Acromegaly management in the Nordic countries: A Delphi consensus survey.

OBJECTIVE: Acromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries. METHODS: A Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as ≥80% of panelists rating their agreement as ≥5 or ≤3 on the Likert-type scale. RESULTS: Consensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists. CONCLUSION: This consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.

Respiratory impairments in patients suffering from Fabry disease - A cross-sectional study.

BACKGROUND: The inherited X-linked disorder, Fabry disease, is caused by deficient lysosomal enzyme α-galactosidase A, with progressive accumulation of globotriaosylceramide in multiple organs including the upper and lower airways. OBJECTIVES: To assess pulmonary function at the time of the first pulmonary function test (PFT) performed among the National Danish Fabry cohort and define the prevalence of affected lung function variables. MATERIALS AND METHOD: A cross-sectional retrospective cohort study of 86 adult patients enrolled in one or both international patient registry databases for Fabry disease, Fabry Registry or FollowME with at least one PFT. The Mainz Severity Score Index (MSSI) was calculated to determine the disease severity. Lung function variables were examined by multivariate regression adjusted for important variables for developing airway illness. RESULTS: Seventeen patients (20%) showed obstructive airflow limitation and 7 (8%) a restrictive lung deficiency. Smoking status (p = .016) and MSSI (p < .001) were associated with increasing obstructive airway limitation. CONCLUSION: The prevalence of affected lung function among the National Danish Fabry cohort was 28%. Patients with classic gene variants frequently developed a decrease in lung function regardless of their smoking status, with significant relationship with disease severity.

Multiple endocrine neoplasia type 1 (MEN-1) and neuroendocrine neoplasms (NENs).

Neuroendocrine neoplasms (NENs) are relatively rare neoplasms with 6.4-times increasing age-adjusted annual incidence during the last four decades. NENs arise from neuroendocrine cells, which release hormones in response to neuronal stimuli and they are distributed into organs and tissues. The presentation and biological behaviour of the NENs are highly heterogeneous, depending on the organ. The increased incidence is mainly due to increased awareness and improved detection methods both in the majority of sporadic NENs (non-inherited), but also the inherited groups of neoplasms appearing in at least ten genetic syndromes. The most important one is multiple endocrine neoplasia type 1 (MEN-1), caused by mutations in the tumour suppressor gene MEN1. MEN-1 has been associated with different tumour manifestations of NENs e.g. pancreas, gastrointestinal tract, lungs, thymus and pituitary. Pancreatic NENs tend to be less aggressive when arising in the setting of MEN-1 compared to sporadic pancreatic NENs. There have been very important improvements over the past years in both genotyping, genetic counselling and family screening, introduction and validation of various relevant biomarkers, as well as newer imaging modalities. Alongside this development, both medical, surgical and radionuclide treatments have also advanced and improved morbidity, quality of life and mortality in many of these patients. Despite this progress, there is still space for improving insight into the genetic and epigenetic factors in relation to the biological mechanisms determining NENs as part of MEN-1. This review gives a comprehensive update of current evidence for co-occurrence, diagnosis and treatment of MEN-1 and neuroendocrine neoplasms and highlight the important progress now finding its way to international guidelines in order to improve the global management of these patients.

Multiple endocrine neoplasia type 2: A review.

Multiple endocrine neoplasias are rare hereditary syndromes some of them with malignant potential. Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant hereditary cancer syndrome due to germline variants in the REarranged during Transfection (RET) proto-oncogene. There are two distinct clinical entities: MEN 2A and MEN 2B. MEN 2A is associated with medullary thyroid carcinoma (MTC), phaeochromocytoma, primary hyperparathyroidism, cutaneous lichen amyloidosis and Hirschprung's disease and MEN 2B with MTC, phaeochromocytoma, ganglioneuromatosis of the aerodigestive tract, musculoskeletal and ophthalmologic abnormalities. Germline RET variants causing MEN 2 result in gain-of-function; since the discovery of the genetic variants a thorough search for genotype-phenotype associations began in order to understand the high variability both between families and within family members. These studies have successfully led to improved risk classification of prognosis in relation to the genotype, thus improving the management of the patients by thorough genetic counseling. The present review summarizes the recent developments in the knowledge of these hereditary syndromes as well as the impact on clinical management, including genetic counseling, of both individual patients and families. It furthermore points to future directions of research for better clarification of timing of treatments of the various manifestations of the syndromes in order to improve survival and morbidity in these patients.

