Marianne Thvilum

Objective: Persistent symptoms and impaired quality of life (QoL) in hypothyroidism despite treatment with levothyroxine (LT4) receive increasing attention. We aimed at reviewing QoL in long-term treated hypothyroidism. Design: This is a systematic review and meta-analysis. Methods: The systematic literature search “hypothyroidism AND quality of life” was conducted in PubMed and Embase. We considered studies on QoL in adults with Hashimoto's thyroiditis (HT) or congenital hypothyroidism (CH), treated with levothyroxine for 6 months. Seven hundred and ninety-seven articles were screened for title-abstract, and 52 were assessed by full-text evaluation. Seventeen articles met eligibility criteria and were included. We summarize study finding within the domains mental well-being, physical well-being, and social role supported by meta-analyses. Studies were evaluated using Newcastle–Ottawa Scale. Two meta-analyses were performed using random effects model. Results: Fourteen studies included patients with HT, and 3 evaluated QoL in CH. Mental and physical well-being was impaired in 10 studies, and social role impairments were detected in 7 studies. Study design was to some degree flawed in 13 studies, potentially hampering conclusions. The most frequent methodological issues were incomparable groups or lack of information on potential confounders like body mass index or comorbidity. However, when focusing on the methodologically most robust studies, conclusions remained and were supported by meta-analyses. Conclusion: Based on this systematic review and meta-analysis, despite methodological concerns in the available literature, QoL in patients with hypothyroidism is impaired. Future studies should address potential residual bias displayed and explore the impact of disease etiology, duration, and timing of diagnosis in relation to comorbidity, to reveal groups of patients susceptible to inadequate treatment response and guide our way to improve QoL in hypothyroidism.

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.

Hashimoto’s thyroiditis (HT) is associated with excess psychiatric in addition to reduced quality of life. However, little is known about risk of unnatural manners of death in HT. We investigated the risk of death by accidents, suicide, violence/homicide, and unknown causes in patients with HT, compared to a matched control population.

An interrelationship between hypothyroidism and glaucoma, due to a shared autoimmune background or based on deposition of mucopolysaccharides in the trabecular meshwork in the eye, has been suggested but is at present unsubstantiated. Therefore, our objective was to investigate, at a nationwide and population-based level, whether there is such an association. Observational cohort study using record-linkage data from nationwide Danish health registers. 121,799 individuals diagnosed with a first episode of hypothyroidism were identified and were matched with 4 non-hypothyroid controls according to age and sex. Prevalence of glaucoma was recorded and cases and controls were followed over a mean of 7.1 years (range 0–17). Logistic and Cox regression models were used to assess the risk of glaucoma before and after the diagnosis of hypothyroidism, respectively. Overall, we found a higher prevalence of glaucoma in subjects with hypothyroidism as compared to controls (4.6% vs. 4.3%, p < 0.001). Prior to the diagnosis of hypothyroidism, the odds ratio (OR) was significantly increased for glaucoma [1.09; 95% confidence interval (CI): 1.04–1.13]. Based on the Cox regression model, there was no increased risk of glaucoma after the diagnosis of hypothyroidism [hazard ratio (HR) 1.00; 95% CI: 0.96–1.06], and the HR decreased further after adjusting for pre-existing co-morbidity (0.88; 95% CI: 0.84–0.93). There was an increased risk of glaucoma before but not after the diagnosis of hypothyroidism, suggesting that screening for glaucoma in hypothyroid individuals is unwarranted.

Summary: Background: The triggering of thyroid autoimmunity in the genetically susceptible remains a conundrum. Environmental exposures during gestation and/or early postnatally have proponents, as suggested in diabetes mellitus, with a higher incidence of births during spring and summer. Whether the development of autoimmune hypothyroidism (AIT) is influenced by month or season of birth is less clear.Method: Nationwide cohort study of 111 565 individuals diagnosed with AIT and four euthyroid controls per case, matched according to age and sex, were identified from Danish health registers. Differences in month of birth across the year were evaluated by the Walter‐Elwood test. The risk of patients with AIT being born in a certain month or season of the year was calculated using a Cox regression model.Results: There was a significant difference in birth month between cases and controls, P<.001. Individuals with AIT had a significantly increased risk of being born in June (Hazard ratio 1.04; 95% Confidence interval (CI): 1.02‐1.08) and in the summer (June‐August; HR 1.02; 95%CI: 1.01‐1.04).Conclusion: In this large‐scale nationwide cohort study, we found a higher risk of AIT when born in the summer season or more specifically in June, supporting the hypothesis that seasonal variations in exposures—gestationally and/or early postnatally—may contribute to the development of AIT.

