Increased risk of dementia in hypothyroidism: A Danish nationwide register-based study.

OBJECTIVE: Globally, the prevalence of individuals with dementia is increasing, and identification of risk factors is of paramount interest. Using population-based registers, we evaluated whether hypothyroidism is a risk factor for dementia. DESIGN: Register-based cohort study. PATIENTS AND METHODS: Risk of dementia was evaluated in two cohorts. The DNPR cohort comprises 111,565 hypothyroid patients, diagnosed between 1995 and 2012, and 446,260 euthyroid age- and sex-matched individuals (median follow-up 6.2 years). The OPENTHYRO cohort comprises 233,844 individuals with at least one measurement of serum thyrotropin (TSH) between 1995 and 2011, of whom 2,894 had hypothyroidism (median follow-up 7.2 years). Primary outcome was dementia defined as an International Classification of Diseases 10 code, or prescription of medicine for dementia. RESULTS: In the DNPR cohort, risk of dementia was significantly increased in subjects with hypothyroidism (HR 1.22; 95% CI: 1.17-1.27), which attenuated after adjusting for pre-existing comorbidity (HR 0.82; 95% CI: 0.79-0.86). Stratification of age into ≤56 and >56 years showed an inverse relationship between age and risk of dementia (HR≤56 years. 2.03; 95% CI: 1.62-2.53 and HR>56 years . 1.00; 95% CI: 0.96-1.05). In the OPENTHYRO cohort, the risk of dementia was significantly increased for each 6 months of elevated TSH (HR 1.12; 95% CI: 1.07-1.16). CONCLUSIONS: Hypothyroidism is associated with increased risk of dementia. The association is influenced by comorbidity and age. Every 6 months of elevated TSH increased the risk of dementia by 12%, suggesting that also the length of hypothyroidism influences the risk of dementia.

Graves' Disease and Toxic Nodular Goiter, Aggravated by Duration of Hyperthyroidism, Are Associated with Alzheimer's and Vascular Dementia: A Registry-Based Long-Term Follow-Up of Two Large Cohorts.

Background: Dementia is an increasing burden to the health care system. It is currently debated whether hyperthyroidism is associated with a risk of dementia. Our aim was to determine the risk of dementia in hyperthyroid individuals and whether this was associated with duration of hyperthyroidism. Methods: Risk of dementia in hyperthyroid individuals was evaluated in two cohorts and matched reference populations. The Danish National Patient Registry (DNPR) cohort is a registry-based Danish nationwide cohort followed for a median of 7.2 years (from 1995 to 2013), whereas the OPENTHYRO registry cohort comprises 235,547 individuals who had at least one serum thyrotropin (TSH) measurement in the period from 1995 to 2011 and was followed for a median of 7.3 years. Each hyperthyroid case was matched with four controls according to age and sex using density sampling. Hyperthyroidism was defined as either an International Classification of Diseases Version 10 (ICD-10) diagnosis of toxic nodular goiter (TNG) or Graves' disease (GD), or two measurements of a TSH below 0.3 mU/L in the DNPR and OPENTHYRO registry cohort, respectively. The primary outcome was all-cause dementia, defined as either an ICD-10 code of dementia or prescription of medicine for dementia, with subgroup analyses of vascular dementia and Alzheimer's disease. Results: The DNPR cohort had 56,128 patients with hyperthyroidism, 2689 of whom were registered with dementia. The reference population had 224,512 individuals, of whom 10,199 had dementia (hazard ratio 1.17; 95% confidence interval [CI]: 1.12-1.23). Risk of dementia, whether Alzheimer's or vascular, was higher in both GD and TNG. The OPENTHYRO registry cohort constituted 2688 hyperthyroid individuals and 10,752 euthyroid control individuals of whom 190 and 473 individuals, respectively, were subsequently diagnosed with dementia (HR 1.06; 95% CI: 0.89-1.26). For each 6 months of decreased TSH, the risk of all-cause dementia was significantly higher (HR 1.16; 95% CI: 1.12-1.22). Conclusions: Using large-scale registry-based data, we found increased risk of dementia in hyperthyroid individuals. Every 6 months of decreased TSH was associated with increased risk of dementia by 16%, compared with individuals with normal TSH. Our data support early diagnosis and intervention in patients with hyperthyroidism.

