The effect of levothyroxine (LT4) therapy for subclinical hypothyroidism (SHypo) on appendicular bone geometry and volumetric density has so far not been studied. In a nested study within the... Show moreThe effect of levothyroxine (LT4) therapy for subclinical hypothyroidism (SHypo) on appendicular bone geometry and volumetric density has so far not been studied. In a nested study within the randomized, placebocontrolled Thyroid Hormone Replacement for Subclinical Hypothyroidism (TRUST) trial, we assessed the effect of LT4 therapy on bone geometry as measured by peripheral quantitative computed tomography (pQCT). In the TRUST trial, community-dwelling adults aged >= 65 years with SHypo were randomized to LT4 with dose titration vs. placebo with mock titration. We analyzed data from participants enrolled at the TRUST site in Bern, Switzerland who had bone pQCT measured at baseline and at 1 to 2 years follow-up. The primary outcomes were the annual percentage changes of radius and tibia epi- and diaphysis bone geometry (total and cortical crosssectional area (CSA) and cortical thickness), and of volumetric bone mineral density (bone mineral content (BMC) and total, trabecular and cortical volumetric bone mineral density (vBMD)). We performed linear regression of the annual percentage changes adjusted for sex, LT4 dose at randomization and muscle crosssectional area. The 98 included participants had a mean age of 73.9 (+/- SD 5.4) years, 45.9% were women, and 12% had osteoporosis. They were randomized to placebo (n = 48) or LT4 (n = 50). Annual changes in BMC and vBMD were similar between placebo and LT4-treated groups, without significant difference in bone geometry or volumetric bone mineral density changes, neither at the diaphysis, nor at the epiphysis. For example, in the placebo group, epiphyseal BMC (radius) decreased by a mean 0.2% per year, with a similar decrease of 0.5% per year in the LT4 group (between-group difference in %Delta BMC 0.3, 95% CI -0.70 to 1.21, p = 0.91). Compared to placebo, LT4 therapy for an average 14 months had no significant effect on bone mass, bone geometry and volumetric density in older adults with subclinical hypothyroidism. Trial registration: The trial was registered on ClinicalTrials.gov numbers NCT01660126 (TRUST Thyroid trial) and NCT02491008 (Skeletal outcomes). Show less
The thyroid gland plays a crucial role in regulating nearly all bodily processes. A particular state of thyroid function, dubbed subclinical hypothyroidism (with high thyroid-stimulating hormone ... Show moreThe thyroid gland plays a crucial role in regulating nearly all bodily processes. A particular state of thyroid function, dubbed subclinical hypothyroidism (with high thyroid-stimulating hormone [TSH] and normal free thyroid hormone [fT4] in blood tests), becomes more prevalent with advancing age and it is unclear how this condition should be interpreted in community-dwelling older people (arbitrarily 65 years and older). Whether or not the condition is associated with negative health consequences, and whether treatment with levothyroxine (artificial thyroid hormone) is warranted, are subjects of decades-long debate. This thesis aims to identify whether subclinical hypothyroidism is associated with a range of relevant outcomes, and whether levothyroxine treatment leads to benefits, in community-dwelling older persons. The results in this thesis demonstrate that subclinical hypothyroidism is not associated with clinically (e.g. physical and cognitive function, mood or mortality risk) or biologically (e.g. thyroid antibodies or anaemia) relevant outcomes. Levothyroxine treatment does not provide benefits. These results suggest that subclinical hypothyroidism in older people is a strictly biochemical diagnosis, they support more conservative diagnostic approaches and do not support routine treatment with levothyroxine. More research is needed before extrapolating to more specific subgroups and to assess whether international guidelines should be updated. Show less
Stuber, M.J.; Moutzouri, E.; Feller, M.; Giovane, C. del; Bauer, D.C.; Blum, M.R.; ... ; Rodondi, N. 2020
