Time for a reassessment of the treatment of hypothyroidism (original) (raw)
Related papers
Frontiers in Endocrinology, 2022
In recent years evidence has accumulated supporting a revised view of the nature of euthyroidism and the biomarkers of thyroid function. Within the normal range, variations in thyroid hormone levels are associated with variations in clinical parameters and outcomes. There are therefore no readily identified individually specific optimum levels of thyroid hormones for any individual. Levels around the middle of the normal population range may best reflect euthyroidism. These levels may have evolutionary advantages on the basis that adverse outcomes often increase with divergence from such levels, and physiological processes tend to minimise such inter-individual and intra-individual divergence. In populations of predominantly untreated individuals, levels of thyroid hormones and in particular levels of free thyroxine (FT4) correlate more often with clinical parameters than do levels of thyrotropin (TSH). Levels of thyroid hormones may therefore be regarded as the best available biomarkers of euthyroidism and dysthyroidism. It follows that 'subclinical hypothyroidism' (normal FT4/raised TSH levels), rather than being an accurate marker of peripheral tissue hypothyroidism is more a marker of decreased thyroid reserve and prognosis. The recent evidence suggests that treatment of hypothyroxinemia, regardless of the TSH level, and monitoring therapy using FT4 and/ or triiodothyronine levels, depending on the replacement regime, may result in more successful treatment of hypothyroidism than relying on thyrotropin levels for patient selection and subsequent treatment monitoring. The equivalents of mid-range levels of thyroid hormones (especially FT4), adjusted by individual comorbidity concerns, may be rational general replacement targets. These implications of the new evidence may create opportunities for novel trials of thyroid replacement therapy.
Individualised requirements for optimum treatment of hypothyroidism: complex needs, limited options
Drugs in Context, 2019
Levothyroxine (LT4) therapy has a long history, a well-defined pharmacological profile and a favourable safety record in the alleviation of hypothyroidism. However, questions remain in defining the threshold for the requirement of treatment in patients with subclinical hypothyroidism, assessing the dose adequacy of the drug, and selecting the best treatment mode (LT4 monotherapy versus liothyronine [LT3]/LT4 combinations) for subpopulations with persisting complaints. Supplied as a prodrug, LT4 is enzymatically converted into the biologically more active thyroid hormone, triiodothyronine (T3). Importantly, tetraiodothyronine (T4) to T3 conversion efficiency may be impaired in patients receiving LT4, resulting in a loss of thyroid-stimulating hormone (TSH)-mediated feed-forward control of T3, alteration of the interlocking equilibria between serum concentrations of TSH, free thyroxine (FT4), and free triiodothyonine (FT3), and a decrease in FT3 to FT4 ratios. This downgrades the value of the TSH reference system derived in thyroid health for guiding the replacement dose in the treatment situation. Individualised conditionally defined setpoints may therefore provide appropriate biochemical targets to be clinically tested, together with a stronger focus on clinical presentation and future endpoint markers of tissue thyroid state. This cautionary note encompasses the use of aggregated statistical data from clinical trials which are not safely applicable to the individual level of patient care under these circumstances.
BMJ, 2019
Objective To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures. Design Retrospective cohort study. Setting The Health Improvement Network (THIN), a database of electronic patient records from UK primary care. Participants Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017. Exposure TSH concentration in patients with hypothyroidism. Main outcome measures Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome. Results 162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)). Conclusions In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.
