Association of Levothyroxine Treatment and Thyroid Peroxidase Antibodies with Antidepressant Use: A Danish Population-Based Longitudinal Study.

Background: Subjects receiving levothyroxine (LT4) treatment have increased prevalence of depression, anxiety, and antidepressant use, but whether the underlying mechanism relates to thyroid autoimmunity is still unclarified. Methods: This is a population-based longitudinal study. Baseline biochemical and questionnaire data from the Danish General Suburban Population Study (GESUS) in 2010-2013 were linked with individual-level longitudinal data in national health registries. The aim was to investigate the associations between thyroid peroxidase antibodies (TPOAbs) and LT4 treatment, separately and through interaction, and at least one redeemed prescription for antidepressants. Logistic and Cox regression were used to evaluate initiation of antidepressant use before and after the baseline examination in GESUS, respectively. All exposures and covariates were fixed at the date of baseline examination. Thyroid autoimmunity was defined as serum TPOAbs >60 U/mL. Adjustments included sex, age, education, income, Charlson comorbidity index, smoking, and alcohol. Sensitivity analyses were performed for missing variables, exclusion of lithium use, exclusion of thyroid surgery, and conservative definitions for LT4 treatment and antidepressant use requiring at least two prescriptions. Results: We included 12,894 individuals, of whom 2353 (18%) had "past or current" antidepressant use at baseline, leaving 10,541 individuals at risk for incident antidepressant use after baseline. The median follow-up was 7.8 years during which 783 individuals (7.4% of 10,541 individuals) had incident antidepressant use. TPOAb positivity was not associated with "past or current" (odds ratio [OR] 0.90 [confidence interval, CI 0.78-1.03], p = 0.13) nor incident antidepressant use (hazard ratio [HR] 1.02 [CI 0.83-1.25], p = 0.88). LT4 treatment was associated with increased "past or current" antidepressant use (OR 1.33 [CI 1.10-1.62], p = 0.004) and increased incident antidepressant use (HR 1.38 [CI 1.03-1.85], p = 0.03). There were no interactions between the effects of TPOAb positivity and LT4 treatment on the use of antidepressants in logistic (p = 0.87) or Cox regression models (p = 0.82). Sensitivity analyses were robust, except that incident use of at least two redeemed antidepressant prescriptions was not statistically significant. Conclusions: LT4 treatment, but not TPOAb positivity, was associated with increased prevalent or incident antidepressant use with at least one prescription. Our findings do not support that thyroid autoimmunity is an important factor for antidepressant use in patients receiving LT4 treatment.

Socioeconomic influence on treatment with liothyronine and desiccated thyroid extract in Denmark.

Introduction: High compared with low educational level increases the odds of starting levothyroxine (L-T4) with a normal thyroid-stimulating hormone - the mechanism is most likely patient request. The use of liothyronine (L-T3) and desiccated thyroid extract (DTE) is also speculated to be initiated at patients' request. Therefore, the primary aim of this study was to evaluate if educational level influences treatment with L-T3 and DTE. Material and methods: In this register-based cross-sectional study, we included all Danish citizens ≥30 years with redeemed prescription of L-T4, L-T3, or DTE during 2017-2020. We defined educational levels as short, medium, and long (<10 years, 10-12 years, and above 12 years, respectively). The association between educational level and treatment with LT3 or DTE vs only LT4 was analyzed in logistic regression models adjusted for age and sex. Results: We included 154,360 individuals using thyroid medication of whom 3829 were treated with L-T3 (2.48%) and 430 with DTE (0.28%). The usage was highest among women (3.15%) and the age group 40-49 (5.6%). Longer education compared with short increased the odds of being treated with DTE or L-T3 (medium education odds ratio (OR) 1.61 (95% CI 1.50-1.8) and long education OR 1.95 (95% CI 1.79-2.13)). Test for trend: OR: 1.37 (95% CI 1.31-1.42). Adjustment for other covariates did not affect the results substantially. Conclusion: Persons with a longer compared to a shorter education are more often treated with either DTE or L-T3, and the usage of these drugs is limited to less than 3% of thyroid hormone users.

Risk of over- and under- treatment with levothyroxine in primary care in Copenhagen, Denmark.

