Introduction and Objective: The excess cardiovascular morbidity and mortality in hyperthyroidism and Graves’ disease (GD) is inadequately understood. We aimed to elucidate whether well-established cardiovascular risk factors such as arterial stiffness in terms of pulse wave velocity (PWV) and blood pressure differ in GD and controls. Methods: This was a cross-sectional study comparing 55 hyperthyroid patients with newly diagnosed GD and 55 euthyroid, population-based controls matched for age, sex and menopausal status. PWV and blood pressure were measured in office (SphygmoCor Xcel) and 24-h ambulatory settings (Arteriograph). Differences between groups were assessed using adjusted linear regression analysis. Results: Compared to controls, GD patients showed higher PWV in the 24-h but not in the office setting with an adjusted 24-h PWV difference of 1.0 (95% CI: 0.6–1.5) m/s. PWV was higher in GD at both day and night, and nightly PWV dipping was lower (–5.5, 95% CI: –10.4 to –0.6%). Furthermore, central and brachial pulse pressure was significantly higher in both the office and 24-h setting, whereas nightly central pulse pressure dipping was significantly lower in GD (–5.4, 95% CI: –10.5 to –0.2%). Mean arterial pressure did not differ between the groups. Conclusions: Despite comparable blood pressure, GD is associated with a higher 24-h PWV that was not detected in the office setting. Pulse pressure was higher in GD, whereas mean arterial pressure did not differ between the groups. Longitudinal studies should pursue whether higher PWV might be a piece to the puzzle of understanding the increased risk of cardiovascular disease in hyperthyroidism and GD.

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.

Purpose: To evaluate the relationship between thyroid variables and health-related quality of life (QoL) in patients with autoimmune hypothyroidism, using the thyroid-specific QoL questionnaire ThyPRO. Methods: In a cross-sectional study, responses to the ThyPRO from 199 outpatients with autoimmune hypothyroidism were analyzed in relation to thyroid volume, thyroid function and markers of thyroid autoimmunity. Based on a classical QoL framework, we hypothesized that physiological dysfunction caused specific physical and psychological symptoms, which affected functioning and well-being, and consequently participation in life and QoL. These hypotheses were tested through multiple regression and multivariate path analysis models. Results: None of the thyroid function tests were associated with QoL scores. However, in the pairwise regression, the thyroid peroxidase antibody (TPOAb) level was associated with several QoL outcomes: Goitre Symptoms (p = 0.024), Depressivity (p = 0.004), Anxiety (p = 0.004), Emotional Susceptibility (p = 0.005) and Impaired Social Life (p = 0.047). In the multivariate model, the TPOAb level was related to Goitre Symptoms (r = 0.17, p = 0.019), Depressivity (r = 0.24, p = 0.001), and Anxiety (r = 0.23, p = 0.002), but no longer to Emotional Susceptibility or Impaired Social Life, indicating that the effect on these were mediated through an effect on the symptom scales (i.e. Goitre Symptoms, Depressivity and Anxiety). Conclusion: Health-related QoL, evaluated with state-of-the-art QoL methodology, was related to TPOAb level but not to thyroid function. This raises the hypothesis that autoimmunity, independent of thyroid function, impacts on QoL in patients with autoimmune hypothyroidism, especially in terms of psychological symptoms. Longitudinal studies, in initially untreated patients, are needed to test this hypothesis.

Introduction and Purpose: Use of electronic questionnaires to collect health-related quality-of-life data has evolved as an alternative to paper questionnaires. For the electronic questionnaire to be used interchangeably with the validated paper questionnaire, measurement properties similar to the original must be demonstrated. The aim of the present study was to assess the equivalence between the paper version and the electronic version of the thyroid-related quality-of-life questionnaire ThyPRO. Methods: Patients with Graves' hyperthyroidism or autoimmune hypothyroidism in a clinically stable phase were included. The patients were recruited from two endocrine outpatient centers. All patients completed both versions in a randomized test-retest set-up. Scores were compared using intraclass correlation coefficients (ICCs), paired t tests and Bland-Altman plots. Limits of agreement were compared with data from a previous paper-paper test-retest study. Results: 104 patients were included. ICCs were generally high for the 13 scales, ranging from 0.76 to 0.95. There was a small but significant difference in the scale score between paper and electronic administration for the Cosmetic complaints scale, but no differences were found for any other scale. Bland-Altman plots showed similar limits of agreement compared to the earlier test-retest study of the paper version of ThyPRO. Conclusion: Based on our analyses using ICCs, paired t tests and Bland-Altman plots, we found adequate agreement between the paper and electronic questionnaires. The statistically significant difference in score found in the Cosmetic complaints scale is small and probably clinically insignificant.

Background: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. Methods: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Results: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 µg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. Discussion: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.

Background and Objective: Graves' disease has been associated with an increased psychiatric morbidity. It is unclarified whether this relates to Graves' disease or chronic disease per se. The aim of our study was to estimate the prevalence of anxiety and depression symptoms in patients with Graves' disease compared to patients with another chronic thyroid disease, nodular goitre, and to investigate determinants of anxiety and depression in Graves' disease. Methods: 157 cross-sectionally sampled patients with Graves' disease, 17 newly diagnosed, 140 treated, and 251 controls with nodular goitre completed the Hospital Anxiety and Depression Scale (HADS). The differences in the mean HADS scores between the groups were analysed using multiple linear regression, controlling for socio-demographic variables. HADS scores were also analysed dichotomized: a score >10 indicating probable ‘anxiety'/probable ‘depression'. Determinants of anxiety and depression symptoms in Graves' disease were examined using multiple linear regression. Results: In Graves' disease levels of anxiety (p = 0.008) and depression (p = 0.014) were significantly higher than in controls. The prevalence of depression was 10% in Graves' disease versus 4% in nodular goitre (p = 0.038), anxiety was 18 versus 13% (p = 0.131). Symptoms of anxiety (p = 0.04) and depression (p = 0.01) increased with comorbidity. Anxiety symptoms increased with duration of Graves' disease (p = 0.04). Neither thyroid function nor autoantibody levels were associated with anxiety and depression symptoms. Conclusions: Anxiety and depression symptoms were more severe in Graves' disease than in nodular goitre. Symptoms were positively correlated to comorbidity and duration of Graves' disease but neither to thyroid function nor thyroid autoimmunity.