Serum Thyroid Function, Mortality and Disability in Advanced Old Age: The Newcastle 85+ Study

Context: Perturbations in thyroid function are common in older individuals but their significance in the very old is not fully understood. Objective: This study sought to determine whether thyroid hormone status and variation of thyroid hormones within the reference range correlated with mortality and disability in a cohort of 85-year-olds. Design: A cohort of 85-year-old individuals were assessed in their own homes (community or institutional care) for health status and thyroid function, and followed for mortality and disability for up to 9 years. Setting and Participants: Six hundred and forty-three 85-year-olds registered with participating general practices in Newcastle and North Tyneside, United Kingdom. Main Outcomes: All-cause mortality, cardiovascular mortality, and disability according to thyroid disease status and baseline thyroid hormone parameters (serum TSH, FT4, FT3, and rT3). Models were adjusted for age, sex, education, body mass index, smoking, and disease count. Results: After adjustment for age and sex, all-cause mortality was associated with baseline serum rT3 and FT3 (both P < .001), but not FT4 or TSH. After additional adjustment for potential confounders, only rT3 remained significantly associated with mortality (P = .001). Baseline serum TSH and rT3 predicted future disability trajectories in men and women, respectively. Conclusions: Our study is reassuring that individuals age 85 y with both subclinical hypothyroidism and subclinical hyperthyroidism do not have a significantly worse survival over 9 years than their euthyroid peers. However, thyroid function tests did predict disability, with higher serum TSH levels predicting better outcomes. These data strengthen the argument for routine use of age-specific thyroid function reference ranges

Antigen-specific immunotherapy with thyrotropin receptor peptides in Grave's Hyperthyroidism: a Phase I study

Graves' disease is one of the most common autoimmune conditions, but treatment remains imperfect. This study explores the first-in-human use of antigen-specific immunotherapy with a combination of two thyrotropin receptor (TSHR) peptides (termed ATX-GD-59) in Graves' hyperthyroidism.This article is freely available via Open Access. Click on the Publisher's URL to access the full-text via the publisher's site.Publishe

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Study of Optimal Replacement of Thyroxine in the Elderly (SORTED) – results from the feasibility randomised controlled trial

BACKGROUND: Hypothyroidism is a common condition, particularly in the older population. Thyroid hormone requirements change with age and serum TSH levels also alter, especially in older patients. However, in practice laboratory reference ranges for thyroid function are not age-specific and treatment in older patients aims to achieve a similar target thyroid function level as younger age groups. METHODS: A dual centre, single blind, randomised controlled trial was conducted to determine the feasibility of a future definitive RCT in hypothyroid individuals aged 80 years or older who were treated with levothyroxine. Potential participants were identified from 17 research-active GP practices (n = 377), by opportunistic invitations (n = 9) or in response to publicity (n = 4). Participants were randomly allocated to either usual (0.4–4.0 mU/L) or a higher (4.1–8.0 mU/L) target serum TSH range. Information on participants’ willingness to enter the trial, acceptability of study design, length of time to complete recruitment and dose titration strategy was collected. RESULTS: Fifteen percent (57/390) of potentially eligible hypothyroid individuals consented to participate in this trial and 48 were randomised to trial medication for 24 weeks, giving a recruitment rate of 12 %. Recruitment averaged 5.5 participants per month over approximately 9 months. Eight participants withdrew (3/24 and 5/24 in the usual and higher TSH arms, respectively) with the commonest reason cited (5 patients) being tiredness. Interestingly, 3/5 participants withdrew from the site that required a visit to a Research Facility whereas only 5/43 participants withdrew from the site that offered home visits. In the higher TSH arm, of those participants who completed the study, approximately half of participants (10/19) reached target TSH. CONCLUSIONS: It is feasible to perform a randomised controlled trial of thyroid hormones in hypothyroid patients aged 80 or older. A definitive trial would require collaboration with a large number of General Practices and the provision of home visits to achieve recruitment to time and target. Power calculations should take into account that approximately 12 % of those approached will be randomised and 1 in 6 participants are likely to withdraw from the study. Finally, several dose adjustments may be required to achieve target serum TSH levels in this age group. TRIAL REGISTRATION: ISRCTN Number: 16043724 Registered 22 June 2012 Clinicaltrial.gov Number: NCT01647750 EudraCT Number: 2011-004425-2

Thyroid function and the risk of fibrosis of the liver, heart and lung in humans: A systematic review and meta-analysis.

