Current utility of first-line FT4 and TSH in screening for central hypothyroidism.

BACKGROUND: Thyroid testing strategies vary across laboratories. First-line combined thyroid stimulating hormone (TSH) and freeT4 (FT4) have historically been preferred by many laboratories as this detects individuals with undiagnosed central hypothyroidism who can be missed with a first-line TSH-only strategy. However, an up-to-date evaluation of the utility of this approach is lacking. OBJECTIVES: We investigated the clinical utility of first-line TSH and FT4 in the detection of central hypothyroidism in current day practice. DESIGN, PATIENTS, AND MEASUREMENTS: The All-Wales laboratory information system was queried to identify thyroid function tests in patients aged ≥16 years with decreased FT4 and inappropriate TSH (low-FT4). The 1-year incidence of low-FT4 was determined using mid-year population data. Clinical information of patients with low-FT4 was reviewed to determine causes of low-FT4 and the incidence of central hypothyroidism. RESULTS: The incidence of low-FT4 varied according to FT4 assay method (range: 98-301 cases/100,000 population/year). Fifteen new cases of central hypothyroidism were detected in two health boards, equivalent to 2 cases/100,000 population/year. Positive predictive value of low-FT4 for central hypothyroidism was 2%-4%. In a cross-section of primary care patients, low-FT4 was detected in 0.5% of all thyroid tests with assay-related differences in detection rates. CONCLUSIONS: Although low-FT4 is a common laboratory finding, the incidence of central hypothyroidism remains rare. With the currently increased rates of thyroid testing and increased use of medications that decrease FT4, low-FT4 has a much lower predictive value for central hypothyroidism than previously reported. Thyroid screening strategies will need to balance the yield from first line TSH and FT4 testing with the cost of investigating individuals with non-pathological laboratory abnormalities.

Late offspring effects of antenatal thyroid screening.

BACKGROUND: Thyroid dysfunction in pregnancy is associated with adverse offspring outcomes and recent birth-cohort studies suggest that even mild degrees of thyroid dysfunction may be linked with a range of late cognitive and behavioural effects in childhood and adolescence. SOURCES OF DATA: This review summarizes recent literature of observational studies and critically appraises randomized controlled trials (RCTs) of antenatal thyroid screening and Levothyroxine intervention. AREAS OF AGREEMENT: Overt hypothyroidism and hyperthyroidism carry significant risks for unfavourable offspring outcomes and should be appropriately corrected in pregnancy. AREAS OF CONTROVERSY: The significance of subclinical hypothyroidism and hypothyroxinaemia is still unclear. Meta-analyses of birth-cohort studies show associations of maternal subclinical hypothyroidism and hypothyroxinaemia with intellectual deficits, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders, while hyperthyroidism and high-normal FT4 were linked with ADHD. RCTs have shown no benefits of screening on neurodevelopmental outcomes although Levothyroxine could have been initiated too late in pregnancy in these trials. GROWING POINTS: A small number of studies have shown inconsistent associations of maternal thyroid dysfunction with offspring cardiometabolic indices including blood pressure and body weight. Correction of maternal thyroid dysfunction was, however, associated with favourable long-term metabolic profiles in mothers, including lipid profiles, fat mass and body mass index. Antenatal thyroid screening may therefore present opportunities for optimizing a wider range of outcomes than envisaged. AREAS FOR DEVELOPING RESEARCH: Future trials with early antenatal thyroid screening and intervention are necessary to clarify the impact of screening on late offspring and maternal effects.

Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta-analysis.