Data on the association between hypothyroidism and glaucoma are conflicting. We sought to shed light on this by conducting a critical review and meta‐analyses. The meta‐analyses were conducted in adherence with the widely accepted MOOSE guidelines. Using the Medical Subject Heading (MeSH) terms: hypothyroidism, myxoedema and glaucoma or intraocular pressure, case–control studies, cohort studies and cross‐sectional studies were identified (PubMed) and reviewed. Using meta‐analysis, the relative risk (RR) of coexistence of glaucoma and hypothyroidism was calculated. Based on the literature search, thirteen studies fulfilled the inclusion criteria and could be categorized into two groups based on the exposure. The designs of the studies varied considerably, and there was heterogeneity related to lack of power, weak phenotype classifications and length of follow‐up. Eight studies had glaucoma (5757 patients) as exposure and hypothyroidism as outcome. Among these, we found a non‐significantly increased risk of hypothyroidism associated with glaucoma (RR 1.65; 95% confidence interval [CI]: 0.97–2.82). Based on five studies (168 006 patients) with hypothyroidism as exposure and glaucoma as outcome, we found the risk of glaucoma to be significantly increased (RR 1.33; 95% CI: 1.13–1.58). Based on these meta‐analyses, there seems to be an association between hypothyroidism and glaucoma, which does not seem to be the case between glaucoma and hypothyroidism. However, larger scale studies with better phenotype classification, longer follow‐up and taking comorbidity and other biases into consideration are needed to address a potential causal relationship.

Background: Hypothyroidism has been linked with an increased risk of morbidity such as cardiovascular disease and diabetes mellitus. However, it is unknown whether the burden of morbidity is present before or after the diagnosis of hypothyroidism. Aim: Evaluate the temporality and type of morbidity in hypothyroid patients. Methods: Observational cohort study. Based on record-linking between official Danish health registers 2822 subjects with hypothyroidism were identified and matched with four non-hypothyroid controls and followed over a mean period of 6 years. Prevalence of cardiovascular diseases (CVD), lung diseases, diabetes mellitus (DM), rheumatic diseases (RHD) and malignant diseases were recorded. Logistic and cox regression models were used to assess the risk of morbidity before and after the diagnosis of hyperthyroidism, respectively. Results: In subjects with hypothyroidism, the odds ratio (OR) was significantly increased for CVD (OR 1.37; 95% CI: 1.19–1.58), lung diseases (OR 1.25; 95% CI: 1.13–1.39), DM (OR 1.92; 95% CI: 1.61–2.29) as well as malignant diseases (OR 1.24; 95% CI: 1.06–1.45), prior to the diagnosis of hypothyroidism. The hazard ratio (HR) for disease after the diagnosis of hypothyroidism was significantly increased for CVD (HR 1.36; 95% CI: 1.15–1.60); lung diseases (HR 1.51; 95% CI: 1.30–1.75); and DM (HR 1.40; 95% CI: 1.11–1.77). Conclusions: Prior to the diagnosis of hypothyroidism there is an increased risk of being diagnosed with CVD, lung diseases, DM, and malignant diseases. Following the diagnosis of hypothyroidism there is an increased frequency of CVD, lung diseases, and DM.

Background: Hyperthyroidism has been associated with increased all-cause mortality. Whether the underlying cause of hyperthyroidism influences this association is unclear. Our hypothesis was that Graves’ disease (GD) and toxic nodular goiter (TNG) differ with respect to mortality risk and cause of death. Methods: An observational cohort study, using record-linkage data from nation-wide Danish health registers. 1.291 and 861 subjects with GD and TNG, respectively, treated in a hospital setting, were identified and followed for a mean period of 11 years. Cases were matched 1:4 with non-hyperthyroid controls with respect to age and sex. The hazard ratio (HR) for mortality was calculated using Cox regression analyses. All analyses were adjusted for co-morbidity, using the Charlson score. Results: Both GD (HR=1.42, 95% CI 1.25–1.60) and TNG (HR=1.22, 95% CI 1.07–1.40) were associated with increased all-cause mortality. After stratification for the cause of death, GD was associated with increased mortality due to cardiovascular diseases (HR=1.49, 95% CI 1.25–1.77) and lung diseases (HR=1.91, 95% CI 1.37–2.65), whereas TNG was associated with increased cancer mortality (HR=1.36, 95% CI 1.06–1.75). When analyzing mortality in GD using TNG individuals as controls, there was no significant difference in all-cause mortality between GD and TNG. However, GD was clearly associated with a higher cardiovascular mortality (HR=1.39, 95% CI 1.10–1.76) compared to TNG. Conclusion: Both GD and TNG, treated in a hospital setting, are associated with increased all-cause mortality. The causes of death differ between the two phenotypes with cardiovascular mortality being significantly higher in GD.