Age-Related Serum Thyroid-Stimulating Hormone Reference Range in Older Patients Treated with Levothyroxine: A Randomized Controlled Feasibility Trial (SORTED 1).
ABSTRACT: Introduction:Serum thyroid-stimulating hormone (TSH) increases with age but target TSH is similar in younger and older hypothyroid patients on treatment. It is unknown if quality of life (QoL), hypothyroid symptoms and cardiovascular risk factors change in older hypothyroid patients treated to an age-appropriate reference range. Objective:To assess if a higher target serum TSH of 4.01-8.0 mU/L is feasible in, and acceptable to, older treated hypothyroid patients. Methods:A single-blind (participant) randomised controlled feasibility trial involving 48 hypothyroid patients aged ?80 years on established and stable levothyroxine (LT4) therapy with serum TSH levels within the standard reference range (0.4-4.0 mU/L) was conducted. Standard (0.4-4.0 mU/L) or higher (4.1-8.0 mU/L) TSH target (standard TSH [ST] or higher TSH [HT] groups) LT4 for 24 weeks was administered. The outcome measures evaluated were thyroid function tests, QoL, hypothyroid symptoms, cardiovascular risk factors and serum marker of bone resorption in participants that completed the trial (n = 21/24 ST group, n = 19/24 HT group). Results:At 24 weeks, in the ST and HT groups, respectively, median (interquartile range) serum TSH was 1.25 (0.76-1.72) and 5.50 (4.05-9.12) mU/L, mean (± SD) free thyroxine (FT4) was 19.4 ± 3.5 and 15.9 ± 2.4 pmol/L, and daily LT4 dose was 82.1 ± 26.4 and 59.2 ± 23.9 µg. There was no suggestion of adverse impact of a higher serum TSH in the HT group with regard to any of the outcomes assessed. Conclusions:In hypothyroid patients aged ?80 years on LT4 therapy for 24 weeks, there was no evidence that a higher target serum TSH was associated with an adverse impact on patient reported outcomes, cardiovascular risk factors or bone resorption marker over 24 weeks. Longer-term trials assessing morbidity and mortality outcomes and health-utility in this age group are feasible and should be performed.
Project description:Levothyroxine replacement treatment in hypothyroidism is unable to restore physiological thyroxine and triiodothyronine concentrations in serum and tissues completely. Normal serum thyroid stimulating hormone (TSH) concentrations reflect only pituitary euthyroidism and, therefore, novel biomarkers representing tissue-specific thyroid state are needed. MicroRNAs (miRNAs), small non-coding regulatory RNAs, exhibit tissue-specific expression patterns and can be detectable in serum. Previous studies have demonstrated differential expression of (precursors of) miRNAs in tissues under the influence of thyroid hormone.To study if serum miRNA profiles are changed in different thyroid states.We studied 13 athyroid patients (6 males) during TSH suppressive therapy and after 4 weeks of thyroid hormone withdrawal. A magnetic bead capture system was used to isolate 384 defined miRNAs from serum. Subsequently, the TaqMan Array Card 3.0 platform was used for profiling after individual target amplification.Mean age of the subjects was 44.0 years (range 20-61 years). Median TSH levels were 88.9 mU/l during levothyroxine withdrawal and 0.006 mU/l during LT4 treatment with a median dosage of 2.1 ?g/kg. After normalization to allow inter-sample analysis, a paired analysis did not demonstrate a significant difference in expression of any of the 384 miRNAs analyzed on and off LT4 treatment.Although we previously showed an up-regulation of pri-miRNAs 133b and 206 in hypothyroid state in skeletal muscle, the present study does not supply evidence that thyroid state also affects serum miRNAs in humans.