OBJECTIVES: The risk of congenital anomalies following in utero exposure to thionamide antithyroid drugs (ATDs) is unresolved. Observational studies are contradictory and existing meta-analyses predate and preclude more recent studies. We undertook an updated meta-analysis of congenital anomaly risk in women exposed to carbimazole or methimazole (CMZ/MMI), propylthiouracil (PTU), or untreated hyperthyroidism in pregnancy. METHODS: We searched Medline, Embase, and the Cochrane database for articles published up till August 2021. We pooled separate crude and adjusted risk estimates using random effects models and subgroup analyses to address heterogeneity. RESULTS: We identified 16 cohort studies comprising 5957, 15,785, and 15,666 exposures to CMZ/MMI, PTU, and untreated hyperthyroidism, respectively. Compared to nondisease controls, adjusted risk ratio (RR) and 95% confidence intervals (95% CIs) for congenital anomalies was increased for CMZ/MMI (RR, 1.28; 95% CI, 1.06-1.54) and PTU (RR, 1.16; 95% CI, 1.08-1.25). Crude risk for CMZ/MMI was increased relative to PTU (RR, 1.20; 95% CI, 1.01-1.43). Increased risk was also seen with exposure to both CMZ/MMI and PTU, that is, women who switched ATDs in pregnancy (RR, 1.51; 95% CI, 1.14-1.99). However, the timing of ATD switch was highly variable and included prepregnancy switches in some studies. The excess number of anomalies per 1000 live births was 17.2 for patients exposed to CMZ/MMI, 9.8, for PTU exposure, and 31.4 for exposure to both CMZ/MMI and PTU. Risk in the untreated group did not differ from control or ATD groups. The untreated group was however highly heterogeneous in terms of thyroid status. Subgroup analysis showed more positive associations in studies with >500 exposures and up to 1-year follow-up. CONCLUSIONS: ATD therapy carries a small risk of congenital anomalies which is higher for CMZ/MMI than for PTU and does not appear to be reduced by switching ATDs in pregnancy. Due to key limitations in the available data, further studies will be required to clarify the risks associated with untreated hyperthyroidism and with switching ATDs in pregnancy.

Preconception management of thyroid dysfunction.

Uncorrected thyroid dysfunction in pregnancy has well-recognized deleterious effects on foetal and maternal health. The early gestation period is one of the critical foetal vulnerability during which maternal thyroid dysfunction may have lasting repercussions. Accordingly, a pragmatic preconception strategy is key for ensuring optimal thyroid disease outcomes in pregnancy. Preconception planning in women with hypothyroidism should pre-empt and mirror the adaptive changes in the thyroid gland by careful levothyroxine dose adjustments to ensure adequate foetal thyroid hormone delivery in pregnancy. In hyperthyroidism, the goal of preconception therapy is to control hyperthyroidism while curtailing the unwanted side effects of foetal and maternal exposure to antithyroid drugs. Thus, pregnancy should be deferred until a stable euthyroid state is achieved, and definitive therapy with radioiodine or surgery should be considered in women with Graves' disease planning future pregnancy. Women with active disease who are imminently trying to conceive should be switched to propylthiouracil either preconception or at conception in order to minimize the risk of birth defects from carbimazole or methimazole exposure. Optimal strategies for women with borderline states of thyroid dysfunction namely subclinical hypothyroidism, isolated hypothyroxinaemia and thyroid autoimmunity remain uncertain due to the dearth of controlled interventional trials. Future trial designs should aspire to recruit and initiate therapy before conception or as early as possible in pregnancy.

Recent trends in thyroid surgery in Wales.

INTRODUCTION: Our objective was to analyse trends in thyroid surgery in Wales over a recent 12-year period. METHODS: Details of patients who underwent thyroid surgery across Wales from 1999 to 2010 were analysed from the Patient Episodes Database for Wales [n = 6570, 83% (5429) female, 86% (5634) benign thyroid disease]. We determined age-adjusted thyroidectomy rates from the European standard population and a Poisson regression model was fitted to assess temporal trends. Joinpoint regression was used to calculate annual percentage change (APC) in thyroidectomy rates. RESULTS: An increase in thyroidectomy rates was observed for malignant disease [APC 4.5, 95% confidence interval (CI) 1.6-7.5] while surgery rates for benign disease declined over the period (APC -3.2, 95% CI -5.1 to -1.3). The use of total thyroidectomy rose from 17% (599/3501) in 1999-2004 to 30% (912/3069) in 2005-2010 (p < 0.001). Total thyroidectomies were performed in a higher proportion of males than females [26% (291/1141) vs. 22% (1220/5429), p = 0.03] and in a greater percentage of patients with malignant disease than benign [36% (337/936) vs. 21% (1174/5634), p < 0.001). General surgeons undertook 83% of thyroid surgery but with a growing involvement of ENT surgeons. Regional disparities were seen in the type of surgery offered to patients with benign thyroid disease. CONCLUSION: The use of total thyroidectomy for benign and malignant thyroid disease has risen in Wales. The increase in surgeries performed for malignancy would support a rising incidence of thyroid cancer in the region. Regional disparities in choice of surgery for benign disease require further exploration.