Globotriaosylsphingosine (lyso-Gb3) and analogues in plasma and urine of patients with Fabry disease and correlations with long-term treatment and genotypes in a nationwide female Danish cohort.

INTRODUCTION: Recent studies showed the usefulness of globotriaosylsphingosine (lyso-Gb3) and related analogues, deacylated forms of globotriaosylceramide (Gb3), for high-risk screening, treatment monitoring and follow-up for patients with Fabry disease. METHODS: We evaluated Gb3, lyso-Gb3 and analogues using tandem mass spectrometry in 57 women with Fabry disease followed during a period of 15.4 years. Twenty-one women were never treated and 36 received treatment (agalsidase-beta, n=30; agalsidase-alfa, n=5; or migalastat, n=1). Lyso-Gb3 and analogues at m/z (-28), (-2), (+16), (+34) and (+50) were analysed in plasma and urine. Total Gb3 and lyso-Gb3 analogues at m/z (-12) and (+14) were evaluated in urine while the analogue at m/z (+18) was evaluated in plasma. RESULTS: A strong correlation between plasma and urine lyso-Gb3 and analogue levels was revealed. Plasma and urine lyso-Gb3 and analogue levels were not statistically different between patients carrying missense (n=49), nonsense (n=6) or deletion mutations (n=2). Never treated patients had lower plasma lyso-Gb3 and analogues at m/z (-28), (-2), (+16), (+34) and the seven urinary lyso-Gb3 analogues compared with pretreatment levels of the treated patients. A significant reduction of plasma lyso-Gb3 and five analogues, as well as urine Gb3 and six lyso-Gb3 analogues, but not lyso-Gb3 and lyso-Gb3 at m/z (+50), was observed post-treatment with agalsidase-beta. The same tendency was observed with agalsidase-alfa. CONCLUSION: Women with Fabry disease who started treatment based on clinical manifestations had higher lyso-Gb3 and analogue biomarker levels than never treated women. This indicates that a biomarker cut-off could potentially be a decision tool for treatment initiation in women with Fabry disease.

Conversion of standard retrospective patient-reported outcomes to momentary versions: cognitive interviewing reveals varying degrees of momentary compatibility.

PURPOSE: The purpose of this study was to adapt different domains of an existing retrospective questionnaire to momentary versions, to use and assess cognitive interviewing for evaluating the new versions, and to compare momentary compatibility (i.e. an item's potential to be validly converted to a momentary version) across different scales. METHODS: Initial momentary versions of retrospective patient-reported outcomes were produced by converting present perfect tense wording to present tense wording. Cognitive interviews were conducted iteratively with 21 patients to determine which reference period they actually employed, and to identify problems with new, revised versions. A think-aloud interview protocol was supplemented with non-specific concurrent and specific retrospective probing. The momentary compatibility of each item was evaluated by calculating the proportion of interviews wherein momentary reference periods were identified; problems were categorized according to cognitive aspects of survey methodology taxonomy. The efficiency of various cognitive interviewing techniques was determined by evaluating whether applied reference periods were identified by think-aloud alone or by supplementary probes. RESULTS: The momentary compatibility varied from 5 to 100% across items. Cognitive interviews revealed potential problems of various severities in the majority of items. Think-aloud alone was sufficient at determining the applied reference period in one-third of the cases, and the efficiency of additional concurrent and retrospective probing was 50 and 94%, respectively. CONCLUSIONS: Cognitive interviewing techniques proved useful for developing and evaluating momentary items. Researchers should be aware of the applied reference period and of emerging problems when evaluating adapted momentary items, since not all concepts are suitable. We recommend the proposed method in future adaptations of existing instruments.