Background Fibrotic diseases have an unclear etiology and poor prognosis. Fluctuations in thyroid function may play a role in the development of fibrosis, but evidence is fragmented and inconclusive. This systematic review and meta-analysis aimed to investigate the association of thyroid function with fibrotic diseases of the liver, heart, and lung, in humans. Methods We searched Pubmed, Medline Ovid, Embase Ovid, and Web-of-Science for studies published from inception to 14 June 2019, to identify observational studies that investigated the association of thyroid function with fibrosis of the liver, heart, and lung, in humans. Study quality was evaluated by Newcastle-Ottawa Scale. The Mantel-Haenszel method was used to pool the odds ratios (ORs) of studies investigating the association of hypothyroidism with liver fibrosis. Results Out of 2196 identified articles, 18 studies were included in the systematic review, of which 11 studies reported on liver fibrosis, 4 on myocardial fibrosis, and 3 on pulmonary fibrosis. The population sample size ranged from 36 to 7259 subjects, with median mean age 51 years (range, 36-69) and median percentage of women 53 (range, 17-100). The risk of bias of studies was low to moderate to high. Higher serum thyrotropin and lower thyroid hormone levels were generally associated with higher likelihood of fibrosis. Compared to euthyroidism, overt and subclinical hypothyroidism were associated with a higher likelihood of fibrosis in the liver (6 of 7 studies), heart (3 of 3 studies), and lung (3 of 3 studies). Based on the results of the 7 studies included in the meta-analysis, overt and subclinical hypothyroidism were associated with an increased risk of liver fibrosis (pooled OR, 2.81; 95% confidence interval [CI], 1.74-4.53; heterogeneity, I2 31.4%; pooled OR, 2.12; CI, 1.45-3.12, heterogeneity, I2 0% respectively), without evidence of publication bias. Conclusions This study suggests that low thyroid function is associated with increased likelihood of chronic fibrotic diseases of the liver, heart, and lung. However, the evidence is mainly based on cross-sectional data. Prospective studies and randomized clinical trials are needed to investigate the potential efficacy of thyroid hormone and its analogues on the occurrence and progression of fibrosis

Reply on the Letter by Stott et al. 'The Dilemma of Treating Subclinical Hypothyroidism: Risk that Current Guidelines Do More Harm than Good'

We appreciate the interest of Stott et al. [1] in the Management of Subclinical Hypothyroidism ETA Guidelines 2013 [2]. We are, however, somewhat puzzled by the authors' statement that the guidelines ‘risk doing more harm than good’, probably the result of misinterpretation of some recommendations of the guidelines. The ETA Guidelines represent a meticulous interpretation of more than 140 articles and were, moreover, posted on the ETA website for about a month for criticism and comments. They offer a unique platform of expertise, supporting those involved in the diagnosis and treatment of both younger and older patients with subclinical hypothyroidism (SCH), in a spirit of collaboration for the benefit of our patients. Stott et al. [1] basically agree with the guidelines that the wait-and-see approach and repeat thyroid testing in patients with SCH is a widely accepted concept. The measurement of thyroid auto-antibodies determines the risk of progression to overt hypothyroidism, especially if the thyroid-stimulating hormone (TSH) level is above 2.5 mU/l [3]. The guidelines are misrepresented by these comments, as we definitely do not recommend treatment based on auto-antibodies. The categorization of the patients by age (60-70 years as moderately old, >70 years as older and >80-85 years as oldest old) is essential for the establishment of a diagnosis that should also consider ‘age-specific reference ranges for serum TSH’ (recommendation 14) in older people. It has clearly been shown that there is a widening of the reference range for serum TSH with increasing age [4,5]. In fact, a recent study from a large population in Scotland demonstrated a significant increase in the 97.5th centile of TSH (3.98-5.94 mU/l, respectively) with increasing age [6]. In addition, there are differences in the nature of the TSH changes with age between iodine-deficient and iodine-replete populations. We therefore do not agree with the authors that the consideration of age-specific guidelines is ‘premature and overly complex’ [1], but feel that this is important information that cannot be omitted from the guideline in an artificial attempt to avoid complexity. Stott et al. [1] are in agreement that levothyroxine treatment, depending on the degree of TSH suppression and age, is associated with lower bone density, increased risk of fractures and atrial fibrillation. The guidelines specifically recommend (recommendation 15) that the oldest old subjects (>80-85 years) with elevated serum TSH ≤10 mU/l should be carefully followed with a wait-and-see strategy, generally avoiding hormonal treatment. This procedure is supported by a recent study showing that older patients are at particular risk for overtreatment, as their upper limit of normal for the level of TSH is slightly higher than that in younger patients [7]. Among 3,900 community-dwelling apparently euthyroid Caucasian Australian men over 70 years of age, those whose free thyroxine was normal but in the highest quartile were 20% more likely to have died over 6 years of follow-up. Finally, we absolutely agree that a randomized controlled trial, such as the one by the TRUST-IEMO collaboration, is needed to reinforce decision making as to whether levothyroxine treatment is required and is beneficial in older patients with SCH and also to determine whether the oldest old may benefit from treatment. Accordingly, the guideline states that appropriately powered randomized controlled trials of levothyroxine in SCH patients, examining hard cardiovascular end points in various classes of age, are clearly warranted. Based on these data and the present joint statement, it is therefore evident that the guidelines, especially recommendation 21 stating ‘In the elderly, any treatment for SCH should be individualized, gradual and closely monitored’, can be of undoubted assistance and will certainly not do harm