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.

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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.

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.

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.

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.

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.

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