Project description:BACKGROUND: Hashimoto's thyroiditis (HT) has been found to coexist with differentiated thyroid cancer (DTC) in surgical specimens, but an association between the two conditions has been discounted by the medical literature. Therefore, we performed this study to determine any potential relationship between HT and the risk of developing DTC. METHODS: We collected data for thyrotropin (TSH), thyroxine (T4), thyroid peroxidase antibody (TPO-Ab) titers, surgical pathology, and weight-based levothyroxine (LT4) replacement dose for patients who were referred for thyroid surgery. Patients with HT at final pathology were studied further. To estimate thyroid function, patients with preoperative hypothyroid HT (Hypo-HT) were divided into three equal groups based on their LT4 replacement: LT4-Low (<0.90 ?g/kg), LT4-Mid (0.90-1.43 ?g/kg), and LT4-High (>1.43 ?g/kg). A group of preoperatively euthyroid (Euth-HT) patients but with HT by pathology was also studied. All subjects were also grouped based on their TPO-Ab titer in TPO-high (titer >1:1000) or TPO-low/negative (titer <1:1000 or undetectable) groups. The relationship of HT and DTC was studied extensively. RESULTS: Of 2811 subjects, 582 had HT on surgical pathology, 365 of whom were Euth-HT preoperatively. DTC was present in 47.9% of the Euth-HT, in 59.7% of LT4-Low, 29.8% of LT4-Mid, and 27.9% of LT4-High groups. The relative risk (RR) for DTC was significantly elevated for the Euth-HT and LT4-Low groups (p<0.001), but not for the LT4-Mid or LT4-High replacement dose groups. TPO-low/negative status conferred an increased RR in the Euth-HT and LT4-Low replacement dose groups (p<0.001 both), while TPO-high status decreased it in Euth-HT group (p<0.05) and made it nonsignificant in the LT4-Low group. CONCLUSIONS: HT pathology increases the risk for DTC only in euthyroid subjects and those with partially functional thyroid glands (LT4-Low) but not in fully hypothyroid HT (LT4-Mid and LT4-High). High TPO-Ab titers appear to protect against DTC in patients with HT.
Project description:There has been recent debate within the thyroid field regarding whether current upper limits of the thyrotropin (TSH) reference range should be lowered. This debate can be better informed by investigation of whether variations in thyroid function within the reference range have clinical effects. One important target organ for thyroid hormone is the brain, but little is known about variations in neurocognitive measures within the reference range for thyroid function.This was a cross-sectional study of 132 otherwise healthy hypothyroid subjects receiving chronic replacement therapy with levothyroxine (LT4) who had TSH levels across the full span of the laboratory reference range (0.34-5.6?mU/L). Subjects underwent detailed tests of health status, mood, and cognitive function, with an emphasis on memory and executive functions.Subjects with low-normal (?2.5?mU/L) and high-normal (>2.5?mU/L) TSH levels did not differ on most tests of health status, mood, or cognitive function, and there were no correlations between TSH, free T4, or free T3 levels and most outcomes. There was, however, a suggestion that thyroid function affected performance on the Iowa Gambling Task, which mimics real life decision-making. Subjects with low-normal TSH levels made more advantageous decisions than those with high-normal TSH levels.Variations in thyroid function within the laboratory reference range do not appear to have clinically relevant effects on health status, mood, or memory in LT4 treated subjects. However, decision making, which encompasses many executive functions, may be affected. Unless further studies strengthen this finding, these data do not support narrowing the TSH reference range.
Project description: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.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.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.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.ISRCTN Number: 16043724 Registered 22 June 2012 Clinicaltrial.gov Number: NCT01647750 EudraCT Number: 2011-004425-27.
Project description:Background:It is unclear whether variations in thyroid status within or near the reference range affect energy expenditure, body mass, or body composition. Methods:138 subjects treated with levothyroxine (LT4) for hypothyroidism with normal TSH levels underwent measurement of total, resting, and physical activity energy expenditure; thermic effect of food; substrate oxidation; dietary intake; and body composition. They were assigned to receive an unchanged, higher, or lower LT4 dose in randomized, double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). The doses were adjusted every 6 weeks to achieve target TSH levels. Baseline measures were reassessed at 6 months. Results:At study end, the mean LT4 doses and TSH levels were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 µg/kg (P < 0.001) and 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. No substantial metabolic differences in outcome were found among the three arms, although direct correlations were observed between decreases in thyroid status and decreases in resting energy expenditure for all subjects. The subjects could not ascertain how their LT4 dose had been adjusted but the preferred LT4 dose they perceived to be higher (P < 0.001). Conclusions:Altering LT4 doses in subjects with hypothyroidism to vary TSH levels in and near the reference range did not have major effects on energy expenditure or body composition. Subjects treated with LT4 preferred the perceived higher LT4 doses despite a lack of objective effect. Our data do not support adjusting LT4 doses in patients with hypothyroidism to achieve potential improvements in weight or body composition.