Echocardiographic and clinical findings in patients with Fabry disease during long-term enzyme replacement therapy: a nationwide Danish cohort study.

OBJECTIVES: In patients with Fabry disease (FD), left ventricular hypertrophy and arrhythmias are frequently observed and cardiac involvement is the leading cause of death. Long-term efficacy of enzyme replacement therapy (ERT) on cardiac involvement is unclear. We assessed and compared long-term progression of cardiac involvement according to ERT and non-ERT. METHODS: We retrospectively assessed and compared long-term progression of cardiac involvement in adult patients with FD in the nationwide Danish cohort. We followed clinical signs, symptoms and findings by echocardiography, electrocardiography and Holter-monitoring. RESULTS: We included 66 patients; 47 patients (27 women) received ERT (ERT group) and 19 patients (15 women) did not (non-ERT group). The groups were followed for a median of 8 [0-12] years and 6 [0-13] years, respectively. Comparison between ERT and non-ERT receiving patients by left ventricular mass (echocardiographic assessment) and Sokolow-Lyon voltage- and Cornell product criteria (electrocardiographic assessment) revealed no significant differences. In the ERT group, we observed no change in left ventricular mass but a decrease in Sokolow-Lyon voltage- and Cornell product criteria from baseline to follow-up; 30 mm [15-53] vs. 25 mm [3-44], p < 0.005 and 1710 mm·ms [480-3740] vs. 1520 mm·ms [550-5740], p < .05, respectively. There were no changes within the non-ERT group. During follow-up, cardiac symptoms and use of cardiovascular procedures and -medication increased significantly in the ERT group, whereas no differences were observed within the non-ERT group. DISCUSSION: We raise concerns regarding the efficacy and benefit of ERT on cardiac involvement in Fabry disease and stress the need for further research.

Intrachiasmatic abscess caused by IgG4-related hypophysitis.

INTRODUCTION: Autoimmune hypophysitis is a rare disease of the pituitary, which may affect vision by inflammation and compression of the optic chiasm. However, intrachiasmatic abscess formation has not been previously reported. METHODS: In this study, we report a case of a 29-year-old female with bitemporal hemianopia due to a cystic intrasellar tumor. The patient underwent surgical decompression of the lesion, which was found to be an intrachiasmatic abscess. RESULTS: The histologic findings were consistent with IgG4 hypophysitis. CONCLUSION: This rare clinical presentation suggests that in case of a disproportionate degree of visual impairment in relation to the size of the lesion, suspicion should lead to an intrachiasmatic lesion.

Thyroid-specific questions on work ability showed known-groups validity among Danes with thyroid diseases.

PURPOSE: We aimed to identify the best approach to work ability assessment in patients with thyroid disease by evaluating the factor structure, measurement equivalence, known-groups validity, and predictive validity of a broad set of work ability items. METHODS: Based on the literature and interviews with thyroid patients, 24 work ability items were selected from previous questionnaires, revised, or developed anew. Items were tested among 632 patients with thyroid disease (non-toxic goiter, toxic nodular goiter, Graves' disease (with or without orbitopathy), autoimmune hypothyroidism, and other thyroid diseases), 391 of which had participated in a study 5 years previously. Responses to select items were compared to general population data. We used confirmatory factor analyses for categorical data, logistic regression analyses and tests of differential item function, and head-to-head comparisons of relative validity in distinguishing known groups. RESULTS: Although all work ability items loaded on a common factor, the optimal factor solution included five factors: role physical, role emotional, thyroid-specific limitations, work limitations (without disease attribution), and work performance. The scale on thyroid-specific limitations showed the most power in distinguishing clinical groups and time since diagnosis. A global single item proved useful for comparisons with the general population, and a thyroid-specific item predicted labor market exclusion within the next 5 years (OR 5.0, 95 % CI 2.7-9.1). CONCLUSIONS: Items on work limitations with attribution to thyroid disease were most effective in detecting impact on work ability and showed good predictive validity. Generic work ability items remain useful for general population comparisons.