Duration of over- and under-treatment of hypothyroidism is associated with increased cardiovascular risk.

Objective To investigate the association between hypothyroidism and cardiovascular disease (CVD) in both treated and untreated hypothyroid patients, and the consequences of over- and under-treatment with respect to cardiovascular risk. Design A registry-based case-control study nested within a population-based cohort of 275 467 individuals with at least one serum thyroid stimulating hormone (TSH) measurement in the period of 1995-2011. Methods Incident cases of CVD were matched with controls according to gender, age and year of birth. Conditional logistic regression analyses were performed to calculate CVD risks associated with exposure to hypothyroidism, with adjustment for 19 pre-existing comorbidities, including cardiovascular disease and diabetes, using the Charlson Comorbidity Index. Results Overall, 20 487 individuals experienced CVD (9.4%, incidence rate 13.1 per 1000 person-years, 95% confidence interval (CI), 13.0-13.3). Risk of CVD was increased in untreated hypothyroidism compared to euthyroidism (odds ratio (OR): 1.83 (95% CI: 1.43-2.35; P < 0.001)). Cardiovascular risk was increased in both treated and untreated hypothyroid individuals per half year of elevated TSH (OR: 1.11 (95% CI: 1.06-1.16; P < 0.001) and OR: 1.15 (95% CI: 1.09-1.23; P = 0.001), respectively). In patients treated with levothyroxine, OR for CVD was 1.12 (95% CI: 1.06-1.18; P < 0.001) for each 6 months of decreased TSH. Conclusion Cardiovascular risk is increased in untreated, but not in treated hypothyroid patients. Among those with treated hypothyroidism, duration of decreased TSH (overtreatment) had a similar impact on cardiovascular risk as duration of elevated TSH (under-treatment), highlighting the importance of initiating treatment and maintaining biochemical euthyroidism in hypothyroid patients in order to reduce the risk of CVD and death.

Duration of Hyperthyroidism and Lack of Sufficient Treatment Are Associated with Increased Cardiovascular Risk.

BACKGROUND: Cardiovascular disease remains the most prevalent cause of death in hyperthyroidism. However, the impact on cardiovascular events of varying thyroid status and of treatment remains unclarified. The aims of this study were to investigate the association between hyperthyroidism and cardiovascular events in treated and untreated hyperthyroid individuals, as well as exploring the impact of cumulative periods of hyperthyroidism as a proxy for undertreatment on cardiovascular events. METHOD: This was a case-control study nested within a population-based cohort of individuals attending health services in Funen County, Denmark, in the period from 1995 to 2011. Data on comorbidities and mortality were collected from The Danish National Patient Register and The Danish Register of Causes of Death. Participants were 275,467 individuals with at least one serum thyrotropin (TSH) measurement in the study period. Hyperthyroidism was defined as at least two measurements of decreased serum TSH within six months, separated by at least 14 days. Incident cases of cardiovascular disease (myocardial infarction, atrial fibrillation, heart failure, stroke, and cardiovascular death) were matched with controls. Conditional logistic regression analyses were performed to calculate odds ratios (OR) for exposure to hyperthyroidism, adjusting for preexisting comorbidities. RESULTS: A total of 20,651 individuals experienced a cardiovascular event (9.5% incidence rate 13.2/1000 person-years [confidence interval (CI) 13.0-13.4]) compared to euthyroid individuals, conditional logistic regression showed increased cardiovascular risk in untreated hyperthyroid patients (OR = 1.25 [CI 1.06-1.48], p = 0.007) but not in treated hyperthyroid patients (OR = 1.04 [CI 0.90-1.22], p = 0.57)]. The OR for cardiovascular events per six months of decreased TSH was 1.09 ([CI 1.05-1.14], p < 0.001) in treated hyperthyroid individuals, and 1.10 ([CI 1.05-1.15], p < 0.001) in untreated hyperthyroid individuals. CONCLUSIONS: The risk of cardiovascular disease was found to be increased in untreated hyperthyroid patients, and the duration of decreased TSH associated with increasing risk of cardiovascular outcomes in both treated and untreated hyperthyroid individuals. This suggests that increased cardiovascular risk is driven not only by lack of treatment but also by insufficient therapy. The results support timely treatment and careful monitoring of hyperthyroid patients in order to reduce cardiovascular risk.

