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Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study.

ABSTRACT: 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.

SUBMITTER: Thayakaran R

PROVIDER: S-EPMC6719286 | biostudies-other | 2019 Sep

REPOSITORIES: biostudies-other

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Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study.

Thayakaran Rasiah R Adderley Nicola J NJ Sainsbury Christopher C Torlinska Barbara B Boelaert Kristien K Šumilo Dana D Price Malcolm M Thomas G Neil GN Toulis Konstantinos A KA Nirantharakumar Krishnarajah K

BMJ (Clinical research ed.) 20190903

<h4>Objective</h4>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.<h4>Design</h4>Retrospective cohort study.<h4>Setting</h4>The Health Improvement Network (THIN), a database of electronic patient records from UK primary care.<h4>Participants</h4>Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 20 ...[more]

PMID: 31481394

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Project description:BACKGROUND:Overt thyroid dysfunction has been associated with adverse obstetric outcomes. However, less is known regarding subclinical hypothyroidism or thyroid autoimmunity and their relationship to pregnancy complications. OBJECTIVE:The purpose of this study was to examine the association between prepregnancy anti-thyroid antibodies and subclinical hypothyroidism and preterm delivery, gestational diabetes mellitus, and preeclampsia. STUDY DESIGN:We conducted a secondary analysis of a prospective cohort of 18- to 40-year-old women with 1-2 previous pregnancy losses (n=1193) who participated in a multicenter randomized, placebo-controlled trial of low-dose aspirin. Prepregnancy levels of thyroid-stimulating hormone, free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibody were measured. Relative risks and 95% confidence intervals were estimated with the use of generalized linear models with adjustment for age and body mass index. RESULTS:Among women with an ongoing pregnancy of >20 weeks estimated gestational age, there was no association between prepregnancy thyroid-stimulating hormone level (>2.5 vs ?2.5 mIU/L) and preterm delivery (adjusted relative risk, 0.77; 95% confidence interval, 0.40-1.47), gestational diabetes mellitus (adjusted relative risk, 1.28; 95% confidence interval, 0.54-3.04), or preeclampsia (adjusted relative risk, 1.20; 95% confidence interval, 0.71-2.04). Similarly, among women with thyroid antibodies, there was no increase in the likelihood of preterm delivery (relative risk, 1.26; 95% confidence interval, 0.65-2.45), gestational diabetes mellitus (relative risk, 1.33; 95% confidence interval, 0.51-3.49), or preeclampsia (relative risk, 1.02; 95% confidence interval, 0.54-1.92), compared with women without these antibodies. CONCLUSION:Among women with 1-2 previous pregnancy losses, subclinical hypothyroidism and thyroid autoimmunity were not associated with an increased risk of preterm delivery, gestational diabetes mellitus, or preeclampsia. These data support current recommendations that low-risk asymptomatic women should not be screened routinely for thyroid dysfunction or autoimmunity.

Project description:BackgroundA 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.MethodsTask 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.ResultsWe 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.ConclusionsWe 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 biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile.

Project description:Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers but are recognized to cause treatment-limiting immune-related adverse events (IrAE). ICI-associated thyroiditis is the most common endocrine IrAE and usually resolves to permanent hypothyroidism. Optimal thyroid hormone replacement in these patients remains unclear. We report the levothyroxine (LT4) dose needed to achieve stable euthyroid state in patients with hypothyroidism from ICI-associated thyroiditis, with comparison to patients with Hashimoto's thyroiditis (HT) and athyreotic state. Methods: We conducted a retrospective study of adults with ICI-associated hypothyroidism treated with LT4 at an academic medical center. Patient data were collected from the electronic medical record. Cases had ICI exposure followed first by hyperthyroidism and then subsequent hypothyroidism. Controls were HT (positive thyroid autoantibodies, requiring LT4) and athyreotic (total thyroidectomy or radioiodine ablation, requiring LT4) patients. Patients with central hypothyroidism, thyroid cancer, pregnancy, gastrointestinal stromal tumors, and use of L-triiodothyronine were excluded. Our primary outcome compared LT4 dose needed to achieve euthyroid state (thyrotropin 0.3-4.7 mIU/L over >6 consecutive weeks) for ICI-associated hypothyroidism, HT, and athyreotic patients, considering the impact of age and possible interfering medications by linear regression modeling. Secondary analysis considered the impact of endocrine specialty care on the time to euthyroid state. Results: One hundred three patients with ICI-associated thyroiditis were identified. Sixty-six of the 103 patients achieved euthyroid state; 2 with intrinsic thyroid gland function recovery and 64 on LT4. The mean LT4 dose achieving stable euthyroid state was 1.45 ± standard deviation (SD) 0.47 mcg/[kg·day] in ICI-associated hypothyroidism, 1.25 ± SD 0.49 mcg/[kg·day] in HT, and 1.54 ± SD 0.38 mcg/[kg·day] in athyreotic patients, using actual body weight. The difference in dose between ICI-associated hypothyroidism and HT was statistically significant (p = 0.0093). Dosing differences were not explained by age or use of interfering medications. Conclusions: ICI-associated thyroiditis represents an increasingly recognized cause of hypothyroidism. Our study demonstrates that patients with ICI-associated hypothyroidism have different thyroid hormone dosing requirements than patients with HT. Based on our findings and prior reports, we recommend that in patients with ICI-associated thyroiditis LT4 therapy be started at an initial weight-based dose of 1.45 mcg/[kg·day] once serum free thyroxine levels fall below the reference range.