Cross-cultural validity of the thyroid-specific quality-of-life patient-reported outcome measure, ThyPRO.

BACKGROUND AND PURPOSE: Thyroid diseases are common and often affect quality of life (QoL). No cross-culturally validated patient-reported outcome measuring thyroid-related QoL is available. The purpose of the present study was to test the cross-cultural validity of the newly developed thyroid-related patient-reported outcome ThyPRO, using tests for differential item functioning (DIF) according to language version. METHODS: The ThyPRO consists of 85 items summarized in 13 multi-item scales and one single item. Scales cover physical and mental symptoms, well-being and function as well as social and daily function and cosmetic concerns. Translation applied standard forward-backward methodology with subsequent cognitive interviews and reviews. Responses (N = 1,810) to the ThyPRO were collected in seven countries: UK (n = 166), The Netherlands (n = 147), Serbia (n = 150), Italy (n = 110), India (n = 148), Denmark (n = 902) and Sweden (n = 187). Translated versions were compared pairwise to the English version by examining uniform and nonuniform DIF, i.e., whether patients from different countries respond differently to a particular item, although they have identical level of the concept measured by the item. Analyses were controlled for thyroid diagnosis. DIF was investigated by ordinal logistic regression, testing for both statistical significance and magnitude (ΔR (2) > 0.02). Scale level was estimated by the sum score, after purification. RESULTS: For twelve of the 84 tested items, DIF was identified in more than one language. Eight of these were small, but four were indicative of possible low translatability. Twenty-one instances of DIF in single languages were identified, indicating potential problems with the particular translation. However, only seven were of a magnitude which could affect scale scores, most of which could be explained by sample differences not controlled for. CONCLUSION: The ThyPRO has good cross-cultural validity with only minor cross-cultural invariance and is recommended for use in international multicenter studies.

Confirmatory factor analysis of the thyroid-related quality of life questionnaire ThyPRO.

BACKGROUND AND AIM: Thyroid diseases are prevalent and chronic. With treatment, quality of life is restored in most, but not all patients. Construct validity of the thyroid-related quality of life questionnaire, ThyPRO, has been established by multi-trait scaling, but not evaluated with more elaborate methods. The purpose of the present study was to evaluate dimensionality of the ThyPRO scales and to attempt to understand possible item misfit through structural equation modeling for categorical data. METHODS: The current 85-item version of ThyPRO consists of 13 scales, covering domains of physical (4 scales) and mental (2 scales) symptoms, function and well-being (3 scales) and participation/social function (4 scales). The data were collected from a cross-sectional sample of 907 thyroid patients. One-factor confirmatory models were fitted to each scale, and evaluated by model fit statistics (comparative fit index >0.95, root mean square error of approximation <0.08), magnitude of factor loadings, model residual correlations and modification indices (MI). Indications of multi-dimensionality were tested in bi-factor models. Possible item misfit was evaluated in a combined, investigational model. RESULTS: Each ThyPRO scale was adequately represented by a unidimensional model after minor revisions. Eleven items were identified in the unidimensional models as potentially misfitting and were investigated further by multidimensional modeling. CONCLUSION: Elaborate psychometric modeling supported the construct validity of the ThyPRO. However, 11 potentially misfitting items and 18 items with local dependence to other items are candidates for removal in future item reduction processes.

Few items in the thyroid-related quality of life instrument ThyPRO exhibited differential item functioning.