OBJECTIVE: A decrease over time in thyroid stimulating hormone (TSH) levels when initiating levothyroxine (L-T4) therapy for hypothyroidism has been reported, where treatment most often is initiated with TSH levels below 10 mIU/L. The primary objective of this study was to investigate whether this lower TSH threshold resulted in an increased number of overtreated patients. DESIGN AND METHOD: Retrospective cohort study comprising inhabitants in Copenhagen had TSH measurements requested by general practitioners which led to a new prescription of L-T4 between 2001 and 2012. Over- and under- treatment were defined as TSH <0.1 mIU/L or above 10 mIU/mL, respectively, in three consecutive measurements. Data were analyzed by Aalen-Johansen estimators and Cox proportional hazards models. RESULTS: In total, 14 533 initiations of L-T4 were included in the study. The cumulative risk of being over- or undertreated was 4.7 and 7.4% after 10 years. The hazard of overtreatment was higher among women, younger adults, and with lower initial TSH levels. The hazard of overtreatment decreased over the time period from 2001 to 2012. Among overtreated individuals, the chance of returning to a normal TSH was about 55% after 10 years. In 18% of the cases, L-T4 therapy was initiated on TSH levels less than 5 mIU/L. CONCLUSION: Although a still decreasing threshold for initiating L-T4 therapy is known, the risk of overtreatment (and undertreatment) was low and lessened in the period 2001-2012 among Danish primary care patients. Nevertheless, as many as 18% were started on L-T4 with normal TSH levels.

Association Between 3-Iodothyronamine (T1am) Concentrations and Left Ventricular Function in Chronic Heart Failure.

CONTEXT: Thyroid hormone metabolites might affect the heart. The endogenous aminergic metabolite 3-iodothyronamine (T1am) reduces left ventricular ejection fraction (LVEF) in rodents. OBJECTIVE: To investigate concentration of T1am and its association with LVEF and biomarkers of heart function in patients with chronic heart failure (CHF) without thyroid disease, including patients with cardiac cachexia (nonedematous weight loss >5% over 6 months). METHODS: Cross-sectional study. CHF was characterized by LVEF <45% and symptoms. Three groups were included (n = 19 in each group, matched on age, sex, and kidney function): patients with cachexia (CAC), patients without (non-CAC), and control (C) patients with prior myocardial infarction and LVEF >45%. T1am was measured by a monoclonal antibody-based chemiluminescence immunoassay. N-amino terminal pro-BNP (NT-proBNP) concentrations were also analyzed. RESULTS: Mean (SD) LVEF: CAC, 32 ± 9%; non-CAC, 38 ± 8%; and C, 60 ± 8% (P < 0.0001). TSH, T4, and T3 levels did not differ between groups and did not correlate to T1am. Serum T1am (nmol/L) concentrations were higher in CHF: CAC (mean ± SD), 12.4 ± 6.6; non-CAC, 9.1 ± 5; and C, 7.3 ± 2.9. A negative association between T1am and LVEF was present after adjusting for sex, age, T3, and estimated glomerular filtration rate (P = 0.03). Further, serum T1am levels tended to be associated with NT-proBNP (P = 0.053). CONCLUSION: Serum T1am levels were increased in patients with CHF and numerically highest (although nonsignificant) in patients with cardiac cachexia. Increasing T1am concentrations were independently associated with reduced LVEF, suggesting a direct effect on the human heart.

Changes in Prescription Routines for Treating Hypothyroidism Between 2001 and 2015: An Observational Study of 929,684 Primary Care Patients in Copenhagen.

Background: Increased public attention toward health and quality-of-life issues has led to more intensified screening for various medical conditions, including hypothyroidism. A falling serum thyrotropin (s-TSH) at initiation of levothyroxine (LT4) treatment has been reported in the United Kingdom between 2001 and 2009, indicating a falling TSH threshold, which may lead to less benefit from therapy and possibly overtreatment. The aim of this study was to investigate changes in s-TSH threshold used by general practitioners to initiate LT4 therapy between 2001 and 2015 in Copenhagen. Methods: Retrospective analysis was conducted of all s-TSH measurements between 2001 and 2015 performed at the general practitioners' joint laboratory merged with The Danish Register of Medicinal Products Statistics and The Danish National Patient Registry. For each year, both the median s-TSH at therapy initiation and the estimated treatment threshold were calculated from all s-TSH measurements performed in that year, representing the s-TSH level where the estimated probability of starting LT4 therapy was 50%. Results: A total of 929,684 individuals with 2,975,277 s-TSH measurements were included in the calculations. The size and composition of the study population remained virtually unchanged. During the study period, the number of performed s-TSH measurements increased from 110,886 to 292,911 (164%), and the number of patients initiating LT4 therapy increased from 786 to 1825 (132%), though this was comparably unchanged from 2010 to 2015. The median s-TSH at therapy initiation decreased from 10 mIU/L (interquartile range 5.2-29.7 mIU/L) in 2001 to 6.8 mIU/L (interquartile range 5.1-11 mIU/L) in 2015, while the estimated treatment threshold decreased from 28.3 mIU/L [confidence interval 21.0-40.2 mIU/L] in 2001 to 14.2 mIU/L [confidence interval 12.0-18.0 mIU/L] in 2007. In 2015, 25% of patients started LT4 therapy with s-TSH ≤5 mIU/L, and during the entire period, 50% of patients started therapy with a single s-TSH measurement >5 mIU/L. Conclusions: This study performed on a sizeable primary care population demonstrates a considerable fall in the threshold for initiating LT4 therapy in hypothyroid patients. This increases the risk of futile treatment as well as overtreatment.