Project description:BACKGROUND:Subclinical hypothyroidism (SCH) is a common condition in elderly people, defined as elevated serum thyroid-stimulating hormone (TSH) with normal circulating free thyroxine (fT4). Evidence is lacking about the effect of thyroid hormone treatment. We describe the protocol of a large randomised controlled trial (RCT) of Levothyroxine treatment for SCH. METHODS:Participants are community-dwelling subjects aged ?65 years with SCH, diagnosed by elevated TSH levels (?4.6 and ?19.9 mU/L) on a minimum of two measures???three months apart, with fT4 levels within laboratory reference range. The study is a randomised double-blind placebo-controlled parallel group trial, starting with levothyroxine 50 micrograms daily (25 micrograms in subjects <50Kg body weight or known coronary heart disease) with titration of dose in the active treatment group according to TSH level, and a mock titration in the placebo group. The primary outcomes are changes in two domains (hypothyroid symptoms and fatigue / vitality) on the thyroid-related quality of life questionnaire (ThyPRO) at one year. The study has 80% power (at p?=?0.025, 2-tailed) to detect a change with levothyroxine treatment of 3.0% on the hypothyroid scale and 4.1% on the fatigue / vitality scale with a total target sample size of 750 patients. Secondary outcomes include general health-related quality of life (EuroQol), fatal and non-fatal cardiovascular events, handgrip strength, executive cognitive function (Letter Digit Coding Test), basic and instrumental activities of daily living, haemoglobin, blood pressure, weight, body mass index and waist circumference. Patients are monitored for specific adverse events of interest including incident atrial fibrillation, heart failure and bone fracture. DISCUSSION:This large multicentre RCT of levothyroxine treatment of subclinical hypothyroidism is powered to detect clinically relevant change in symptoms / quality of life and is likely to be highly influential in guiding treatment of this common condition. TRIAL REGISTRATION:Clinicaltrials.gov NCT01660126 ; registered 8th June 2012.

Project description:Thyroid hormone is a potent stimulator of metabolism, playing a critical role in regulating energy expenditure and in key physiological mechanisms, such as growth and development. Although administration of thyroid hormone in the form of levo thyroxine (l-thyroxine) has been used to treat hypothyroidism for many years, the precise molecular basis of its physiological actions remains uncertain. Our objective was to define the changes in circulating protein levels that characterize alterations in thyroid hormone status. To do this, an integrated untargeted proteomic approach with network analysis was used. This study included 10 age-matched subjects with newly diagnosed overt hypothyroidism. Blood was collected from subjects at baseline and at intervals post-treatment with l-thyroxine until they reached to euthyroid levels. Plasma protein levels were compared by two-dimensional difference in gel electrophoresis (2D-DIGE) pre- and post-treatment. Twenty differentially expressed protein spots were detected. Thirteen were identified, and were found to be unique protein sequences by MALDI-TOF mass spectrometry. Ten proteins were more abundant in the hypothyroid vs. euthyroid state: complement C2, serotransferrin, complement C3, Ig κ chain C region, α-1-antichymotrypsin, complement C4-A, haptoglobin, fibrinogen α chain, apolipoprotein A-I, and Ig α-1 chain C region. Three proteins were decreased in abundance in the hypothyroid vs. euthyroid state: complement factor H, paraneoplastic antigen-like protein 6A, and α-2-macroglobulin. The differentially abundant proteins were investigated by Ingenuity Pathway Analysis (IPA) to reveal their associations with known biological functions. Their connectivity map included interleukin-6 (IL-6) and tumour necrosis factor α (TNF-α) as central nodes and the pathway identified with the highest score was involved in neurological disease, psychological disorders, and cellular movement. The comparison of the plasma proteome between the hypothyroid vs euthyroid states revealed differences in the abundance of proteins involved in regulating the acute phase response.

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Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study.

Publications

Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study.

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