The Impact of Post-Thyroidectomy Neck Stretching Exercises on Neck Discomfort, Pressure Symptoms, Voice and Quality of Life: A Randomized Controlled Trial.

BACKGROUND: Following surgery for benign nodular goiter, patients may experience neck and shoulder pain, neck pressure and tightness, choking sensation, altered voice function, and dysphagia leading to decreased short-term quality of life (QoL). This single-blinded randomized controlled trial investigated the effect of post-thyroidectomy rehabilitative neck stretching and movement exercises on these variables including QoL. METHODS: Patients undergoing thyroid lobectomy or total thyroidectomy were randomized to perform neck stretching and movement exercises three times daily in four weeks following surgery (intervention group) or conventional follow-up without exercises (control group). Outcome measures were scores in the following questionnaires: Disease-specific Thyroid-Related Patient-Reported Outcome (ThyPRO-39) involving symptoms of "sense of fullness in the neck," "pressure in the throat," and "discomfort swallowing" combined in the multi-item Goiter Symptom Scale, the Voice Handicap-Index-10 (VHI-10), neck and shoulder pain measurement by a numeric rating scale (NRS), and General measure of health (EQ-5D-5L). All scores were assessed prior to surgery and one, two, four weeks, and three months after surgery. Data were analyzed using a linear mixed model. RESULTS: Eighty-nine patients were included and randomized to the control (n = 45) or the intervention group (n = 44). At three months after surgery, both the control and the intervention group experienced large to moderate improvements in the Goiter symptom and Hyperthyroid symptom scale of the ThyPRO questionnaire (p < 0.004). No significant between-group differences were found in any of the other applied scales. CONCLUSIONS: This study confirms that patients experience profound improvements in QoL after surgery for benign nodular goiter. However, early post-thyroidectomy neck stretching and movement exercises did not result in further QoL improvement, reduction in pain or less impacted subjective voice function for patients primarily undergoing thyroid lobectomy. Trial Registration Number NCT04645056 ( https://clinicaltrials.gov ).

Month of birth is associated with the subsequent diagnosis of autoimmune hypothyroidism. A nationwide Danish register-based study.

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.

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.

Hyperthyroidism and the risk of non-thyroid cancer: a Danish register-based long-term follow-up study.

Objective: Cancer is the second most common cause of death worldwide. It is currently debated whether thyroid dysfunction is a modifiable cancer risk factor. Our aim was to evaluate the risk of cancer in patients with hyperthyroidism. Methods: This is a register-based nationwide cohort study of individuals with a diagnosis of hyperthyroidism. Each hyperthyroid case was matched with four reference individuals according to age and sex. Using Fine and Gray competing risk regression models, we studied the association of hyperthyroidism and subsequent all-cause cancer diagnoses, adjusted for preexisting morbidity. Sub-analyses were stratified for cause of hyperthyroidism (Graves' disease and toxic nodular goiter, age when diagnosed with hyperthyroidism, sex, and cancer localization (lung, prostate, breast, and colorectal cancer)). Results: The cohort consisted of 95,469 patients with hyperthyroidism (followed for a median of 10.9 years (range: 5.2-17.2)), and 364,494 reference individuals (followed for a median of 11.2 years (range: 5.4-17.4)). Hyperthyroidism was associated with increased all-cause cancer risk (sub-distribution hazard ratio (SHR): 1.12; 95% CI: 1.10-1.14), as well as an increased risk of breast (SHR: 1.07; 95% CI: 1.02-1.13), lung (SHR: 1.20; 95% CI: 1.16-1.26), and prostate cancer (SHR: 1.10; 95% CI: 1.02-1.19), but not colorectal cancer (SHR: 1.04; 95% CI: 0.99-1.09). Sub-analyses stratified for age when diagnosed with hyperthyroidism and cause of hyperthyroidism yielded similar results. Conclusion: In this register-based study, patients with hyperthyroidism had an increased risk of cancer, in particular lung, prostate, and breast cancer. Whether a causal link exists remains to be proven.

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Lingual thyroid in a 16-year-old girl.

Lingual thyroid is a rare congenital disorder displaying ectopic thyroid tissue at the base of the tongue. This is the most common location for ectopic thyroid tissue and is usually the only thyroid tissue present. This is a case report of a 16-year-old female who presented with nasal congestion. Fiberoptic laryngoscopy showed swelling at the base of the tongue and an ultrasound examination of the neck was without visible thyroid tissue. A 99mTc-pertechnetate scintigraphy confirmed the clinical diagnosis. As the patient was euthyroid and without symptoms active surveillance was planned.