Levothyroxine/Liothyronine Combination Therapy and Quality of Life: Is It All about Weight Loss?

OBJECTIVES: According to one hypothesis, the popularity of levothyroxine (L-T4)/liothyronine (L-T3) combination therapy relates to weight loss. The purpose of this study was to detect a possible correlation between thyroid-related quality of life (QoL) and weight loss in hypothyroid patients switched from L-T4 monotherapy to L-T4/L-T3 combination therapy. METHODS: In an open-label cohort study, all hypothyroid patients referred to the University Hospital endocrine clinic due to persistent symptoms despite adequate L-T4 monotherapy (without other explanations for the symptoms) were switched from L-T4 monotherapy to L-T4/ L-T3 combination therapy at a ratio of approximately 17/1. At baseline and after 3 months of treatment we measured: QoL by the Thyroid Patient-Reported Outcome (ThyPRO-39) questionnaire, thyroid hormones, body weight, body composition by a DEXA-scan, and cognitive function by evaluating participants' reaction time as well as working memory by the California Computerized Assessment Package (CalCAP®). QoL was re-evaluated after 12 months. RESULTS: Twenty-three patients participated (91% women, median age 47 years). The ThyPRO-39 composite score decreased from a median of 54 (quartiles: 34, 74) to 15 (11, 28) after 3 months (p < 0.0001), and 20 (14, 26) after 12 months, indicating a better QoL. There was no change in body weight, and no correlations between QoL and weight. There was a slight improvement in cognitive function, whereas body composition, heart rate, and serum TSH did not change. CONCLUSION: Our study on hypothyroid patients switched from L-T4 monotherapy to L-T4/L-T3 combination therapy showed a substantial improvement in QoL measured by the ThyPRO-39. This improvement could not be explained by weight loss.

Neither Baseline nor Changes in Serum Triiodothyronine during Levothyroxine/Liothyronine Combination Therapy Predict a Positive Response to This Treatment Modality in Hypothyroid Patients with Persistent Symptoms.

BACKGROUND: Despite biochemical euthyroidism, some levothyroxine (L-T4)-treated hypothyroid patients report persisting symptoms and some of these patients are tentatively treated with a combination of L-T4 and liothyronine (L-T3). Combination therapy and the appropriate choice of blood tests to monitor treatment are highly debated among specialists and patients. AIM: To evaluate whether measuring serum triiodothyronine (S-T3) at baseline or during combination therapy can be used as an indicator of a positive effect from L-T4/L-T3 combination therapy. MATERIALS AND METHODS: Observational retrospective study of patients (n = 42) with persisting symptoms of hypothyroidism despite L-T4 therapy who had normal TSH levels and did not have any comorbidities that could explain their symptoms. All were then treated with L-T4/L-T3 combination therapy at a dose ratio of 17/1 according to European Thyroid Association guidelines. Based on patient-reported outcome, they were divided into responders and nonresponders. RESULTS: Five patients were lost to follow-up and thus excluded. At the 3-month follow-up, 11 were classified as nonresponders and 26 as responders. At 12 months these figures had changed to 13 (35%) and 24 (65%), respectively. When comparing responders versus nonresponders, no differences were seen at baseline or during follow-up in S-T3 and in free T3 estimates. Further, logistic regression showed no correlation between S-T3 and free T3 estimates and responder/nonresponder status. CONCLUSION: Our data indicate that serum T3 measurements are not suitable to predict which patient will benefit from L-T4/L-T3 combination therapy, and treatment response cannot be followed by repeated T3 measurements either.

Radioiodine Therapy Does Not Change the Atherosclerotic Burden of the Carotid Arteries.

