Individualised requirements for optimum treatment of hypothyroidism: complex needs, limited options (original) (raw)
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The Turkish Journal of Endocrinology and Metabolism
Objective: Several lines of evidence suggest that the symptoms of hypothyroidism, including psychological symptoms and metabolic effects, persist in a significant percentage of patients treated with levothyroxine (L-T4). A hypothesis to explain this phenomenon is that the triiodothyronine (L-T3) serum levels may not be completely normalized. This study aimed to compare the level of serum free T3 (FT3) in patients who are biochemically euthyroid after L-T4 monotherapy with different underlying causes of hypothyroidism. Material and Methods: This cross-sectional study was conducted on patients with hypothyroidism who received L-T4 monotherapy and were biochemically euthyroid. The serum levels of thyroid-stimulating hormone (TSH), free T4 (FT4), FT3, and FT3/FT4 ratio were measured in these patients. Patients were divided into three groups based on the cause of hypothyroidism (radioiodine therapy, thyroidectomy and Hashimoto), and the results of biochemical tests of the thyroid were compared in three groups. Results: Of the 78 patients studied, 12 (15.4%) cases were male, and 66 (84.6%) cases were female. Among the variables studied, only the mean value of FT3 was significantly different in the three groups (p=0.006), where the highest mean value was seen in the Hashimoto group, and the lowest mean value was seen in the radioiodine therapy group. Conclusion: The results of this study showed that although hypothyroidism patients can be optimally treated with L-T4 alone, in many of these patients, the level of FT3 will not be in therapeutic range, and the mean serum FT3 levels in these patients could be related to their hypothyroidism causes.
Curēus, 2024
Background: Hypothyroidism is one of the most common endocrine disorders with a simple therapy, that is levothyroxine (LT4). A normal thyroid-stimulating hormone (TSH) measurement is used as a marker of optimal replacement. But, many patients still have symptoms. Triiodothyronine (T3), thyroxine (T4), and their ratio may correlate with clinical improvement. The study aims to assess the T3/T4 ratio as a marker of clinical response in patients with hypothyroidism. Method: A cross-sectional study was conducted from June to November 2022 at Faiha Specialized Diabetes, Endocrine, and Metabolism Center, in Basrah, southern Iraq. We included 48 adult patients with primary hypothyroidism on LT4 treatment only and TSH within the target reference range for at least within the last six months. Each patient was subjected to a questionnaire that was designed to capture hypothyroidismrelated complaints in the form of a five-point Likert scale. Biochemical assessments were done with the measurement of TSH, T3, and T4. Results: Despite having a normal TSH level, nearly all the patients had persistent and varying severity of clinical complaints of hypothyroidism. Tiredness, hair problems, weight gain, and cold intolerance were the most severely persistent symptoms. Patients with scores of two and more for weight gain, cold intolerance, and skin problems had significantly lower T3/T4 ratios (P = 0.04, 0.002, and 0.02, respectively), while in the remaining clinical symptoms, the T3/T4 ratio did not differ significantly. Conclusion: A low T3/T4 ratio was significantly associated with resistant symptoms of hypothyroidism and may be used as a marker for treatment efficacy with TSH rather than TSH value alone.
Frontiers in Endocrinology, 2019
Sodium salt of levothyroxine (L-T4) is the treatment of choice of hypothyroidism. Yet, L-T4 monotherapy produces supoptimal 3,5,3 ′-triiodothyronine (T3)/T4 ratio in serum, as compared to normal subjects, and a minority of hypothyroid individuals on L-T4 complain for an incomplete well-being. Orally administered 3,5,3 ′-triiodothyronine sulfate (T3S) can be converted to T3 in humans, resulting in steady-state serum T3 concentrations for up to 48 h. In this study (EudraCT number 2010-018663-42), 36 thyroidectomized hypothyroid patients receiving 100 (group A), 125 (group B), or 150 µg (group C) L-T4 were enrolled in a 75 days study in which 25 µg L-T4 were replaced by 40 µg of T3S. A significant, progressive reduction in mean FT4 values was observed, being the largest in the group A and the smallest in group C, while no relevant variations in FT3 and total T3 serum values were observed in the three groups. TSH serum levels increased in all groups, the highest value being observed in group A. Lipid parameters did not show clinically significant changes in all groups. No T3S-related changes in the safety laboratory tests were recorded. No adverse event was judged as related to experimental treatment, and no patient discontinued the treatment. Twelve patients judged the L-T4+T3S treatment better than L-T4 alone, while no patient reported a preference for L-T4 over the combined treatment. In conclusion, the results of this study indicate that a combination of L-T4+T3S in hypothyroid subjects may allow mainteinance of normal levels of serum T3, with restoration of a physiological FT4/FT3 ratio and no appearance of adverse events. Further studies are required to verify whether the LT4+T3S chronic combined treatment of hypothyroidism is able to produce additional benefits over L-T4 monotherapy.
