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.

Controlled Antenatal Thyroid Screening Study III: Effects of gestational thyroid status on adolescent brain morphology.

CONTEXT: Children born to mothers with gestational hypo- or hyperthyroidism may have increased risk of adverse neurodevelopmental outcomes. However, the effects of maternal thyroid status on offspring brain development are unclear. OBJECTIVE: To establish whether adolescent brain morphology is affected by suboptimal gestational thyroid function (SGTF). DESIGN AND SETTING: The Controlled Antenatal Thyroid Screening (CATS) study randomized mothers with SGTF to levothyroxine or no supplementation from ∼12 weeks' gestation. At age 9, children born to mothers who were over-treated with levothyroxine had a higher risk of conduct and hyperactivity traits. For the current CATS III study, children underwent neuroimaging studies, including T1-weighted structural magnetic resonance imaging (MRI). PARTICIPANTS: A total of 85 children aged 11-16 years had usable T1-weighted MRI data (exposed to untreated SGTF (n=21), normal GTF (n=24), or treated SGTF (optimally-treated (n=21), over-treated (n=20)). MAIN OUTCOME MEASURES: Primary outcome: to examine the association of SGTF and its treatment with global brain volumes. Secondary and exploratory outcomes: to investigate the association of maternal TSH and free T4 levels with global and subregional brain volumes. Results were adjusted for age, sex and pubertal scores. RESULTS: There were no significant differences in global brain volumetric measures between groups, including total gray matter volume (p=0.373). Weak positive correlations were found between maternal TSH, but not FT4, levels and several brain volumes, but these did not survive testing for multiple comparisons. CONCLUSIONS: We found no evidence that SGTF was associated with differences in adolescent brain morphology, and no impact of levothyroxine supplementation.

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.

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.

Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement.

Persistent symptoms in patients treated for hypothyroidism are common. Despite more than 20 years of debate, the use of liothyronine for this indication remains controversial, as numerous randomised trials have failed to show a benefit of treatment regimens that combine liothyronine (T3) with levothyroxine over levothyroxine monotherapy. This consensus statement attempts to provide practical guidance to clinicians faced with patients who have persistent symptoms during thyroid hormone replacement therapy. It applies to non-pregnant adults and is focussed on care delivered within the UK National Health Service, although it may be relevant in other healthcare environments. The statement emphasises several key clinical practice points for patients dissatisfied with treatment for hypothyroidism. Firstly, it is important to establish a diagnosis of overt hypothyroidism; patients with persistent symptoms during thyroid hormone replacement but with no clear biochemical evidence of overt hypothyroidism should first have a trial without thyroid hormone replacement. In those with established overt hypothyroidism, levothyroxine doses should be optimised aiming for a TSH in the 0.3-2.0 mU/L range for 3 to 6 months before a therapeutic response can be assessed. In some patients, it may be acceptable to have serum TSH below reference range (e.g. 0.1-0.3 mU/L), but not fully suppressed in the long term. We suggest that for some patients with confirmed overt hypothyroidism and persistent symptoms who have had adequate treatment with levothyroxine and in whom other comorbidities have been excluded, a trial of liothyronine/levothyroxine combined therapy may be warranted. The decision to start treatment with liothyronine should be a shared decision between patient and clinician. However, individual clinicians should not feel obliged to start liothyronine or to continue liothyronine medication provided by other health care practitioners or accessed without medical advice, if they judge this not to be in the patient's best interest.

Preconception Management of Hyperthyroidism and Thyroid Status in Subsequent Pregnancy: A Population-Based Cohort Study.