OBJECTIVE: To evaluate the extent of differential item functioning (DIF) within the thyroid-specific quality of life patient-reported outcome measure, ThyPRO, according to sex, age, education and thyroid diagnosis. STUDY DESIGN AND SETTING: A total of 838 patients with benign thyroid diseases completed the ThyPRO questionnaire (84 five-point items, 13 scales). Uniform and nonuniform DIF were investigated using ordinal logistic regression, testing for both statistical significance and magnitude (∆R(2) > 0.02). Scale level was estimated by the sum score, after purification. RESULTS: Twenty instances of DIF in 17 of the 84 items were found. Eight according to diagnosis, where the goiter scale was the one most affected, possibly due to differing perceptions in patients with auto-immune thyroid diseases compared to patients with simple goiter. Eight DIFs according to age were found, of which 5 were in positively worded items, which younger patients were more likely to endorse; one according to gender: women were more likely to report crying, and three according to educational level. The vast majority of DIF had only minor influence on the scale scores (0.1-2.3 points on the 0-100 scales), but two DIF corresponded to a difference of 4.6 and 9.8, respectively. CONCLUSION: Ordinal logistic regression identified DIF in 17 of 84 items. The potential impact of this on the present scales was low, but items displaying DIF could be avoided when developing abbreviated scales, where the potential impact of DIF (due to fewer items) will be larger.

Development and implementation of PROgmatic: A clinical trial management system for pragmatic multi-centre trials, optimised for electronic data capture and patient-reported outcomes.

Background Many clinical trials are conducted as explanatory trials, but the applicability of results from explanatory trials to clinical practice may be questioned. Pragmatic trials elucidate both benefits and harms of an intervention under conditions close to daily clinical practice. We have planned a pragmatic multi-centre trial in patients with Graves' hyperthyroidism. However, trial management is a complicated task in pragmatic trials, due to limited interaction between participants and trial personnel. Purpose The aim of this project was to develop and implement PROgmatic, a fully integrated trial management system for pragmatic multi-centre trials, optimised for electronic data capture and patient-reported outcomes (PROs). Methods Necessary tasks and logistical challenges that should be handled by PROgmatic were identified, and the system was designed and developed to handle these tasks. A combination of generic applications and custom coding was applied to develop an integrated system that met the required needs. PROgmatic features include secure web-based data entry; electronic case report forms (eCRFs); central participant registration and randomisation; automated emails linking to electronic PROs; automated reminders to participants; automated notifications to trial personnel regarding booking of trial visits, safety and compliance alerts; and monitoring of trial progress. PROgmatic underwent rigorous pilot testing, including data verification and validation, before it was released for trial management. Results PROgmatic was successfully implemented in the GRAves' Selenium Supplementation (GRASS) trial (ClinicalTrials.gov: NCT01611896) December 2012. The feedback from trial personnel on usability and utility has been positive, and PROgmatic has handled all intended tasks properly. Limitations Implementation of PROgmatic in future studies requires adaptation of the custom coding. Not all email systems accept emails with active links, and participants who use these systems therefore need to complete paper surveys. Conclusions PROgmatic facilitated the complex task of conducting a pragmatic multi-centre trial. The automated electronic capture of PRO data is time saving and reduces the risk of erroneous data entry. Email notifications to trial personnel combined with serially activated eCRFs that logically lead patient flow through the trial have helped making the pragmatic trial feasible. PROgmatic provides a template for other pragmatic multi-centre trials with patient-reported measures as high-priority outcomes.

Incidence, Treatment, and Survival of Adrenocortical Carcinoma in Denmark 2003-2019.