Thyroid, 2020
Background: Though the functional states of other endocrine systems are not defined on the basis of levels of controlling hormones, the assessment of thyroid function is based on levels of the controlling hormone thyrotropin (TSH). We, therefore, addressed the question as to whether levels of thyroid hormones [free thyroxine (fT4), total triiodothyronine (TT3)/free triiodothyronine (fT3)], or TSH levels, within and beyond the reference ranges, provide the better guide to the range of clinical parameters associated with thyroid status. Methods: A PubMed/MEDLINE search of studies up to October 2019, examining associations of levels of thyroid hormones and TSH, taken simultaneously in the same individuals, with clinical parameters was performed. We analyzed atrial fibrillation, other cardiac parameters, osteoporosis and fracture, cancer, dementia, frailty, mortality, features of the metabolic syndrome, and pregnancy outcomes. Studies were assessed for quality by using a modified Newcastle-Ottawa score. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. A meta-analysis of the associations was performed to determine the relative likelihood of fT4, TT3/fT3, and TSH levels that are associated with the clinical parameters. Results: We identified 58 suitable articles and a total of 1880 associations. In general, clinical parameters were associated with thyroid hormone levels significantly more often than with TSH levels-the converse was not true for any of the clinical parameters. In the 1880 considered associations, fT4 levels were significantly associated with clinical parameters in 50% of analyses. The respective frequencies for TT3/fT3 and TSH levels were 53% and 23% (p < 0.0001 for both fT4 and TT3/fT3 vs. TSH). The fT4 and TT3/fT3 levels were comparably associated with clinical parameters (p = 0.71). More sophisticated statistical analyses, however, indicated that the associations with TT3/fT3 were not as robust as the associations with fT4. Conclusions: Thyroid hormones levels, and in particular fT4 levels, seem to have stronger associations with clinical parameters than do TSH levels. Associations of clinical parameters with TSH levels can be explained by the strong negative population correlation between thyroid hormones and TSH. Clinical and research components of thyroidology currently based on the measurement of the thyroid state by reference to TSH levels warrant reconsideration.
Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. Results: We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non–levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones. Conclusions: We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine– liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior bio-markers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine
Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. Results: We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxinebased thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones. Conclusions: We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxineliothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine
Review Article TSH Levels in Subclinical Hypothyroidism in the 97.5th Percentile of the Population
e debate regarding the cutoff point in the treatment of patients with subclinical hypothyroidism (Shypo) is ongoing. Generally, two different groups are identified for treatment by levels of 10 and 20 mIU/L. Nevertheless, the question remains, "what cutoff point should be chosen?" We have written a selective nonsystematic review focused on the 97.5 percentile reference value reported in healthy subjects in a number of countries and observed important disparities, which partly show the challenge of identifying a single cutoff point for those patients needing medication. We identified studies of TSH on the natural history of subclinical hypothyroidism from population-based prospective cohort studies, which follow up patients for several years. e evolution of TSH levels in these patients is variable. Some cases of TSH may return to lower levels at different stages over the years, but others may not, possibly even developing into overt thyroid failure, also variable. We analyzed factors that may explain the normalization of serum TSH levels. In addition, we found that thorough population-based prospective cohort studies following up on TSH levels, thyroid antibodies, and ultrasonography are important in decisions made in the treatment of patients. However, the 97.5 percentile reference value varies in different countries; therefore, an international cutoff point for subclinical hypothyroidism cannot be recommended.
TSH Levels in Subclinical Hypothyroidism in the 97.5th Percentile of the Population
International Journal of Endocrinology, 2020
The debate regarding the cutoff point in the treatment of patients with subclinical hypothyroidism (Shypo) is ongoing. Generally, two different groups are identified for treatment by levels of 10 and 20 mIU/L. Nevertheless, the question remains, “what cutoff point should be chosen?” We have written a selective nonsystematic review focused on the 97.5 percentile reference value reported in healthy subjects in a number of countries and observed important disparities, which partly show the challenge of identifying a single cutoff point for those patients needing medication. We identified studies of TSH on the natural history of subclinical hypothyroidism from population-based prospective cohort studies, which follow up patients for several years. The evolution of TSH levels in these patients is variable. Some cases of TSH may return to lower levels at different stages over the years, but others may not, possibly even developing into overt thyroid failure, also variable. We analyzed fac...
Journal of Thyroid Research
The pituitary hormone, thyrotropin (TSH), is regarded as the primary biomarker for evaluating thyroid function and is useful in guiding treatment with levothyroxine for patients with hypothyroidism. The amplified response of TSH to slight changes in thyroid hormone levels provides a large and easily measured signal in the routine care setting. Laboratories provide reference ranges with upper and lower cutoffs for TSH to define normal thyroid function. The upper limit of the range, used to diagnose subclinical (mild) hypothyroidism, is itself a matter for debate, with authoritative guidelines recommending treatment to within the lower half of the range. Concomitant diseases, medications, supplements, age, gender, ethnicity, iodine status, time of day, time of year, autoantibodies, heterophilic antibodies, smoking, and other factors influence the level of TSH, or the performance of current TSH assays. The long-term prognostic implications of small deviations of TSH from the reference ...