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Background: Although hypothyroidism is associated with various comorbidities, its relationship with increased all-cause mortality remains controversial. The aim of this nationwide retrospective cohort study was to investigate whether hypothyroid patients treated with levothyroxine had increased mortality compared to controls., Methods: Hypothyroid subjects were identified through the Korean National Health Insurance Service Claims database between 2008 and 2017. Hypothyroidism in this study was defined as overt hypothyroidism treated with long-term prescription of levothyroxine (>6 months). After 1:3 age-, sex- and index year-matching, 501,882 patients with newly diagnosed hypothyroidism and 1,505,646 controls without hypothyroidism were included., Results: During a mean follow-up of 6 years, 25,954 (5.2%) hypothyroid patients and 59,105 (3.9%) controls died. Hypothyroidism was significantly associated with increased all-cause mortality (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI] 1.12-1.16) even with levothyroxine treatment. When stratified by age, sex, and cardiovascular disease risk, independent associations between hypothyroidism and mortality remained significant in all subgroups. The risk of mortality was higher in the < 65 age group (HR: 1.25, 95% CI: 1.22-1.29), men (HR: 1.28, 95% CI: 1.25-1.31), and the high cardiovascular disease risk group (HR: 1.31, 95% CI: 1.29-1.34). The mortality rate of hypothyroid patients was highest within 1 year of treatment and decreased with time., Conclusion: This nationwide, population-based cohort study showed that all-cause mortality was significantly higher in levothyroxine-treated hypothyroid patients than in non-hypothyroid controls. This association remained significant regardless of age, sex, and cardiovascular disease risk., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sohn, Seo and Chung.)

Since the introduction of sensitive assays for serum thyroid-stimulating hormone (TSH) clinicians have advised hypothyroid patients to adjust the dose of levothyroxine (L-T4) in order to achieve a normal serum TSH. A minority of patients are dissatisfied with this treatment strategy and experience symptoms. Some indirect evidence suggests that a normal serum TSH may not necessarily reflect euthyroidism at the tissue level in patients treated with L-T4. Increasingly hypothyroid patients demand higher doses of L-T4 or liothyronine (L-T3) or animal thyroid extract, often purchased online, and titrate the dose against symptoms, although ample evidence suggests that combination treatment (L-T4 with L-T3) is no more effective than L-T4 alone. Community surveys show that up to 53% of treated hypothyroid patients at any time have a serum TSH outside the normal range. The recommendation by guidelines that the upper limit of the normal range for serum TSH should not be exceeded is supported by robust evidence and is generally accepted by clinicians and patients. However, until recently the lower limit of serum TSH for optimal L-T4 replacement has been controversial. New evidence obtained by two independent large population studies over the past two years has shown that mortality of hypothyroid patients treated with levothyroxine is increased when the serum TSH exceeds or is reduced outside the normal reference range. It is estimated that the implementation of a policy of normalising serum TSH in hypothyroid patients will reduce the risk of death of 28.3 million people in the USA and Europe alone.

Objective: This study investigated the association between hypothyroidism and mortality in both treated and untreated hypothyroid patients, and the consequences of over- and under-treatment with respect to mortality., Patients and Methods: This was a register-based cohort study of 235,168 individuals who had at least one serum thyrotropin (TSH) during 1995-2011 (median follow-up 7.2 years). Hypothyroidism was defined as at least two measurements of TSH >4.0 mIU/L within a half year spaced by at least 14 days, or one measurement of TSH >4.0 mIU/L and two filled prescriptions of levothyroxine the following year. All-cause mortality rates were calculated using multivariable Cox regression analysis adjusted for age, sex, and comorbidities using the Charlson Comorbidity Index., Results: Mortality was increased in untreated hypothyroid individuals (n = 673; hazard ratio [HR] = 1.46 [confidence interval (CI) 1.26-1.69]; p < 0.001) compared to euthyroid controls. Results remained significant even when subdividing according to mild (TSH >4.0 mIU/L and ≤10 mIU/L; p < 0.001) and marked hypothyroidism (TSH >10 mIU/L; p = 0.002). Mortality was increased in both treated and untreated hypothyroid individuals for each six months a patient had increased TSH (HR = 1.05 [CI 1.02-1.07], p < 0.0001, and HR = 1.05 [CI 1.02-1.07], p = 0.0009, respectively). In patients who received levothyroxine, the HR for mortality increased by a factor 1.18 ([CI 1.15-1.21]; p < 0.0001) for each six months a patient exhibited decreased TSH. This finding was essentially unchanged after stratification by disease severity (mild or marked hypothyroidism) and age (older and younger than 65 years)., Conclusions: Mortality was increased in untreated but not in treated hypothyroid individuals, independently of age and severity of hypothyroidism. Duration of decreased TSH in treated individuals had a greater impact on mortality than did duration of elevated TSH. These results stress the need for close monitoring of treatment in individuals receiving thyroid hormone replacement therapy.