Non-thionamide antithyroid drug options in Graves' hyperthyroidism.

INTRODUCTION: The thionamide anti-thyroid drugs namely carbimazole, methimazole, and propylthiouracil, have been the predominant therapy modality for Graves' hyperthyroidism for over 60 years. Although these agents have proven efficacy and favorable side-effect profiles, non-thionamide alternatives are occasionally indicated in patients who are intolerant or unresponsive to thionamides alone. This review examines the available non-thionamide drug options for the control of Graves' hyperthyroidism and summarizes their clinical utility, efficacy, and limitations. AREAS COVERED: We reviewed existing literature on mechanisms, therapeutic utility, and side-effect profiles of non-thionamide anti-thyroid drugs. Established non-thionamide agents act on various phases of the synthesis, release, and metabolism of thyroid hormones and comprise historical agents such as iodine compounds and potassium perchlorate as well as drug repurposing candidates like lithium, glucocorticoids, beta-blockers, and cholestyramine. Novel experimental agents in development target key players in Graves' disease pathogenesis including B-cell depletors (Rituximab), CD40 blockers (Iscalimab), TSH-receptor antagonists, blocking antibodies, and immune-modifying peptides. EXPERT OPINION: Non-thionamide anti-thyroid drugs are useful alternatives in Graves' hyperthyroidism and more clinical trials are needed to establish their safety and long-term efficacy in hyperthyroidism control. Ultimately, the promise for a cure will lie in novel approaches that target the well-established immunopathogenesis of Graves' disease.

Cardiovascular morbidity and mortality in patients in Wales, UK with resistance to thyroid hormone ß (RTHß): a linked-record cohort study.

BACKGROUND: Individuals with resistance to thyroid hormone owing to mutations in the thyroid hormone receptor ß gene (RTHß) exhibit impaired tissue sensitivity to thyroid hormones, but retain sensitivity in cardiac tissue. Long-term health and survival outcomes in this rare disorder have not been evaluated. We investigated all-cause mortality and cardiovascular event risk in a cohort of patients with RTHß, followed-up in UK endocrine clinics. METHODS: In a retrospective cohort design, we linked genetically confirmed patients with RTHß and age-matched and sex-matched population controls to outcomes in datasets within the Welsh Secure Anonymised Information Linkage (SAIL) Databank. Kaplan-Meier and Cox regression models analysed associations of RTHß with all-cause mortality and cardiovascular events. FINDINGS: We identified 61 patients with a genetic diagnosis of RTHß between Jan 1, 1997, and Dec 31, 2019, and matched them with 2750 controls. Compared with controls, patients exhibited increased risks for all-cause mortality (hazard ratio [HR] 2·84, 95% CI 1·59-5·08), atrial fibrillation (10·56, 4·72-23·63), heart failure (HR 6·35, 95% CI 2·26-17·86), and major adverse cardiovascular events (MACE), comprising cardiovascular death, acute myocardial infarction, heart failure, or strokes (HR 3·49, 95% CI 2·04-5·99). The median age of first occurrence of any adverse event was 11 years earlier in patients (56 years, 95% CI 44-65) compared with controls (67 years, 65-70). Cubic spline analyses showed positive associations between FT4 concentrations at diagnosis and mortality or MACE, with FT4 concentration of 30 pmol/L or greater conferring increased risk. Compared with no intervention, treatment with antithyroid drugs, surgery or radioiodine gland ablation, or thyroxine did not control thyroid hormone excess. INTERPRETATION: We have documented reduced survival and increased cardiovascular morbidity in a cohort of patients with RTHß for the first time. These outcomes might be driven by lifelong cardiac exposure to thyroid hormone excess; and effective therapies, targeting hormone resistant pathways, could potentially curtail this risk. FUNDING: Royal College of Physicians, Wellcome Trust Investigator Award, and NIHR Cambridge Biomedical Research Centre.

Designing a combined liothyronine (LT3), L- thyroxine (LT4) trial in symptomatic hypothyroid subjects on LT4 - the importance of patient selection, choice of LT3 and trial design.