Over- and Under-Treatment of Hypothyroidism Is Associated with Excess Mortality: A Register-Based Cohort Study.

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.

Excess Mortality in Treated and Untreated Hyperthyroidism Is Related to Cumulative Periods of Low Serum TSH.

Introduction and Aim: Cumulative time-dependent excess mortality in hyperthyroid patients has been suggested. However, the effect of antithyroid treatment on mortality, especially in subclinical hyperthyroidism, remains unclarified. We investigated the association between hyperthyroidism and mortality in both treated and untreated hyperthyroid individuals. Patients and Methods: Register-based cohort study of 235,547 individuals who had at least one serum thyroid-stimulating hormone (TSH) measurement in the period 1995 to 2011 (7.3 years median follow-up). Hyperthyroidism was defined as at least two measurements of low serum TSH. Mortality rates for treated and untreated hyperthyroid subjects compared with euthyroid controls were calculated using multivariate Cox regression analyses, controlling for age, sex, and comorbidities. Cumulative periods of decreased serum TSH were analyzed as a time-dependent covariate. Results: Hazard ratio (HR) for mortality was increased in untreated [1.23; 95% confidence interval (CI), 1.12 to 1.37; P < 0.001], but not in treated, hyperthyroid patients. When including cumulative periods of TSH in the Cox regression analyses, HR for mortality per every 6 months of decreased TSH was 1.11 (95% CI, 1.09 to 1.13; P < 0.0001) in untreated hyperthyroid patients (n = 1137) and 1.13 (95% CI, 1.11 to 1.15; P < 0.0001) in treated patients (n = 1656). This corresponds to a 184% and 239% increase in mortality after 5 years of decreased TSH in untreated and treated hyperthyroidism, respectively. Conclusions: Mortality is increased in hyperthyroidism. Cumulative periods of decreased TSH increased mortality in both treated and untreated hyperthyroidism, implying that excess mortality may not be driven by lack of therapy, but rather inability to keep patients euthyroid. Meticulous follow-up during treatment to maintain biochemical euthyroidism may be warranted.

Is previous hyperthyroidism associated with long-term cognitive dysfunction? A twin study.

OBJECTIVE: Hyperthyroidism has been suggested to adversely affect cognitive function. However, this association could also be caused by genetic and environmental factors affecting both the development of hyperthyroidism and cognitive functioning. By investigating twin pairs discordant for hyperthyroidism, this potential confounding can be minimized. The aim of the study was to examine whether hyperthyroidism is associated with long-term cognitive dysfunction. DESIGN: Twin case-control study. PATIENTS: Twin pairs discordant for hyperthyroidism were identified by record linkage between The Danish National Patient Registry and 3036 twin pairs from The Danish Twin Registry, who had participated in nationwide surveys on health conditions. MEASUREMENTS: Among other investigations, survey participants had carried out cognitive tests including a Mini-mental state examination (MMSE) and six separate cognitive tests. Based on five of the tests, a composite cognitive score was calculated. RESULTS: Fifty-five of 3036 twin pairs were discordant for hyperthyroidism. The mean time from diagnosis until survey participation was 7·3 years (range: 0-24·1 years). In both the intrapair and individual-level analyses, the hyperthyroid twin scored significantly better in the MMSE than did the healthy co-twin (P = 0·023 and P = 0·038, respectively). The same tendency was found in the other cognitive tests, and after analysing twins diagnosed with hyperthyroidism more than 2 years before participating, although none were statistically significant. CONCLUSION: Utilizing discordant twin pairs to control for genetic as well as early environmental factors, we could not demonstrate any clinically relevant negative impact of previous hyperthyroidism on long-term cognitive function.