Objectives: Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal cortex. The aim of the study was to report the incidence of ACC and survival of ACC in Denmark. The secondary objective was to describe the impact of treatment with mitotane on survival. Design: Retrospective population study of patients diagnosed with ACC between 2003 and 2019 in Denmark. Methods: Individuals at risk for ACC were identified in the national Danish Health registries, and diagnosis of ACC was confirmed by review of the health records. Data on demographics, presentation, treatment, recurrence, and death was evaluated. Results: 138 patients were included in the study with more females (59.4%) than males (40.6%). Incidence rate was 1.4 per million per year. The incidence rate ratio significantly increased only in females by 1.06 [95% confidence interval (CI): 1.02-1.12] per year. Overall median survival was 1.93 (95% CI: 1.24-3.00) years with no differences between males and females. The proportion of patients treated with mitotane (either as adjuvant treatment or as part of a chemotherapeutic regime) was 72.3%. Survival was significantly decreased in women not treated with mitotane compared to women treated with mitotane (either as adjuvant or as part of a chemotherapeutic regime) hazards ratio .30 (95% CI: .10-.89), adjusted for European Network for the Study of Adrenal Tumours score, age at diagnosis, and year of diagnosis, but survival was unaffected by mitotane treatment in men. Conclusion: Incidence of ACC in Denmark was 1.4 per million per year and increased in women but not in males during the study period 2003-2019.

Alemtuzumab-induced thyroid disease: A Danish cohort study.

OBJECTIVES: Alemtuzumab, a monoclonal antibody against the cluster of differentiation 52 (CD52) molecule, is used in the treatment of multiple sclerosis (MS). A side effect of the treatment is development of secondary autoimmune thyroid disease. The aim of this study was to evaluate the rate, type and course of thyroid disease in Danish patients with multiple sclerosis (MS) treated with alemtuzumab. METHODS: We conducted a retrospective cohort study of patients treated with a first series of alemtuzumab for MS in the Capital and Zealand regions of Denmark (population: 2.6 million) between 2014 and 2018 (n = 60 RESULTS: The duration of follow-up was median 81 months (range 54-105). Thyroid disease occurred in 47 % of the patients with the following distribution: Graves' disease (GD), thyrotropin (TSH) receptor antibody (TRAb) positive hyper- or hypothyroidism 35 %; multinodular goitre 5 %; silent thyroiditis, gestational transient thyrotoxicosis or unclassified hyperthyroidism 7 %. Of patients with GD, 14 % had an additional silent or postpartum thyroiditis before onset or after remission of GD. Unusual courses of GD occurred in 67 %, most commonly fluctuation from hypo- to hyperthyroidism or vice versa, mainly treated with antithyroid drug alone or thyroxine substitution regime but switched to concomitant block and replace treatment in 25 % and/or subsequent total thyroidectomy in less than 25 %. CONCLUSION: Data from the largest Danish MS center supports previous observations of unusual, long-lasting and unpredictable courses of alemtuzumab-induced GD. Thus, follow-up of these patients may require long lasting and more frequent biochemical measurements compared to other patients with GD. Also, concomitant block and replace treatment or definitive treatment, such as thyroidectomy, should be considered in a subgroup of patients.

Chemotherapy for post-menopausal women with early breast cancer seems not to result in clinically significant changes in thyroid function.

OBJECTIVE: Adjuvant chemotherapy is often indicated in patients diagnosed with early breast cancer (EBC). Among others, weight gain is one of the observed side effects of both chemotherapy and other cancer treatments; however, the mechanism is not well-described. In this study, we aimed to assess thyroid function before and shortly after the course of chemotherapy for EBC. METHODS: This is a prospective cohort study of women diagnosed with EBC. The main outcome was the thyroid function and body weight before and after completing chemotherapy. Secondary outcomes were the presence of thyroid autoantibodies and treatment radiation dosage. We included 72 patients treated with adjuvant chemotherapy, whereas 59 patients also received supraclavicular locoregional radiotherapy. Triple-negative breast cancer (BC) patients receiving chemoimmunotherapy were excluded. RESULTS: After the chemotherapy, we observed an increase in thyroid-stimulating hormone (p = 0.03) and a decrease in free-thyroxine (p = 0.0006), with no significant weight change. The prevalence of autoimmune thyroiditis was low. On average 3 months post-chemo, we found no statistically significant difference in the thyroid function of women treated versus not treated with supraclavicular locoregional radiotherapy. CONCLUSIONS: Although statistically significant changes in thyroid hormones were observed, this study suggests no obvious clinically significant changes in thyroid function in women with early BC after the course of chemotherapy. The decrease in thyroid function was not related to autoimmunity, non-thyroidal illness, radiotherapy, or high-dose corticosteroids. Further studies with a longer follow-up of thyroid function after adjuvant chemotherapy and supraclavicular locoregional radiotherapy are needed.