Approximately 10%-15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL). Although the cause is unclear, there is evidence that "tissue T3 lack" may be responsible. If so, combining liothyronine (LT3) with LT4 would be helpful. However, randomized controlled trials (RCT), have not established greater efficacy for the LT3 + LT4 combination in these subjects than for LT4 alone. While the trial design may have been responsible, the use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures (PROMs) may have contributed. We recommend attention to the following aspects of trial design for future RCTs of LT3 + LT4 compared to LT4 alone: (a) Subject selection-(i) measurable symptoms (disadvantages should be recognized); (ii) using a validated thyroid specific PROM such as ThyPRO39 or the Composite scale derived from it; (iii) those taking over 1.2 µg/day or 100 µg/day (for pragmatic reasons) of LT4 defining a population likely without intrinsic thyroid activity who depend on exogenous LT4; (iv) recruiting a preponderance of subjects with autoimmune thyroiditis increasing generalisability; and (v) those with a high symptom load with a greater response to combination therapy e.g. those with the deiodinase 2 polymorphism. (b) The use of physiological LT3 preparations producing pharmacokinetic similarities to T3 profiles in unaffected subjects: two long-acting LT3 preparations are currently available and must be tested in phase 2b/3 RCTs. (c) The superiority of a crossover design in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication.

Method-dependent variation in TSH and FT4 reference intervals in pregnancy: A systematic review.

BACKGROUND: Gestational TSH and FT4 reference intervals may differ according to assay method, but the extent of variation is unclear and has not been systematically evaluated. We conducted a systematic review of published studies on TSH and FT4 reference intervals in pregnancy. Our aim was to quantify method-related differences in gestation reference intervals, across four commonly used assay methods, Abbott, Beckman, Roche and Siemens. METHODS: We searched the literature for relevant studies, published between January 2000 and December 2020, in healthy pregnant women without thyroid antibodies or disease. For each study, we extracted trimester-specific reference intervals (2.5-97.5 percentiles) for TSH and FT4 as well as the manufacturer-provided reference interval for the corresponding non-pregnant population. RESULTS: TSH reference intervals showed a wide range of study-to-study differences with upper limits ranging from 2.33 to 8.30 mU/L. FT4 lower limits ranged from 4.40 to 13.93 pmol/L, with consistently lower reference intervals observed with the Beckman method. Differences between non-pregnant and first trimester reference intervals were highly variable, and for most studies, the TSH upper limit in the first trimester could not be predicted or extrapolated from non-pregnant values. CONCLUSIONS: Our study confirms significant intra- and intermethod disparities in gestational thyroid hormone reference intervals. The relationship between pregnant and non-pregnant values is inconsistent and does not support the existing practice in many laboratories of extrapolating gestation references from non-pregnant values. Laboratories should invest in deriving method-specific gestation reference intervals for their population.

Thyroid Autoimmunity and Dysfunction in Sri Lankan Children and Adolescents After 22 Years of Sustained Universal Salt Iodization.

Background: Sri Lanka introduced universal salt iodization (USI) in 1995 after which we demonstrated a high thyroglobulin antibody (TgAb) prevalence in 1998. However, it is unclear whether thyroid autoimmunity persists in the long term in populations exposed to sustained USI and whether such populations have an excess of thyroid dysfunction. We evaluated the prevalence of thyroid autoantibodies and dysfunction in Sri Lankan children and adolescents after more than two decades of sustained USI. Methods: We selected 10- to 18-year-old subjects of both sexes (randomized cluster sampling) from all 9 provinces of Sri Lanka in this cross-sectional study. Blood, urine, and anthropometric data were collected and thyroid ultrasound scans were performed. Validated statistical methods were used to derive local population-specific reference ranges for all thyroid parameters. We also measured urine iodine concentration (UIC), salt, and water iodine concentrations. Results: Blood and urine samples from 2507 and 2473 subjects respectively, and ultrasound scans from 882 subjects were analyzed. Population-derived upper limits for thyroid peroxidase antibody (TPOAb) and TgAb, and reference ranges for triiodothyronine, thyroxine, and thyrotropin (total and age-year-related groups) were significantly different from manufacturer's reference ranges. Using these derived ranges, the prevalence of TPOAb was 10.3% and TgAb was 6.4%. Of the TPOAb-positive subjects, TPOAb were of low concentration in 66.2% (1-3 times the upper limit of the reference range [ULRR]) and showed the strongest association with subclinical hypothyroidism (SCH) at the highest concentrations (>4 ULRR). The prevalence of SCH was 3%. Median UIC (interquartile range) was 138.5 µg/L (79.4-219.0) with regional variability, and median thyroglobulin was 8.3 ng/mL (4.1-13.5). Goiter prevalence was 0.6% and 1.93% (thyroid volume compared to age and body surface area, respectively). Salt and water iodine concentrations were satisfactory. Conclusions: Sri Lanka has safely and effectively implemented USI with good sources of iodine, leading to sustained iodine sufficiency over more than two decades. The early postiodization TgAb surge (42.1%) has settled (6.4%), and despite a persistently high TPOAb prevalence (10.3%), SCH prevalence remains low (3%). Further studies should be undertaken to monitor thyroid autoimmune dysfunction in Sri Lankan children, using age-specific, population-derived reference ranges.