BACKGROUND AND AIM: Atherosclerosis evolves or accelerates when arteries are exposed to ionizing radiation, both early and late after exposure. Radioiodine therapy of benign thyroid disease exposes the carotid arteries to 4-50 Gy, and may thereby increase the risk of atherosclerosis. Increased risk of cerebrovascular events has been reported after radioiodine therapy. This study aimed to examine whether atherosclerosis develops early or late after radioiodine therapy of benign thyroid disease. METHOD: Patients treated for benign thyroid disorders (nontoxic goiter, adenoma, and hyperthyroidism) were examined with ultrasound for the main outcome, carotid intima media thickness (CIMT), and for plaque presence (plaque presence only in late damage). Signs of early damage from radioiodine were studied in 39 radioiodine-treated patients, who were examined before treatment and at 1, 3, 6, and 12 months after treatment. Late changes were studied in a cross-sectional case-control design, with radioiodine-treated patients as cases (n = 193) and patients treated with surgery as controls (n = 95). Data were analyzed with repeated measurement for longitudinal data, and with multivariate regression for cross-sectional data. Results were adjusted for age, sex, cholesterol, smoking status, known atherosclerotic disease, and body mass index. RESULTS: No changes in CIMT were found in the patients followed prospectively for one year after treatment with radioactive iodine for benign thyroid disease (p = 0.58). In the study on late effects, there was no difference in CIMT (p = 0.25) or presence of plaques (p = 0.70) between those treated with radioactive iodine and those treated with surgery (9.8 and 5.6 years since treatment, respectively). Furthermore, the level of thyrotropin (TSH) did not influence these atherosclerosis markers. CONCLUSION: No early changes in CIMT were detected in patients treated with radioactive iodine for benign thyroid disease. No signs of late effects of radioactive iodine on CIMT or plaque presence were found after 10 years of follow-up. The radiation to the carotid arteries by radioactive iodine therapy for benign thyroid disease may therefore have no or low effect on atherosclerotic burden of the carotid arteries in general.

Radioiodine therapy increases the risk of cerebrovascular events in hyperthyroid and euthyroid patients.

BACKGROUND AND OBJECTIVE: Hyperthyroid patients treated with radioiodine have increased morbidity and mortality from cerebrovascular events. This risk has until now has been attributed to the hyperthyroidism. However, radioiodine therapy of benign thyroid diseases exposes the carotid arteries to radiation and is capable of inducing atherosclerosis. The objective of the study was to elucidate whether ionizing radiation from radioiodine might contribute to cerebrovascular morbidity. METHODS: In a retrospective register cohort study, 4000 hyperthyroid and 1022 euthyroid goitre patients treated with radioiodine between 1975 and 2008 were matched 1:4 on age and sex with random controls. The cohort was followed from the date of treatment until hospitalization due to cerebrovascular event, death, 20 years of follow-up or March 2013. Data were analyzed in competing risk models adjusting for age, sex, Charlson's comorbidity score, atrial fibrillation and previous cerebrovascular events. RESULTS: Mean follow-up time was 11.5 years, mean age 61 years, with a total number of 3228 events. Comparing all radioiodine-treated patients with controls, the fully adjusted model showed increased risk of cerebrovascular events among all treated patients, hazard ratio (HR) 1.18 (95% CI 1.09-1.29). The risk was increased among hyperthyroid (HR 1.17; 95% CI 1.07-1.28) as well as euthyroid patients (HR 1.21; 95% CI 1.02-1.44). CONCLUSIONS: We report an increased risk of cerebrovascular events in hyperthyroid as well as euthyroid patients treated with radioiodine for benign thyroid disorders. That these patient groups have similar risks suggests the possibility that radiation from radioiodine contributes to cerebrovascular morbidity via acceleration or initiation of atherosclerosis.

Treating Hypothyroidism with Thyroxine/Triiodothyronine Combination Therapy in Denmark: Following Guidelines or Following Trends?

BACKGROUND: Five to ten percent of patients with hypothyroidism describe persistent symptoms despite being biochemically well regulated on levothyroxine (L-T4). Thyroxine (T4)/triiodothyronine (T3) combination therapy [L-T4/liothyronine (L-T3) or desiccated thyroid] are still regarded as experimental with no evidence of superior effect on persistent symptoms according to meta-analyses. However, some randomized controlled trials have demonstrated patients' preference for T4/T3 combination therapy as compared to L-T4 monotherapy. In 2013, attention to combination therapy increased in Denmark after a patient published a book describing her experiences with hypothyroidism and treatment. OBJECTIVE: To investigate current Danish trends in the use of T4/T3 combination therapy. METHODS: We used an Internet-based questionnaire, distributed as a link via two Danish patient fora. Further, information was obtained from the Division of Pharmacies and Reimbursement at the Danish Health and Medicines Authority and from the only pharmacy in Denmark producing desiccated thyroid and L-T3 tablets. RESULTS: A total of 384 patients answered the questionnaire, and 293 responders were included. Sixty-nine percent of the responders had six or more symptoms, and 84% reported a treatment effect. Forty-four percent of the responders received their prescriptions from general practitioners; 50% received desiccated thyroid and 28% reported that they adjust their dose themselves. Responders followed by general practitioners more frequently received desiccated thyroid and adjusted their dose themselves. CONCLUSIONS: Increased media focus has changed the prescription pattern of thyroid hormones; European guidelines on T4/T3 combination therapy are not always followed in Denmark and many patients adjust their medication themselves and may therefore be at risk of overtreatment.