Hyperthyroidism in pregnancy: design and methodology of a Danish multicenter study.

BACKGROUND: Graves' disease (GD) is the main cause of hyperthyroidism in women of the fertile age. In pregnant women, the disease should be carefully managed and controlled to prevent maternal and fetal complications. Observational studies provide evidence of the adverse effects of untreated hyperthyroidism in pregnancy and have in more recent years substantiated a risk of teratogenic side effects with the use of antithyroid drugs (ATDs). These findings have challenged the clinical recommendations regarding the choice of treatment when patients become pregnant. To extend observational findings and support future clinical practice, a systematic collection of detailed clinical data in and around pregnancy is needed. METHODS: With the aim of collecting clinical and biochemical data, a Danish multicenter study entitled 'Pregnancy Investigations on Thyroid Disease' (PRETHYR) was initiated in 2021. We here describe the design and methodology of the first study part of PRETHYR. This part focuses on maternal hyperthyroidism and recruits female patients in Denmark with a past or present diagnosis of GD, who become pregnant, as well as women who are treated with ATDs in the pregnancy, irrespective of the underlying etiology. The women are included during clinical management from endocrine hospital departments in Denmark, and study participation includes patient questionnaires in pregnancy and postpartum as well as review of medical records from the mother and the child. RESULTS: Data collection was initiated on November 1, 2021 and covered all five Danish Regions from March 1, 2022. Consecutive study inclusion will continue, and we here report the first status of inclusion. As of November 1, 2022, a total of 62 women have been included in median pregnancy week 19 (interquartile range (IQR): 10-27) with a median maternal age of 31.4 years (IQR: 28.5-35.1). At inclusion, 26 women (41.9%) reported current use of thyroid medication; ATDs (n = 14), Levothyroxine (n = 12). CONCLUSION: This report describes a newly established systematic and nationwide collection of detailed clinical data on pregnant women with hyperthyroidism and their offspring. Considering the course and relatively low prevalence of GD in pregnant women, such nationwide design is essential to establish a sufficiently large cohort.

Twin studies as a model for exploring the aetiology of autoimmune thyroid disease.

Twins are an important resource for evaluating the relative contribution of genetic and environmental factors in determining a phenotype. During the last decades, a number of twin studies have investigated the aetiology of several phenotypes related to thyroid autoimmunity. Taken together, these studies have provided valid and unbiased information regarding the influence of genetic and environmental factors in the aetiology of autoimmune thyroid disease (AITD). The comparison of concordance rates between monozygotic (MZ) and dizygotic twins provides irrefutable evidence of a genetic component, and biometric twin modelling shows that approximately 75% of the total phenotypic variance in AITD is because of genetic effects. On the other hand, the lack of complete concordance in MZ twin pairs is proof of environmental and/or epigenetic factors also playing an important role. The impact of environmental triggers such as cigarette smoking, birth characteristics, infection with Yersinia enterocolitica, microchimerism and degree of X chromosome inactivation (XCI) has been evaluated by investigating AITD discordant twin pairs. These studies indicate that smoking, Y. enterocolitica infection and skewed XCI may be causally associated with clinically overt AITD, but not with the presence of thyroid autoantibodies in euthyroid subjects. Microchimerism, but not birth weight, might play a role in AITD. Twin studies offer several features that uniquely enhance our ability to localize genes and understand their function. Future twin studies should incorporate information on genetic, epigenetic and environmental variation thereby enhancing our ability to quantify the precise effect of specific risk factors.

Consequences of Hyperthyroidism and Its Treatment for Bone Microarchitecture Assessed by High-Resolution Peripheral Quantitative Computed Tomography.