Current controversies in the management of Graves' hyperthyroidism.

Introduction: The management of Graves' disease centers on the use of effective and well-established therapies, namely thionamide antithyroid drugs, radioactive iodine, and thyroidectomy. Optimal treatment strategies are however controversial and vary significantly across centers.Areas covered: This review addresses specific controversies in Graves' disease management including the choice of primary therapy, the approach to women planning pregnancy, and optimal strategies for antithyroid drug and radioiodine therapy.Expert opinion: Important considerations in choosing therapy include treatment efficacy, adverse effects, patient convenience, and resource settings. Recent data suggest that early and effective control of hyperthyroidism is key to improving cardiovascular morbidity and mortality. Studies addressing cancer risk in radioiodine-treated patients face methodological challenges and require clarification in appropriately designed studies. Remission rates with antithyroid drugs are comparable when thionamides are used alone (titration-regimen) or in combination with levothyroxine (block and replace) and can be optimized by extending treatment for at least 12-18 months. Fixed and calculated radioiodine activity regimens are both effective but entail a trade-off between convenience and precision in the administered activity. Optimal preconception strategies are still evolving but ablative treatment in advance of pregnancy offers the most pragmatic means of reducing adverse effects of hyperthyroidism in subsequent pregnancy.

Should radioiodine now be first line treatment for Graves' disease?

BACKGROUND: Radioiodine represents a cost-effective treatment option for Graves' disease. In the UK, it is traditionally reserved for patients who relapse after initial thionamide therapy. In a change from current practice, the new guidelines of the National Institute for Health and Care Excellence (NICE) recommends that radioiodine should now be first line therapy for Graves' disease. However, the safety of radioiodine with respect to long-term mortality risk has been the subject of recent debate. This analysis examines evidence from treatment related mortality studies in hyperthyroidism and discusses their implications for future Graves' disease treatment strategies. MAIN BODY: Some studies have suggested an excess mortality in radioiodine treated cohorts compared to the background population. In particular, a recent observational study reported a modest increase in cancer-related mortality in hyperthyroid patients exposed to radioiodine. The interpretation of these studies is however constrained by study designs that lacked thionamide control groups or information on thyroid status and so could not distinguish the effect of treatment from disease. Two studies have shown survival advantages of radioiodine over thionamide therapy, but these benefits were only seen when radioiodine was successful in controlling hyperthyroidism. Notably, increased mortality was associated with uncontrolled hyperthyroidism irrespective of therapy modality. CONCLUSIONS: Early radioiodine treatment will potentially reduce mortality and should be offered to patients with severe disease. However, thionamides are still suitable for patients with milder disease, contraindications to radioiodine, or individuals who choose to avoid permanent hypothyroidism. Ultimately, a patient individualised approach that prioritises early and sustained control of hyperthyroidism will improve long-term outcomes regardless of the therapy modality used.

Safety of antithyroid drugs in pregnancy: update and therapy implications.