Project description:Levothyroxine sodium (LT4) is the therapy of choice for hypothyroidism. In the last decade, new LT4 formulations, such as liquid and softgel capsules, became available. Even if some evidence has been reached in the efficacy of liquid LT4 in patients with suboptimal TSH on tablet LT4, the usefulness of softgel LT4 has been rarely studied. This study aimed at evaluating the effect of switching from tablet to softgel LT4 patients without increased need for LT4. TSH was used as proxy of LT4 bioavailability and effectiveness.During the period from April to August 2017, 19 patients on tablet LT4 treatment for hypothyroidism, mostly due to autoimmune thyroiditis, were enrolled. Subjects with causes of malabsorption or increased requirement of LT4 were previously excluded. Patients finally included were asked to switch from tablet to softgel LT4 formulation at unchanged dose and ingestion fashion (30?min before breakfast). TSH was measured with chemiluminescence immunoassays.According to exclusion and inclusion criteria, 19 patients were finally selected. One of these had headache 4?days later and come back to tablet LT4, and 18 of them (16W/2M; mean age?=?55?years; BMI 22.7?kg/m2) completed the study. They were treated with a median LT4 dose of 88??g/day and showed a median TSH value of 3.33?mIU/L. The rate of cases with TSH???4.0?mIU/L was 61.1% (11/18 cases). When patients were re-evaluated after 3?months of softgel LT4, we observed that TSH reached levels under 4.0?mIU/L in 16/18 (88.9%) patients, TSH was lower in 11 cases, and in 6 out of 7 patients with pre-switch TSH values over the normal range. Overall, TSH values on softgel LT4 (median 1.90?mIU/L) was significantly lower from that observed during tablet LT4 (p?=?0.0039).These data show that hypothyroid patients with no proven malabsorption may have an improved TSH following 3?months from the switch from tablet to softgel LT4 preparation at unchanged dose.
Project description:Background: For significant numbers of patients dissatisfied on standard levothyroxine (LT4) treatment for hypothyroidism, patient-specific responses to T4 could play a significant role. Aim: To assess response heterogeneity to LT4 treatment, identifying confounders and hidden clusters within a patient panel, we performed a secondary analysis using data from a prospective cross-sectional and retrospective longitudinal study. Methods: Multivariate and multivariable linear models adjusted for covariates (gender, age, and BMI) were stratified by disease-specific treatment indication. During follow-up, pooled observations were compared from the same patient presenting either with or without self-reported symptoms. Statistical analysis was extended to multilevel models to derive intra-class correlation coefficients and reliability measures during follow-up. Results: Equilibria between TSH, FT4, and FT3 serum concentrations in 342 patients were examined by treatment indication (benign goiter, autoimmune thyroiditis, thyroid carcinoma), consequently displaying complex interactive response patterns. Seventy-seven patients treated with LT4 and monitored for thyroid carcinoma presented, in association with changes in LT4 dose, either with hypothyroid symptoms or symptom-free. Significant biochemical differences appeared between the different presentations. Leveled trajectories by subject to relief from hypothyroid symptoms differed significantly, indicating distinct responses, and denying a single shared outcome. These were formally defined by a high coefficient of the intraclass correlation (ICC1, exceeding 0.60 in all thyroid parameters) during follow-up on multiple visits at the same LT4 dose, when lacking symptoms. The intra-personal clusters were clearly differentiated from random variability by random group resampling. Symptomatic change in these patients was strongly associated with serum FT3, but not with FT4 or TSH concentrations. In 25 patients transitioning from asymptomatic to symptomatically hyperthyroid, FT3 concentrations remained within the reference limits, whilst at the same time marked biochemical differences were apparent between the presentations. Conclusions: Considerable intra-individual clustering occurred in the biochemical and symptomatic responses to LT4 treatment, implying statistically multileveled response groups. Unmasking individual differences in the averaged treatment response hereby highlights clinically distinguishable subgroups within an indiscriminate patient panel. This, through well-designed larger clinical trials will better target the different therapeutic needs of individual patients.
Project description:Hypothyroidism is characterized by increased thyrotropin (TSH) levels and reduced free thyroid hormone fractions while, subclinical hypothyroidism (sHT) by elevated serum TSH in the face of normal thyroid hormones. The high frequency of hypothyroidism among the general population in Western Countries made levothyroxine (LT4) one of the 10 most prescribed drugs. However, circulating TSH has been demonstrated to increase with aging, regardless the existence of an actual thyroid disease. Thus, when confronting an increase in circulating TSH levels in the elderly, especially in the oldest old, it is important to carry an appropriate diagnostic path, comprehensive of clinical picture as well as laboratory and imaging techniques. In the current review, we summarize the recommendations for a correct diagnostic workup and therapeutic approach to older people with elevated TSH value, with special attention to the presence of frailty, comorbidities, and poly-therapy. The treatment of choice for hypothyroid patients is hormone replacement with LT4 but, it is important to consider multiple factors before commencing the therapy, from the age dependent TSH increase to the presence of an actual thyroid disease and comorbidities. When treatment is necessary, a tailored therapy should be chosen, considering poly-pharmacy and frailty. A careful follow-up and treatment re-assessment should be always considered to avoid the risk of over-treatment. It is important to stress the need of educating the patient for a correct administration of LT4, particularly when poly-therapy is in place, and the importance of a tailored therapeutic approach and follow-up, to avoid overtreatment.