Selenium supplementation and placebo are equally effective in improving quality of life in patients with hypothyroidism.

PURPOSE: We investigated whether selenium supplementation improves quality-of-life (QoL) in patients with autoimmune thyroiditis (ID:NCT02013479). METHODS: We included 412 patients ≥18 years with serum thyroid peroxidase antibody (TPOAb) level ≥100 IU/mL in a multicentre double-blinded randomised clinical trial. The patients were allocated 1:1 to daily supplementation with either 200 µg selenium as selenium-enriched yeast or matching placebo tablets for 12 months, as add-on to levothyroxine (LT4) treatment. QoL, assessed by the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39), was measured at baseline, after six weeks, three, six, 12, and 18 months. RESULTS: In total, 332 patients (81%) completed the intervention period, of whom 82% were women. Although QoL improved during the trial, no difference in any of the ThyPRO-39 scales was found between the selenium group and the placebo group after 12 months of intervention. In addition, employing linear mixed model regression no difference between the two groups was observed in the ThyPRO-39 composite score (28.8 [95%CI:24.5-33.6] and 28.0 [24.5-33.1], respectively; P=0.602). Stratifying the patients according to duration of the disease at inclusion, ThyPRO-39 composite score, TPOAb level, or selenium status at baseline did not significantly change the results. TPOAb levels after 12 months of intervention were lower in the selenium group than in the placebo group (1995 [95%CI:1512-2512] vs. 2344 kIU/L [1862-2951]; P=0.016) but did not influence LT4 dosage or free triiodothyronine/free thyroxin ratio. CONCLUSION: In hypothyroid patients on LT4 therapy due to autoimmune thyroiditis, daily supplementation with 200 µg selenium or placebo for 12 months improved QoL to the same extent.

Influence of the anti-oestrogens tamoxifen and letrozole on thyroid function in women with early and advanced breast cancer: A systematic review.

INTRODUCTION: Breast cancer (BC) is a common type of cancer in women. Advances in therapy options have resulted in higher overall survival rates but side effects of cancer treatment are increasingly in the spotlight. The beneficial effects of anti-oestrogen therapy with tamoxifen and letrozole in the prevention of BC recurrence are well documented. While the most common side-effects of this therapy are well-defined, less is known about its effects on thyroid function. In women treated for early BC, an average of 1-5 kg weight gain has been observed after treatment with chemotherapy/anti-oestrogens. We aim to evaluate the current knowledge on the side effects of tamoxifen and letrozole treatments on thyroid function, followed by its potential influence on the observed weight gain. METHODS: We searched PubMed and found 16 publications on thyroid function and tamoxifen treatment in pre- and post-menopausal women with early- and advanced BC, whereas five publications on letrozole treatment in post-menopausal women with advanced BC. RESULTS: According to the current literature, there is an overall tendency towards a mild and transient thyroid dysfunction, that is, subclinical hypothyroidism in tamoxifen-treated patients. Only one publication reported further significant changes in thyroid hormones beyond one year of tamoxifen treatment. No significant changes in thyroid function have been observed among letrozole-treated patients. CONCLUSION: Tamoxifen-treated patients can develop mild and transient thyroid dysfunction within the first 12 months, yet further significant changes in thyroid function beyond one year of tamoxifen treatment have been reported in a single study. There is no evidence of thyroid dysfunction in letrozole-treated patients. Current literature does not focus on subclinical hypothyroidism as a possible cause of weight gain in patients with BC. Subgrouping of BC patients and studies with a longer observation of thyroid hormones and weight changes during and after anti-oestrogen treatment are needed to further elucidate how anti-oestrogens affect thyroid function.