Modeling the absorbed dose to the common carotid arteries following radioiodine treatment of benign thyroid disease.

INTRODUCTION: External fractionated radiotherapy of cancer increases the risk of cardio- and cerebrovascular events, but less attention has been paid to the potential side effects on the arteries following internal radiotherapy with radioactive iodine (RAI), i.e. 131-iodine. About 279 per million citizens in the western countries are treated each year with RAI for benign thyroid disorders (about 140,000 a year in the EU), stressing that it is of clinical importance to be aware of even rare radiation-induced side effects. In order to induce or accelerate atherosclerosis, the dose to the carotid arteries has to exceed 2 Gy which is the known lower limit of ionizing radiation to affect the endothelial cells and thereby to induce atherosclerosis. OBJECTIVE: To estimate the radiation dose to the carotid arteries following RAI therapy of benign thyroid disorders. METHODS: Assuming that the lobes of the thyroid gland are ellipsoid, that the carotid artery runs through a part of the lobes, that there is a homogeneous distribution of RAI in the lobes, and that the 24 h RAI uptake in the thyroid is 35 % of the (131)I orally administrated, we used integrated modules for bioassay analysis and Monte Carlo simulations to calculate the dose in Gy/GBq of administrated RAI. RESULTS: The average radiation dose along the arteries is 4-55 Gy/GBq of the (131)I orally administrated with a maximum dose of approximately 25-85 Gy/GBq. The maximum absorbed dose rate to the artery is 4.2 Gy/day per GBq (131)I orally administrated. CONCLUSION: The calculated radiation dose to the carotid arteries after RAI therapy of benign thyroid disorder clearly exceeds the 2 Gy known to affect the endothelial cells and properly induce atherosclerosis. This simulation indicates a relation between the deposited dose in the arteries following RAI treatment and an increased risk of atherosclerosis and subsequent cerebrovascular events such as stroke.

Emergency teams in Danish emergency departments.

INTRODUCTION: The use of designated emergency teams for cardiac arrest and trauma patients is widely implemented. However, the use of designated teams in Danish emergency departments (EDs) has not been investigated. Our aim was to investigate the use and staffing of emergency teams in Danish EDs. MATERIAL AND METHODS: A cross-sectional questionnaire study was sent to all 20 Danish EDs designated for emergency care. RESULTS: The response rate was 95% (n = 19). Three EDs were excluded due to incomplete data. All EDs (n = 16) received critically ill patients, cardiac arrests and trauma patients. In all EDs, a designated team responded to cardiac arrest (CAT) and trauma patients (TT). Only 31% of EDs had access to a designated medical emergency team (MET). CAT consisted of a median of six (range 5-10) different personnel groups. Of these, three (1-6) were physicians and only one (0-2) was a senior physician. TTs consisted of a median of nine (7-11) different personnel groups. Of these, four (2-6) were physicians, and three (2-4) were senior physicians. In 25% of the EDs, there was no access to a MET. In 31% of the EDs, an ad hoc-team was created. In 14%, a team was created by the attending emergency physician. The staffing of ad hoc-teams relied on diagnosis, symptoms and triage scores. CONCLUSION: Designated teams for patients in cardiac arrest and trauma patients are available in all Danish EDs. More senior staff form part of trauma teams than cardiac arrest teams. There is limited access to designated teams caring for critically ill medical patients in Danish EDs.

Inconsistent reporting of surrogate outcomes in randomised clinical trials: cohort study.

OBJECTIVE: To assess if authors of randomised clinical trials convey the fact that they have used surrogate outcomes and discussed their validity. DESIGN: Cohort study. SETTING: Six major general medical journals. PARTICIPANTS: Randomised clinical trials published in 2005 and 2006 that used a surrogate as a primary outcome. RESULTS: Of 626 published randomised clinical trials, 109 (17%) used a surrogate as a primary outcome. Of these trials, 62 (57%, 95% confidence interval 47% to 67%) clearly reported that the primary outcome was a surrogate. Only 38 (35%, 26% to 45%) also discussed the validity of the surrogate. CONCLUSION: Only about one third of authors of randomised clinical trials that used a surrogate as a primary outcome reported adequately on the surrogate. Better reporting is needed.