Project description:ObjectiveEvidence indicates that L-T4 in liquid and softgel capsule are absorbed better than tablets in hypothyroid patients, even when patients are under medications that impair the intestinal absorption of L-T4. However, no study has evaluated all three L-T4 formulations in the same hypothyroid patients. This study aims to fill this gap. The outcome was the degree of TSH change in the liquid and softgel formulations, using tablet L-T4 as the reference, regardless of sequence of formulation and regardless of whether patients were co-ingesting with interfering medications.MethodsWe recorded serum TSH levels in two groups of L-T4 replaced patients with primary hypothyroidism (23 subjects who did not co-ingest interfering medications, and 20 subjects who did). Either group of patients took one formulation of L-T4 at a time with variable sequences. In the first group, the median durations of exposure to tablet, liquid or softgel L-T4 were 14, 9 and 10?months, respectively. In the second group the corresponding durations were 13, 11 and 10?months, during which patients co-ingested interfering medications.ResultsIn the 23 patients, there were 78, 74 or 101 TSH determinations during liquid, softgel capsule or tablet L-T4 regimens. Serum TSH levels associated with liquid, capsule or tablet L-T4 were 1.62?±?0.51, 1.77?±?0.44?mU/L (P?=?0.049 vs liquid) or 2.38?±?0.69?mU/L (P?<?0.0001 vs liquid or capsule). Rates of TSH???2.50?mU/L were 97.4% (liquid), 95.9% (softgel) or 64.4% (tablet, P?<?0.0001 vs liquid or capsule). Rates of TSH???4.12?mU/L were 100%, 100% or 98.0%.In the 20 patients, the corresponding TSH determinations were 56, 57 and 41, and corresponding TSH levels were 2.74?±?0.98, 2.70?±?0.79 or 7.53?±?2.82?mU/L. Rates of TSH???2.50?mU/L were 51.8% (liquid), 47.4% (capsule, P?=?0.64) or 2.4% (tablet, P?<?0.0001 vs liquid or capsule). Rates of TSH???4.12?mU/L were 92.8% (liquid), 94.7% (capsule, P?=?0.68) or 12.2% (tablet, P?<?0.0001 vs liquid or capsule).ConclusionsL-T4 ingested as liquid solution or softgel capsule is more bioavailable compared to L-T4 ingested as tablet, and it is slightly superior to capsule L-T4 only in the absence of co-ingestion of interfering medications.
Project description:BACKGROUND:The aging population is associated with increased multimorbidity and polypharmacy. Older adults are at a higher risk of adverse events and reduced therapeutic response. This phenomenon is partially explained by drug interactions and treatment adherence. Most randomized clinical trials have found no significant differences between morning and evening levothyroxine (LT4) administration in young adults, but there is little evidence regarding alternative LT4 regimens in older populations. Thus, the MONIALE trial aims to test an alternative schedule for LT4 administration in older adults. METHODS/DESIGN:This randomized crossover clinical trial will include participants aged 60?years or older with primary hypothyroidism. The trial groups will consist of morning LT4 intake (60?min before breakfast) or evening LT4 intake (60?min after supper). The primary outcome will be variation in serum thyrotropin (TSH) levels after 24?weeks of the LT4 protocol. The secondary outcomes will be the prevalence of drugs that potentially interact with LT4 and hypothyroidism control according to interaction status. The sample size was calculated to detect a minimum mean difference of 1 mUI/L in serum TSH level between the groups with 80% power and a 5% probability of type I error, resulting in 91 patients per group. The project was approved by the Hospital de Clínicas de Porto Alegre Ethics Committee. DISCUSSION:Considering the aging population, the increased prevalence of multimorbidity and polypharmacy, as well as potential drug interactions and treatment adherence difficulties, an alternative LT4 protocol could be useful for hypothyroidism treatment in the elderly. Prior studies comparing alternative LT4 administration protocols have mainly included young adult populations and have not addressed potential drug interactions. TRIAL REGISTRATION:ClinicalTrials.gov, NCT03614988. Registered 30 July 2018.