Background: Fatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have... Show moreBackground: Fatigue often triggers screening for and treatment of subclinical hypothyroidism. However, data on the impact of levothyroxine on fatigue is limited and previous studies might not have captured all aspects of fatigue.Method: This study is nested within the randomized, placebo-controlled, multicenter TRUST trial, including community-dwelling participants aged >= 65 and older, with persistent subclinical hypothyroidism (TSH 4.60-19.99 mIU/L, normal free thyroxine levels) from Switzerland and Ireland. Interventions consisted of daily levothyroxine starting with 50 mu g (25 mu g if weight <50 kg or known coronary heart diseases) together with dose adjustments to achieve a normal TSH and mock titration in the placebo group. Main outcome was the change in physical and mental fatigability using the Pittsburgh Fatigability Scale over 1 year, assessed through multivariable linear regression with adjustment for country, sex, and levothyroxine starting dose.Results: Among 230 participants, the mean +/- standard deviation (SD) TSH was 6.2 +/- 1.9 mIU/L at baseline and decreased to 3.1 +/- 1.3 with LT4 (n = 119) versus 5.3 +/- 2.3 with placebo (n = 111, p < .001) after 1 year. After adjustment we found no between-group difference at 1 year on perceived physical (0.2; 95% CI -1.8 to 2.1; p = .88), or mental fatigability (-1.0; 95% CI -2.8 to 0.8; p = .26). In participants with higher fatigability at baseline (>= 15 points for the physical score [n = 88] or >= 13 points for the mental score [n = 41]), the adjusted between-group differences at 1 year were 0.4 (95% CI -3.6 to 2.8, p = .79) and -2.2 (95% CI -8.8 to 4.5, p = .51).Conclusions: Levothyroxine in older adults with mild subclinical hypothyroidism provides no change in physical or mental fatigability. Show less
Gencer, B.; Moutzouri, E.; Blum, M.R.; Feller, M.; Collet, T.H.; Delgiovane, C.; ... ; Rodondi, N. 2020
BACKGROUND: Subclinical hypothyroidism has been associated with heart failure, but only small trials assessed whether treatment with levothyroxine has an impact on cardiac function.METHODS: In a... Show moreBACKGROUND: Subclinical hypothyroidism has been associated with heart failure, but only small trials assessed whether treatment with levothyroxine has an impact on cardiac function.METHODS: In a randomized, double-blind, placebo-controlled, trial nested within the TRUST trial, Swiss participants ages >= 65 years with subclinical hypothyroidism (thyroid-stimulating hormone [TSH] 4.60-19.99 mIU/L; free thyroxine level within reference range) were randomized to levothyroxine (starting dose of 50 mu g daily) to achieve TSH normalization or placebo. The primary outcomes were the left ventricular ejection fraction for systolic function and the ratio between mitral peak velocity of early filling to early diastolic mitral annular velocity (E/e' ratio) for diastolic function. Secondary outcomes included e' lateral/septal, left atrial volume index, and systolic pulmonary artery pressure.RESULTS: A total of 185 participants (mean age 74.1 years, 47% women) underwent echocardiography at the end of the trial. After a median treatment duration of 18.4 months, the mean TSH decreased from 6.35 mIU/L to 3.55 mIU/L with levothyroxine (n = 96), and it remained elevated at 5.29 mIU/L with placebo (n = 89). The adjusted between-group difference was not significant for the mean left ventricular ejection fraction (62.7% vs 62.5%, difference = 0.4%, 95% confidence interval -1.8% to 2.5%, P = 0.72) and the E/e' ratio (10.6 vs 10.1, difference 0.4, 95% confidence interval -0.7 to 1.4, P = 0.47). No differences were found for the secondary diastolic function parameters or for interaction according to sex, baseline TSH, preexisting heart failure, and treatment duration (P value > 0.05).CONCLUSION: Systolic and diastolic heart function did not differ after treatment with levothyroxine compared with placebo in older adults with mild subclinical hypothyroidism. (C) 2020 Elsevier Inc. All rights reserved. Show less
