ContextWith age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown.ObjectiveTo investigate incidence and... Show moreContextWith age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown.ObjectiveTo investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism.DesignPooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial).SettingCommunity-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom.ParticipantsThe pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included.Main Outcome MeasuresIncidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization.ResultsIn the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization.ConclusionBecause TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment. Show less
Netzer, S.; Chocano-Bedoya, P.; Feller, M.; Janett-Pellegri, C.; Wildisen, L.; Buchi, A.E.; ... ; Rodondi, N. 2023
Background loss of skeletal muscle function, strength and mass is common in older adults, with important socioeconomic impacts. Subclinical hypothyroidism is common with increasing age and has been... Show moreBackground loss of skeletal muscle function, strength and mass is common in older adults, with important socioeconomic impacts. Subclinical hypothyroidism is common with increasing age and has been associated with reduced muscle strength. Yet, no randomized placebo-controlled trial (RCT) has investigated whether treatment of subclinical hypothyroidism affects muscle function and mass. Methods this is an ancillary study within two RCTs conducted among adults aged >= 65 years with persistent subclinical hypothyroidism (thyrotropin (TSH) 4.60-19.99 mIU/l, normal free thyroxine). Participants received daily levothyroxine with TSH-guided dose adjustment or placebo and mock titration. Primary outcome was gait speed at final visit (median 18 months). Secondary outcomes were handgrip strength at 1-year follow-up and yearly change in muscle mass. Results we included 267 participants from Switzerland and the Netherlands. Mean age was 77.5 years (range 65.1-97.1), 129 (48.3%) were women, and their mean baseline TSH was 6.36 mIU/l (standard deviation [SD] 1.9). At final visit, mean TSH was 3.8 mIU/l (SD 2.3) in the levothyroxine group and 5.1 mIU/l (SD 1.8, P < 0.05) in the placebo group. Compared to placebo, participants in the levothyroxine group had similar gait speed at final visit (adjusted between-group mean difference [MD] 0.01 m/s, 95% confidence interval [CI] -0.06 to 0.09), similar handgrip strength at one year (MD -1.22 kg, 95% CI -2.60 to 0.15) and similar yearly change in muscle mass (MD -0.15 m(2), 95% CI -0.49 to 0.18). Conclusions in this ancillary analysis of two RCTs, treatment of subclinical hypothyroidism did not affect muscle function, strength and mass in individuals 65 years and older. Show less
Subclinical hypothyroidism (SCHT) is defined as a consistently elevated thyroid stimulating hormone (TSH) with a free T4 (fT4) within the reference range. This diagnosis may lead to additional... Show moreSubclinical hypothyroidism (SCHT) is defined as a consistently elevated thyroid stimulating hormone (TSH) with a free T4 (fT4) within the reference range. This diagnosis may lead to additional monitoring, levothyroxine therapy and increased patient concerns, despite lack of evidence of treatment benefit in older adults. In order to avoid this diagnosis, we evaluated the efficiency of fT4-based screening for thyroid dysfunction, in older adults in primary care and compared it with TSH-based screening. Individuals aged >65years in primary care were selected for this retrospective study when both TSH and fT4 were individually requested irrespective of the TSH value. Exclusion criteria were C-reactive protein > 10 mg/l or a history of thyroid hormone monitoring in the previous year. Screening based on fT4 instead of TSH decreased reflex testing from 23.8% to 11.2%. The positive predictive value (PPV) for clinical hypothyroidism increased from 17.3% to 52.2%. The negative predictive value was 96.1% with TSH-based screening versus 97.8% with fT4-based screening. Elevation of the TSH cutoff value from 4.2 to 6.5 mU/l resulted in a reflex test percentage of 12.5% and a PPV of 31.0%. Our results suggest that screening for thyroid dysfunction in older individuals in primary care can be improved by screening based on fT4 instead of TSH or by adjusting the TSH cutoff value. Adjustment of the screening strategy may be of interest to health policy makers because of potential cost reduction. From a patient perspective, medical concerns and unnecessary biochemical follow-up might be reduced by circumventing the diagnosis SCHT. Show less
Lyko, C.; Blum, M.R.; Abolhassani, N.; Stuber, M.J.; Giovane, C. del; Feller, M.; ... ; Rodondi, N. 2022