Introduction: The thionamide antithyroid drugs, methimazole (MMI), its pro-drug derivative carbimazole (CMZ), and propylthiouracil (PTU) are the mainstay of treatment for hyperthyroidism in pregnancy. However, antithyroid drugs carry risks of adverse effects that can affect fetal and maternal well-being.Areas covered: This review provides an update on the safety of antithyroid drugs in pregnancy, focusing on the most serious concerns of severe liver disease and congenital anomalies.Expert opinion: PTU-induced liver disease is uncommon but can run a catastrophic course in pregnancy with a risk of liver failure and threats to maternal or fetal survival. Acute pancreatitis is a relatively rare occurrence that has been linked to thionamide use in a handful of reports in non-pregnant individuals. Observational studies on the risk of birth defects with antithyroid drug exposure in pregnancy overall show an increase in birth defect risk with exposure to CMZ/MMI, and to a lesser extent, PTU. Further studies are required to determine whether the currently recommended approach of switching between thionamide drugs in pregnancy improves outcomes. Ultimately, a preventative strategy of offering definitive therapy to hyperthyroid women of childbearing potential offers the best approach to truly reduce the risks of antithyroid drug adverse effects in pregnancy.

Stable Iodine Nutrition During Two Decades of Continuous Universal Salt Iodisation in Sri Lanka.

Universal salt iodisation (USI) was introduced in Sri Lanka in 1995. Since then, four national iodine surveys have assessed the iodine nutrition status of the population. We retrospectively reviewed median urine iodine concentration (mUIC) and goitre prevalence in 16,910 schoolchildren (6-12 years) in all nine provinces of Sri Lanka, the mUIC of pregnant women, drinking-water iodine level, and the percentage of households consuming adequately (15 mg/kg) iodised salt (household salt iodine, HHIS). The mUIC of schoolchildren increased from 145.3 µg/L (interquartile range (IQR) = 84.6-240.4) in 2000 to 232.5 µg/L (IQR = 159.3-315.8) in 2016, but stayed within recommended levels. Some regional variability in mUIC was observed (178.8 and 297.3 µg/L in 2016). There was positive association between mUIC in schoolchildren and water iodine concentration. Goitre prevalence to palpation was a significantly reduced from 18.6% to 2.1% (p < 0.05). In pregnant women, median UIC increased in each trimester (102.3 (61.7-147.1); 217.5 (115.6-313.0); 273.1 (228.9-337.6) µg/L (p = 0.000)). We conclude that the introduction and maintenance of a continuous and consistent USI programme has been a success in Sri Lanka. In order to sustain the programme, it is important to retain monitoring of iodine status while tracking salt-consumption patterns to adjust the recommended iodine content of edible salt.

Primary therapy of Graves' disease and cardiovascular morbidity and mortality: a linked-record cohort study.

BACKGROUND: Graves' disease is routinely treated with antithyroid drugs, radioiodine, or surgery, but whether the choice of initial therapy influences long-term outcomes is uncertain. We evaluated cardiovascular morbidity and mortality according to the method and effectiveness of primary therapy in Graves' disease. METHODS: In this retrospective cohort study, we identified patients with hyperthyroidism, diagnosed between Jan 1, 1998, and Dec 31, 2013, from a thyroid-stimulating hormone (TSH)-receptor antibody (TRAb) test register in south Wales, UK, and imported their clinical data into the All-Wales Secure Anonymised Information Linkage (SAIL) Databank (Swansea University, Swansea, UK). Patients with Graves' disease, defined by positive TRAb tests, were selected for the study, and their clinical data were linked with outcomes in SAIL. We had no exclusion criteria. Patients were matched by age and sex to a control population (1:4) in the SAIL database. Patients were grouped by treatment within 1 year of diagnosis into the antithyroid drug group, radioiodine with resolved hyperthyroidism group (radioiodine group A), or radioiodine with unresolved hyperthyroidism group (radioiodine group B). We used landmark Kaplan-Meier and Cox regression models to analyse the association of treatment with the primary outcome of all-cause mortality and the secondary outcome of major adverse cardiovascular events (myocardial infarction, heart failure, ischaemic stroke, or death) with the landmark set at 1 year after diagnosis. We analysed the association between outcomes and concentration of TSH using Cox regression and outcomes and free thyroxine (FT4) concentration using restricted cubic-spline regression models. FINDINGS: We extracted patient-level data on 4189 patients (3414 [81·5%] females and 775 [18·5%] males) with Graves' disease and 16 756 controls (13 656 [81·5%] females and 3100 [18·5%] males). In landmark analyses, 3587 patients were in the antithyroid drug group, 250 were in radioiodine group A, 182 were in radioiodine group B. Patients had increased all-cause mortality compared with controls (hazard ratio [HR] 1·22, 95% CI 1·05-1·42). Compared with patients in the antithyroid drug group, mortality was lower among those in radioiodine group A (HR 0·50, 95% CI 0·29-0·85), but not for those in radioiodine group B (HR 1·51, 95% CI 0·96-2·37). Persistently low TSH concentrations at 1 year after diagnosis were associated with increased mortality independent of treatment method (HR 1·55, 95% CI 1·08-2·24). Spline regressions showed a positive non-linear relationship between FT4 concentrations at 1 year and all-cause mortality. INTERPRETATION: Regardless of the method of treatment, early and effective control of hyperthyroidism among patients with Graves' disease is associated with improved survival compared with less effective control. Rapid and sustained control of hyperthyroidism should be prioritised in the management of Graves' disease and early definitive treatment with radioiodine should be offered to patients who are unlikely to achieve remission with antithyroid drugs alone. FUNDING: National Institute for Social Care and Health Research, Wales.