Thyroid research, 2018
Whilst trials of combination levothyroxine/liothyronine therapy versus levothyroxine monotherapy for thyroid hormone replacement have not shown any superiority, there remains a small subset of patients who do not feel well on monotherapy. Whilst current guidelines do not suggest routine use of combination therapy they do acknowledge a trial in such patients may be appropriate. It appears that use of combination therapy and dessicated thyroid extract is not uncommon but often being used by non-specialists and not adequately monitored. This review aims to provide practical advice on selecting patients, determining dose and monitoring of such a trial. It is important to select the correct patient for a trial so as to not delay diagnosis or potentially worsen an undiagnosed condition. An appropriate starting dose may be calculated but accuracy is limited by available formulations and cost. Monitoring of thyroid function, benefits and adverse effects are vital in the trial setting given ...
Time for a reassessment of the treatment of hypothyroidism
BMC Endocrine Disorders
Background: In the treatment for hypothyroidism, a historically symptom-orientated approach has given way to reliance on a single biochemical parameter, thyroid stimulating hormone (TSH). Main body: The historical developments and motivation leading to that decision and its potential implications are explored from pathophysiological, clinical and statistical viewpoints. An increasing frequency of hypothyroid-like complaints is noted in patients in the wake of this directional shift, together with relaxation of treatment targets. Recent prospective and retrospective studies suggested a changing pattern in patient complaints associated with recent guideline-led low-dose policies. A resulting dramatic rise has ensued in patients, expressing in various ways dissatisfaction with the standard treatment. Contributing factors may include raised problem awareness, overlap of thyroid-related complaints with numerous non-specific symptoms, and apparent deficiencies in the diagnostic process itself. Assuming that maintaining TSH anywhere within its broad reference limits may achieve a satisfactory outcome is challenged. The interrelationship between TSH, free thyroxine (FT4) and free triiodothyronine (FT3) is patient specific and highly individual. Population-based statistical analysis is therefore subject to amalgamation problems (Simpson's paradox, collider stratification bias). This invalidates group-averaged and range-bound approaches, rather demanding a subject-related statistical approach. Randomised clinical trial (RCT) outcomes may be equally distorted by intra-class clustering. Analytical distinction between an averaged versus typical outcome becomes clinically relevant, because doctors and patients are more interested in the latter. It follows that population-based diagnostic cutoffs for TSH may not be an appropriate treatment target. Studies relating TSH and thyroid hormone concentrations to adverse effects such as osteoporosis and atrial fibrillation invite similar caveats, as measuring TSH within the euthyroid range cannot substitute for FT4 and FT3 concentrations in the risk assessment. Direct markers of thyroid tissue effects and thyroid-specific quality of life instruments are required, but need methodological improvement. Conclusion: It appears that we are witnessing a consequential historic shift in the treatment of thyroid disease, driven by over-reliance on a single laboratory parameter TSH. The focus on biochemistry rather than patient symptom relief should be reassessed. A joint consideration together with a more personalized approach may be required to address the recent surge in patient complaint rates.
European Thyroid Journal
Association guidelines. Based on patient-reported outcome, they were divided into responders and nonresponders. Results: Five patients were lost to follow-up and thus excluded. At the 3-month follow-up, 11 were classified as nonresponders and 26 as responders. At 12 months these figures had changed to 13 (35%) and 24 (65%), respectively. When comparing responders versus nonresponders, no differences were seen at baseline or during follow-up in S-T 3 and in free T 3 estimates. Further, logistic regression showed no correlation between S-T 3 and free T 3 estimates and responder/nonresponder status. Conclusion: Our data indicate that serum T 3 measurements are not suitable to predict which patient will benefit from L-T 4 /L-T 3 combination therapy, and treatment response cannot be followed by repeated T 3 measurements either.
Thyroid
Background: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. Methods: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/ LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Results: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 lg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. Discussion: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.
Journal of Thyroid Research
Randomised controlled trials are deemed to be the strongest class of evidence in evidence-based medicine. Failure of trials to prove superiority of T3/T4 combination therapy over standard LT4 monotherapy has greatly influenced guidelines, while not resolving the ongoing debate. Novel studies have recently produced more evidence from the examination of homeostatic equilibria in humans and experimental treatment protocols in animals. This has exacerbated a serious disagreement with evidence from the clinical trials. We contrasted the weight of statistical evidence against strong physiological counterarguments. Revisiting this controversy, we identify areas of improvement for trial design related to validation and sensitivity of QoL instruments, patient selection, statistical power, collider stratification bias, and response heterogeneity to treatment. Given the high individuality expressed by thyroid hormones, their interrelationships, and shifted comfort zones, the response to LT4 tr...