Background Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed... Show moreBackground Antithyroid antibodies increase the likelihood of developing overt hypothyroidism, but their clinical utility remains unclear. No large randomized controlled trial (RCT) has assessed whether older adults with subclinical hypothyroidism (SHypo) caused by autoimmune thyroid disease derive more benefits from levothyroxine treatment (LT4). Objective To determine whether older adults with SHypo and positive antibodies derive more clinical benefits from LT4 than those with negative antibodies. Methods We pooled individual participant data from two RCTs, Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism and IEMO 80+. Participants with persistent SHypo were randomly assigned to receive LT4 or placebo. We compared the effects of LT4 versus placebo in participants with and without anti-thyroid peroxidase (TPO) at baseline. The two primary outcomes were 1-year change in Hypothyroid Symptoms and Tiredness scores on the Thyroid-Related Quality-of-Life Patient-Reported Outcome Questionnaire. Results Among 660 participants (54% women) >= 65 years, 188 (28.5%) had positive anti-TPO. LT4 versus placebo on Hypothyroid Symptoms lead to an adjusted between-group difference of -2.07 (95% confidence interval: -6.04 to 1.90) for positive antibodies versus 0.89 (-1.76 to 3.54) for negative antibodies (p for interaction = 0.31). Similarly, there was no treatment effect modification by baseline antibody status for Tiredness scores-adjusted between-group difference 1.75 (-3.60 to 7.09) for positive antibodies versus 1.14 (-1.90 to 4.19) for negative antibodies (p for interaction = 0.98). Positive anti-TPO were not associated with better quality of life, improvement in handgrip strength, or fewer cardiovascular outcomes with levothyroxine treatment. Conclusions Among older adults with SHypo, positive antithyroid antibodies are not associated with more benefits on clinical outcomes with LT4. Show less
Puy, R.S. du; Poortvliet, R.K.E.; Mooijaart, S.P.; Stott, D.J.; Quinn, T.; Sattar, N.; ... ; Elzen, W.P.J. den 2022
Context Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age. Objective The aim of this study was to assess whether levothyroxine... Show moreContext Subclinical thyroid dysfunction and anemia are common disorders, and both have increasing prevalence with advancing age. Objective The aim of this study was to assess whether levothyroxine treatment leads to a rise in hemoglobin levels in older persons with subclinical hypothyroidism. Methods This preplanned combined analysis of 2 randomized controlled trials included community-dwelling persons aged 65 years and older with subclinical hypothyroidism who were randomly assigned to levothyroxine or placebo treatment. The levothyroxine dose was periodically titrated aiming at thyroid stimulating hormone (TSH) level within the reference range, with mock titrations in the placebo group. The main outcome measure was the change in hemoglobin level after 12 months. Results Analyses included 669 participants (placebo n = 337, levothyroxine n = 332) with a median age of 75 years (range, 65-97) and mean baseline hemoglobin of 13.8 +/- 1.3 g/dL. Although levothyroxine treatment resulted in a reduction in TSH from baseline after 12 months of follow-up compared with placebo, the change in hemoglobin level was not different between the levothyroxine and the placebo groups (-0.03 g/dL [95% CI, -0.16 to 0.11]). Similar results were found in stratified analyses including sex, age, or TSH levels. No difference in change of hemoglobin levels after 12 months was identified in 69 participants with anemia at baseline (-0.33 g/dL [95% CI, -0.87 to 0.21]). Conclusion In persons aged 65 years and older with subclinical hypothyroidism, treatment with levothyroxine does not lead to a rise in hemoglobin levels, regardless of the presence of anemia. Show less
BackgroundThe cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in... Show moreBackgroundThe cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD).ObjectiveTo determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH.MethodsCombined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged >= 65 years for TRUST (n=737) and >= 80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age.ResultsThe median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38 +/- SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 +/- 3.3 mIU/L in the placebo group, compared with 3.66 +/- 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 mu g. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age.ConclusionTreatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age. Show less
Akintola, A.A.; Jansen, S.W.; Bodegom, D. van; Grond, J. van der; Westendorp, R.G.; Craen, A.J.M. de; Heemst, D. van 2015