Global epidemiology of hyperthyroidism and hypothyroidism.

Thyroid hormones are essential for growth, neuronal development, reproduction and regulation of energy metabolism. Hypothyroidism and hyperthyroidism are common conditions with potentially devastating health consequences that affect all populations worldwide. Iodine nutrition is a key determinant of thyroid disease risk; however, other factors, such as ageing, smoking status, genetic susceptibility, ethnicity, endocrine disruptors and the advent of novel therapeutics, including immune checkpoint inhibitors, also influence thyroid disease epidemiology. In the developed world, the prevalence of undiagnosed thyroid disease is likely falling owing to widespread thyroid function testing and relatively low thresholds for treatment initiation. However, continued vigilance against iodine deficiency remains essential in developed countries, particularly in Europe. In this report, we review the global incidence and prevalence of hyperthyroidism and hypothyroidism, highlighting geographical differences and the effect of environmental factors, such as iodine supplementation, on these data. We also highlight the pressing need for detailed epidemiological surveys of thyroid dysfunction and iodine status in developing countries.

Attitudes and perceptions of health professionals towards management of hypothyroidism in general practice: a qualitative interview study.

OBJECTIVE: To explore the attitudes and perceptions of health professionals towards management of hypothyroidism that contributes to the suboptimal treatment of hypothyroidism in general practice. DESIGN: A qualitative interview study using semistructured interviews. PARTICIPANTS: Sixteen participants were interviewed between March and August 2016 comprising nine general practitioners (GPs), four pharmacists, two practice nurses and one nurse practitioner. SETTING: General practice and community pharmacies in the counties of Northumberland, Tyne and Wear, Stockton-on-Tees and North Cumbria, North of England, UK. METHOD: A grounded-theory approach was used to generate themes from interviews, which were underpinned by the theory of planned behaviour to give explanation to the data. RESULTS: Although health professionals felt that hypothyroidism was easy to manage, GPs and nurses generally revealed inadequate knowledge of medication interactions and levothyroxine pharmacokinetics. Pharmacists felt limited in the advice that they provide to patients due to lack of access to patient records. Most GPs and nurses followed local guidelines, and relied on blood tests over clinical symptoms to adjust levothyroxine dose. The information exchanged between professional and patient was usually restricted by time and often centred on symptoms rather than patient education. Health professionals felt that incorrect levothyroxine adherence was the main reason behind suboptimal treatment, although other factors such as comorbidity and concomitant medication were mentioned. Enablers perceived by health professionals to improve the management of hypothyroidism included continuity of care, blood test reminders, system alerts for interfering medications and prescription renewal, and accessible blood tests and levothyroxine prescriptions for patients. CONCLUSION: There is a significant health professional behavioural component to the management of hypothyroidism. Addressing the differences in patient and professional knowledge and perceptions could reduce the barriers to optimal treatment, while continuity of care and increased involvement of pharmacists and practice nurses would help to promote optimal thyroid replacement.