by their physician and have completed an arduous journey before accessing such medication. In such cases, belief perseverance might prevail when the result is disappointing.
There are at least two additional contributors to the extraordinary phenomenon of the use (and misuse) of liothyronine continuing to rise, despite robust evidence of non-superiority of combination treatment over levothyroxine monotherapy. First, published guidelines by professional organizations have produced ambiguous recommendations on this topic, which are widely open to interpretation(5,6). Second, some influential experts are focused on combination treatment as the principal remedy for persistent symptoms, and allow little room for exploration of other approaches.
Overtreatment with levothyroxine (and probably liothyronine), leading to low (and particularly suppressed) serum levels of TSH, is associated with increased risks of cardiovascular morbidity, osteoporosis, dementia and death (2). Use of liothyronine often leads to low serum levels of TSH3. A study published in 2022 has highlighted an excess risk of heart failure and stroke in patients treated with liothyronine (7). In this retrospective, propensity-matched study in Korea including 1,434 people taking liothyronine and 3,908 taking levothyroxine alone (34.7% and 40.1%, respectively, had a history of thyroid cancer), the use of liothyronine was associated with increased incidence of heart failure and stroke in patients with a longer duration of liothyronine use and a history of thyroid cancer. The risk of stroke was also higher in people taking liothyronine who did not have a history of thyroid cancer and had ≥52 weeks of liothyronine treatment, as compared with people taking levothyroxine alone (7). The potential consequences of failing to address all possible root causes of persistent symptoms and offering a treatment that could be no more effective than what patients are already receiving raises additional ethical concerns.
The non-superiority of combination treatment over levothyroxine should not surprise us, as there is no consistent correlation between serum levels of T3 and persistent symptoms (8). Furthermore, the symptoms that combination treatment aims to address are exceedingly common and widely experienced by the non-hypothyroid population and people with other morbidities. Titrating thyroid hormones against symptoms that often fluctuate widely and unpredictably is inherently problematic. Therefore, it is necessary to consider alternative possibilities. Exclusion of comorbidities (such as other autoimmune diseases) is recommended by guidelines and is probably done effectively by most physicians. However, the role of ‘medically not yet explained symptoms’ (MNYES) is often unappreciated (2).
Endocrinologists usually do not receive training in recognizing and managing MNYES. Yet, up to 30% of patients attending internal medicine outpatient clinics have MNYES2. A large international survey of people treated with thyroid hormones has revealed a high prevalence (58.6%) of probable somatic symptom disorder, a diagnosis that is closely related to MNYES9. The same survey showed that type D personality (a vulnerability factor for general psychological distress related to somatic symptom disorder and MNYES) was present in 54.2% of respondents (10). Both somatic symptom disorder and type D personality were associated with the perception that symptoms were poorly controlled by thyroid medication and with dissatisfaction with care and treatment.
The diagnosis of MNYES is reached by excluding other causes of symptoms. An empathetic approach during the medical consultation and reassurance that there is no underlying serious cause (a skill set that should be in the toolbox of every physician) can help most people presenting with MNYES. For more difficult cases, collaboration with primary care physicians and sometimes input from other healthcare professionals is needed (2).
In summary, the conundrum of unexplained persistent symptoms in people treated with thyroid hormones poses a considerable challenge for both patients and physicians. This hypothyroid controversy has featured in every annual meeting of the European and American thyroid associations over the past decade. Consensus has not been reached, and progress is limited by the narrow view that it can be fixed by finding an elixir with the right mix of levothyroxine and liothyronine. In our view, the negative randomized controlled trials do not invalidate the low tissue T3 hypothesis. However, the evidence suggests that it is much rarer than has been proposed. If MNYES is the true elephant in the room, then low tissue T3 is the mouse in the corner. Both live in the echo chamber of the hypothyroid controversy.
Limiting the overuse and misuse of liothyronine requires an honest and unbiased consideration of both elephant and mouse.
Published online: 24 October 2024
References
1. Hegedüs, L. et al. Primary hypothyroidism and quality of life. Nat. Rev. Endocrinol. 18, 230–242 (2022).
2. Hegedüs, L. et al. Medically not yet explained symptoms in hypothyroidism. Nat. Rev. Endocrinol. 20, 685–693 (2024).
3. Michaelsson, L. F. et al. Treating hypothyroidism with thyroxine/triiodothyronine combination therapy in Denmark: following guidelines or following trends? Eur. Thyroid J. 4, 174–180 (2015).
4. Perros, P. & Hegedüs, L. Enhanced well-being associated with thyrotoxicosis: a neglected effect of thyroid hormones? Int. J. Endocrinol. Metab. 20, e127230 (2022). 5. Bianco, A. C. & Taylor, P. N. Optimizing the treatment of hypothyroidism. Nat. Rev. Endocrinol. 20, 379–380 (2024).
6. Biondi, B., Celi, F. S. & McAninch, E. A. Critical approach to hypothyroid patients with persistent symptoms. J. Clin. Endocrinol. Metab. 108, 2708–2716 (2023).
7. Yi, W. et al. Heart failure and stroke risks in users of liothyronine with or without levothyroxine compared with levothyroxine alone: a propensity score-matched analysis. Thyroid 32, 764–771 (2022).
8. Medici, B. B., la Cour, J. L., Michaelsson, L. F., Faber, J. O. & Nygaard, B. Neither baseline nor changes in serum triiodothyronine during levothyroxine/liothyronine combination therapy predict a positive response to this treatment modality in hypothyroid patients with persistent symptoms. Eur. Thyroid J 6, 89–93 (2017).
9. Perros, P. et al. Hypothyroidism and somatization: results from E-Mode Patient Self-Assessment of Thyroid Therapy, a cross-sectional, international online patient survey. Thyroid 33, 927–939 (2023).
10. Perros, P. et al. Hypothyroidism and type D personality: results from E-MPATHY, a cross- sectional international online patient survey. J. Clin. Endocrinol. Metab. doi.org/ 10.1210/clinem/dgae140 (2024).
Nature reviews endocrinology Volume 21 | January 2025 | 3–4 | 4
Interesting page I Found On Hypothyroidism