Background: Hyperthyroidism is associated with bone mass reduction and increased fracture risk, but the effects on other important bone parameters have been sparsely examined. Therefore, we investigated bone microarchitecture and estimated bone strength by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hyperthyroid patients at diagnosis and after being euthyroid for at least one year. Methods: Two approaches were used: (A) a case-control study comparing 61 hyperthyroid women with 61 euthyroid women matched for age and menopause status; (B) a follow-up study, in which 46 of the 61 women were re-examined after having been euthyroid for one year. HR-pQCT of the distal radius and tibia, and dual-energy X-ray absorptiometry (DXA) of the lumbar spine and the hip were performed. Results: In analysis A: In the radius, compared with the healthy controls, hyperthyroid patients had higher total area (16.9% ± 29.5%; p < 0.001), trabecular area (28.6% ± 45.7%; p < 0.001), and lower cortical area (-11.7% ± 23.2%; p < 0.001). Total volumetric bone mineral density (vBMD) (-13.9% ± 26.5%; p < 0.001), cortical vBMD (-5.8% ± 7.9%; p < 0.001), cortical thickness (-16.7% ± 26.0%; p < 0.001), and estimated bone strength (-6.6% ± 19.5%; p < 0.01) were lower. No significant differences were found in the tibia or in the DXA parameters. In analysis B: In the radius, significant improvements were observed in the cortical area (2.1% ± 4.6%; p < 0.01), cortical thickness (2.5% ± 5.1%; p < 0.001), and total vBMD (0.8% ± 3.0%; p < 0.05). Trabecular area decreased (-0.5% ± 1.0%; p < 0.01) and trabecular separation increased (2.0% ± 8.3%; p < 0.05). In the tibia, cortical area (3.6% ± 7.3%; p < 0.01) and cortical thickness (3.8% ± 7.6%; p < 0.01) increased, and trabecular area decreased (-0.5% ± 1.1%; p < 0.01). Areal BMD, measured by DXA, increased in the spine (1.1% ± 3.4%; p < 0.05) and in the hip (2.0% ± 3.8%; p < 0.01). Conclusions: Compared with the healthy control group, hyperthyroid women had lower vBMD, lower estimated bone strength, and compromised cortical microarchitecture in the radius. After restoration of euthyroidism, significant improvements in vBMD and cortical microarchitecture were observed, highlighting the importance of achieving and maintaining euthyroidism.

Restoration of euthyroidism in women with Hashimoto's thyroiditis changes bone microarchitecture but not estimated bone strength.

PURPOSE: Fracture risk in hypothyroid patients is debated, and since the effects of hypothyroidism on bone microarchitecture and strength are unclarified, we investigated these characteristics by high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: Two approaches were used: a cross-sectional control study, comparing 32 hypothyroid women (mean age; 47 ± 12 years) suffering from Hashimoto's thyroiditis with 32 sex-, age-, and menopause-matched healthy controls; a prospective study, where 27 of the women were reexamined 1 year after restoration of euthyroidism. HR-pQCT of the distal radius and tibia, and dual-energy X-ray absorptiometry (DXA) of the spine and hip were performed. Bone strength was estimated using a finite element analysis (FEA). RESULTS: Cross-sectional control study: in the radius, total (mean 14.6 ± 29.3% (SD); p = 0.04) and trabecular bone areas (19.8 ± 37.1%, p = 0.04) were higher, and cortical volumetric bone mineral density (vBMD) lower (-2.2 ± 6.5%, p = 0.032) in hypothyroid patients than in controls. All indices of tibia cortical and trabecular vBMD, microarchitecture, and estimated bone strength were similar between groups, as was hip and spine areal BMD (aBMD). Prospective study: in the radius, mean cortical (-0.9 ± 1.8%, p = 0.02) and trabecular (-1.5 ± 4.6%, p = 0.02) vBMD decreased, and cortical porosity increased (18.9 ± 32.7%, p = 0.02). In the tibia, mean total vBMD (-1.1 ± 1.9%, p = 0.01) and cortical vBMD (-0.8 ± 1.4%, p = 0.01) decreased, while cortical porosity (8.2 ± 11.5%, p = 0.002) and trabecular area (0.2 ± 0.6%, p = 0.047) increased. No changes in FEA were detected. Lumbar spine aBMD decreased (-1.3 ± 3.0%, p = 0.04). CONCLUSIONS: Hypothyroidism was associated with an increased trabecular bone area and a lower mineral density of cortical bone in the radius, as assessed by HR-pQCT. Restoration of euthyroidism mainly increased cortical porosity, while estimated bone strength was unaffected.

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.

X Chromosome inactivation pattern is not associated with interindividual variations in thyroid volume: a study of euthyroid Danish female twins.