Introduction: It is uncertain whether subclinical hypothyroidism should be treated with levothyroxine, particularly in the elderly. This study evaluated the association between levothyroxine treatment and mortality in individuals 65years or older with subclinical hypothyroidism and TSH values <10mIU/L., Methods: A case-control study in which patients 65years or older with TSH levels of 4.2-10mIU/L who died in the years 2012-2016 ('cases') were compared with matched individuals who did not die during this period ('controls'). Matching was based on gender, age, Charlson comorbidity index, date of TSH testing, duration of follow-up and TSH quartile. All cases of known thyroid disease or cases in which anti-thyroid medications or glucocorticoids were dispensed in the year preceding the TSH evaluation were excluded. Use of levothyroxine was compared between groups., Results: During the follow-up period, 419 individuals died and these were matched with 1558 individuals who did not. Factors found to be associated with mortality were age, senile dementia, congestive heart failure, chronic renal failure and a history of cerebrovascular disease. On multivariate analysis, treatment with levothyroxine was associated with significantly increased mortality (HR=1.19 CI 1.03-1.38). Femoral fractures and atrial fibrillation following initiation of levothyroxine therapy were not more prevalent in individuals who died during the follow-up period., Conclusions: Treatment with levothyroxine is associated with significantly increased mortality in individuals 65years or older with subclinical hypothyroidism and TSH<10., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

The number of elderly people, mostly aged over 85 years (the 'oldest old'), is increasing worldwide. As a consequence, accompanying morbidity and disability have been increasing, and frailty, defined as an age-related condition of decline of physiological reserves and vulnerability, represents an emerging problem. Caring for older frail people may represent a challenge, since the elderly differ significantly from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions. Specific criteria of therapeutic appropriateness and modified goals of care are needed in such patients, also in endocrine care settings. Indeed, thyroid dysfunctions are among the most common conditions in older, multimorbid populations. The prevalence of overt and subclinical hypothyroidism is as high as 20% and thyroid hormone prescription is common in the elderly, with a trend toward levothyroxine treatment of more marginal degrees of hypothyroidism. In addition, older patients have the highest rate of overtreatment during replacement therapy and are more susceptible to developing adverse effects from thyroid hormone excess. Recently, results of a multicentric randomized controlled trial, the TRUST-IEMO collaboration trial, added further insights to the debated question of whether and when levothyroxine treatment is required and if it is beneficial in the elderly. With this in mind, we revised the relevant literature on the impact of thyroid dysfunction and replacement therapy among older people, with the aim to better define indications, benefits and risks of l-T4 replacement therapy in the frail elderly., (© 2017 European Society of Endocrinology.)

Objective: Thyroid dysfunction predicts poorer health outcomes, but the relationship between thyroid hormone levels within the reference range and mortality in older adults remains unclear. In this study, we examined the associations between the concentrations of free thyroxine (FT4) and TSH and all-cause mortality in older men without thyroid disease., Subjects and Methods: We performed a longitudinal study in community-dwelling men aged 70-89 years. Men with thyroid disease or taking thyroid-related medications were excluded. Baseline FT4 and TSH levels were assayed. Incident deaths were ascertained using data linkage., Results: There were 3885 men without thyroid disease followed for (means.d.) 6.41.5 years, during which time 837 had died (21.5%). men who had died had higher baseline ft4 levels (16.22.3 vs 15.82.1 pmol/l, p0.001), but comparable tsh levels (2.41.5 vs 2.31.5 miu/l, P=0.250). After accounting for age, smoking, physical factors and medical comorbidities, higher circulating ft4 levels predicted all-cause mortality (quartile Q4 vs quartiles Q1Q3: FT4 levels ≥ 17.32 vs <17.32 pmol/l: adjusted hazard ratio (HR)=1.19, 95% CI=1.02-1.39, P=0.025). TSH levels did not predict mortality. After excluding men with subclinical hyperthyroidism or hypothyroidism, there were 3442 men and 737 who had died (21.4%). In these men, higher FT4 levels remained independently associated with all-cause mortality (quartile Q4 vs quartiles Q1-Q3: adjusted HR=1.19, 95% CI=1.02-1.41, P=0.032)., Conclusions: Higher FT4 levels are associated with all-cause mortality in euthyroid older men, independently of conventional risk factors and medical comorbidities. Additional research is needed to determine whether or not this relationship is causal and to clarify the utility of thyroid function testing to stratify mortality risk in ageing men.

Hypothyroidism remains a common late effect after irradiation of the neck/mediastinum for Hodgkins lymphoma (HL). We evaluated the protective effect of TSH suppression during neck/mediastinum irradiation. From 1998 to 2001, 14 consecutive euthyroid children were given, before and until the end of their radiotherapy on neck/mediastinum, L-thyroxine at TSH-suppressive doses. The 14 patients had adequate TSH suppression during irradiation in 8, inadequate in 6. The 8-year hypothyroidism-free-survival after irradiation was 75 ± 15% for the former group, 0% for the latter (P = 0.009). TSH suppression could have a protective effect on thyroid function as shown in a small group of patients with HL., (Copyright © 2011 Wiley-Liss, Inc.)