Severity of hypothyroidism is inversely associated with impaired quality of life in patients referred to an endocrine clinic.

PURPOSE: We investigated the association between health-related quality of life (HRQL) and the severity of hypothyroidism at diagnosis in patients referred to a secondary hospital clinic. METHODS: Sixty-seven adult patients referred from primary care were enrolled. All patients had newly diagnosed hypothyroidism due to autoimmune thyroiditis and were treated with levothyroxine (LT4). The dose was adjusted according to thyroid function tests aiming at a normal plasma thyrotropin. Patients were stratified according to the severity of hypothyroidism in two different ways: the conventional approach (subclinical or overt hypothyroidism) and a novel approach according to the change (decrease or increase) in plasma level of free triiodothyronine index (FT3I) following LT4 treatment. The ThyPRO-39 questionnaire was used for measurement of HRQL at referral to the Endocrine Outpatient Clinic (higher score corresponds to worse HRQL). RESULTS: Free thyroxine index (FT4I) at diagnosis correlated positively with the scores on the Hypothyroid Symptoms and Tiredness scales (p = 0.018 for both). In accordance, patients with subclinical hypothyroidism (n = 36) scored higher on Hypothyroid Symptoms (p = 0.029) than patients with overt hypothyroidism (n = 31). The difference in HRQL was more pronounced if patients were stratified according to the dynamics in FT3I following LT4 treatment. Thus, patients who showed a decrease in FT3I following treatment (n = 24) scored significantly worse for Anxiety (p = 0.032) and Emotional Susceptibility (p = 0.035) than patients with an increase in FT3I (n = 43). CONCLUSION: Patients referred to an endocrine clinic with mild hypothyroidism had an impaired HRQL, compared to patients with more severe hypothyroidism. The most likely explanation of this finding is a lower threshold for seeking medical consultation and secondary care referral if HRQL is deteriorated. The dynamics in plasma FT3I following treatment may be more sensitive for such a discrimination in HRQL than a stratification according to the thyroid function tests at diagnosis.

Imaging surveillance in multiple endocrine neoplasia type 1: Ten years of experience with somatostatin receptor positron emission tomography.

Guidelines for multiple endocrine neoplasia type 1 (MEN1) recommend intensive imaging surveillance without specifying a superior regimen, including the role of somatostatin receptor imaging (SRI) with positron emission tomography (PET). The primary outcomes were to: (1) Assess change in treatment of duodenal-pancreatic neuroendocrine neoplasms (DP-NENs), bronchopulmonary NENs, and thymic tumors attributed to use of SRI PET/computed tomography (CT) and (2) estimate radiation from imaging and risk of cancer death attributed to imaging radiation. This was a retrospective single center study, including all MEN1 patients, who had had at least one SRI PET/CT. A total of 60 patients, median age 42 (range 21-54) years, median follow-up 6 (range 1-10) years were included. Of 470 cross sectional scans (MRI, CT, SRI PET/CT), 209 were SRI PET/CT. The additional information from SRI PET had implications in 1/14 surgical interventions and 2/12 medical interventions. The estimated median radiation dose per patient was 104 (range 51-468) mSv of which PET contributed with 13 (range 5-55) mSv and CT with 91 mSv (range 46-413 mSv), corresponding to an estimated increased median risk of cancer death of 0.5% during 6 years follow-up. SRI PET had a significant impact on 3/26 decisions to intervene in 60 MEN1 patients followed for a median of 6 years with SRI PET/CT as the most frequently used modality. The surveillance program showed a high radiation dose. Multi-modality imaging strategies designed to minimize radiation exposure should be considered. Based on our findings, SRI-PET combined with CT cannot be recommended for routine surveillance in MEN1 patients.