Ahigher frequency of skewed X chromosome inactivation (XCI) is found in patients with autoimmune thyroid disease (AITD) than in controls. Although goitre is often present in AITD, a recent study failed to show an association between XCI and clinically overt nontoxic goitre. However, the etiology of overt goitre is complex, and the mechanisms influencing thyroid volume may involve fewer factors than the mechanisms underlying overt goitre. In order to examine the impact of XCI on thyroid volume in euthyroid females, we studied whether within cohort (n = 138) and within twin pair (n = 69) differences in XCI are correlated with differences in thyroid volume. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid volume was determined by ultrasound. Neither in the within cohort nor in the within twin pair analysis could we demonstrate a statistically significant association between XCI and thyroid volume: Regression coefficient (beta) = 0.023 (95% confidence interval, -0.062-0.108), p = 0.592 and beta = 0.038 (-0.080-0.156), p = 0.521, respectively. Controlling for potential confounders such as zygosity, age, TSH, smoking habits and use of oral contraceptives did not change the findings. In conclusion, in a sample of euthyroid Danish female twins, we found no evidence of a relationship between XCI pattern and thyroid volume.

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.

No evidence of a causal relationship between hypothyroidism and glaucoma: A Danish nationwide register-based cohort study.

BACKGROUND: 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. SUBJECTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

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.

No link between season of birth and subsequent development of Graves' disease or toxic nodular goitre: a nationwide Danish register-based study.

BACKGROUND: Season of birth, an exogenous indicator of early life environment, has been linked with a higher risk of adverse health outcomes such as autoimmune thyroiditis, multiple sclerosis and schizophrenia later in life. Whether the development and cause of hyperthyroidism is influenced by season of birth is unclarified. We aimed, at a nationwide level, to investigate whether season of birth influences the risk of hyperthyroidism due to Graves' disease (GD) and/or toxic nodular goitre (TNG). METHOD: Register-based nationwide cohort study. By record-linkage between Danish health registers, 36,087 and 20,537 patients with GD and TNG, respectively, were identified. Each case was matched with four controls without thyroid disease, according to age and sex. Differences in month-of-birth across the year were evaluated by the Walter-Elwood test. Hazard ratios, for the risk of GD and TNG in individuals born in a certain month or season of the year, were calculated using Cox regression models. RESULTS: Neither for GD nor for TNG could we demonstrate a significant difference in birth rate across months or seasons of the year (Walter-Elwood's test; X2 = 5.92 and X2 = 1.27, p = 0.052 and p=0.53, respectively). CONCLUSION: Irrespective of its cause, our findings do not support the hypothesis that season of birth is significantly related to the development of hyperthyroidism.

The interrelation between hypothyroidism and glaucoma: a critical review and meta-analyses.

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.

Death by Suicide in Graves' Disease and Graves' Orbitopathy: A Nationwide Danish Register Study.

BACKGROUND: Graves' disease (GD) is associated with excess morbidity and mortality, but little is known about unnatural manners of death and the potential relation with Graves' orbitopathy (GO). This study investigated the risk of unnatural death in Graves' patients with and without orbitopathy compared to matched control populations. METHODS: This was a cohort study covering all adult Danes (≥18 years) diagnosed with GD or GO during 1995-2012. Median follow-up time was 7.9 years (range 0-17.5 years). Utilizing the Danish Register of Causes of Death and the Danish National Patient Registry, 28,461 subjects with GD and 3965 with GO were identified and matched for age and sex with four subjects from the background population. The manner of death was identified, and hazard ratios (HR) for mortality due to unnatural deaths (accident, suicide, violence/homicide, and unknown) were calculated using Cox regression analyses, adjusted for pre-existing somatic and psychiatric morbidity. RESULTS: In Graves' disease overall (GD + GO), there was an increased risk of death from unknown unnatural manners (HR = 2.01 [confidence interval (CI) 1.17-3.45], p = 0.012) and of suicide, although the latter difference was not with certainty statistically significant (HR = 1.43 [CI 1.00-2.04], p = 0.053). There was no significant difference in risk of death from suicide in GD subjects compared to their controls (HR = 1.27 [CI 0.85-1.89], p = 0.253). However, GO patients had a significantly higher risk of death from suicide (HR = 2.71 [CI 1.16-6.32], p = 0.022). CONCLUSIONS: Mortality by suicide was increased in Graves' disease overall, most significantly in patients with GO, also after adjustment for pre-existing somatic and psychiatric disease. These findings indicate that GD and GO may have a significant role in the pathophysiological mechanisms of suicidal behavior. Beyond independent confirmation, reasons for this need to be explored in order to introduce preventive measures.