CONTEXT: Optimal thyroid status in pregnancy is essential in reducing the risk of adverse outcomes. The management of hyperthyroidism in women of reproductive age poses unique challenges and it is unclear how preconception treatment strategies impact on thyroid status in subsequent pregnancy. OBJECTIVE: We aimed to determine trends in the management of hyperthyroidism before and during pregnancy and to assess the impact of different preconception treatment strategies on maternal thyroid status. METHODS: We utilized the Clinical Practice Research Datalink database to evaluate all females aged 15-45 years with a clinical diagnosis of hyperthyroidism and a subsequent pregnancy (January 2000 to December 2017). We compared thyroid status in pregnancy according to preconception treatment, namely, (1) antithyroid drugs up to or beyond pregnancy onset, (2) definitive treatment with thyroidectomy or radioiodine before pregnancy, and (3) no treatment at pregnancy onset. RESULTS: Our study cohort comprised 4712 pregnancies. Thyrotropin (TSH) was measured in only 53.1% of pregnancies, of which 28.1% showed suboptimal thyroid status (TSH >4.0 mU/L or TSH <0.1 mU/L plus FT4 >reference range). Pregnancies with prior definitive treatment were more likely to have suboptimal thyroid status compared with pregnancies starting during antithyroid drug treatment (odds ratio 4.72, 95% CI 3.50-6.36). A steady decline in the use of definitive treatment before pregnancy was observed from 2000 to 2017. One-third (32.6%) of first trimester carbimazole-exposed pregnancies were switched to propylthiouracil while 6.0% of propylthiouracil-exposed pregnancies switched to carbimazole. CONCLUSION: The management of women with hyperthyroidism who become pregnant is suboptimal, particularly in those with preconception definitive treatment, and needs urgent improvement. Better thyroid monitoring and prenatal counseling are needed to optimize thyroid status, reduce teratogenic drug exposure, and ultimately reduce the risk of adverse pregnancy outcomes.

Age-related variation in thyroid function - a narrative review highlighting important implications for research and clinical practice.

BACKGROUND: Thyroid hormones are key determinants of health and well-being. Normal thyroid function is defined according to the standard 95% confidence interval of the disease-free population. Such standard laboratory reference intervals are widely applied in research and clinical practice, irrespective of age. However, thyroid hormones vary with age and current reference intervals may not be appropriate across all age groups. In this review, we summarize the recent literature on age-related variation in thyroid function and discuss important implications of such variation for research and clinical practice. MAIN TEXT: There is now substantial evidence that normal thyroid status changes with age throughout the course of life. Thyroid stimulating hormone (TSH) concentrations are higher at the extremes of life and show a U-shaped longitudinal trend in iodine sufficient Caucasian populations. Free triiodothyronine (FT3) levels fall with age and appear to play a role in pubertal development, during which it shows a strong relationship with fat mass. Furthermore, the aging process exerts differential effects on the health consequences of thyroid hormone variations. Older individuals with declining thyroid function appear to have survival advantages compared to individuals with normal or high-normal thyroid function. In contrast younger or middle-aged individuals with low-normal thyroid function suffer an increased risk of adverse cardiovascular and metabolic outcomes while those with high-normal function have adverse bone outcomes including osteoporosis and fractures. CONCLUSION: Thyroid hormone reference intervals have differential effects across age groups. Current reference ranges could potentially lead to inappropriate treatment in older individuals but on the other hand could result in missed opportunities for risk factor modification in the younger and middle-aged groups. Further studies are now needed to determine the validity of age-appropriate reference intervals and to understand the impact of thyroid hormone variations in younger individuals.

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.

Gut Microbiome Associated With Graves Disease and Graves Orbitopathy: The INDIGO Multicenter European Study.

CONTEXT: Gut bacteria can influence host immune responses but little is known about their role in tolerance-loss mechanisms in Graves disease (GD; hyperthyroidism caused by autoantibodies, TRAb, to the thyrotropin receptor, TSHR) and its progression to Graves orbitopathy (GO). OBJECTIVE: This work aimed to compare the fecal microbiota in GD patients, with GO of varying severity, and healthy controls (HCs). METHODS: Patients were recruited from 4 European countries (105 GD patients, 41 HCs) for an observational study with cross-sectional and longitudinal components. RESULTS: At recruitment, when patients were hyperthyroid and TRAb positive, Actinobacteria were significantly increased and Bacteroidetes significantly decreased in GD/GO compared with HCs. The Firmicutes to Bacteroidetes (F:B) ratio was significantly higher in GD/GO than in HCs. Differential abundance of 15 genera was observed in patients, being most skewed in mild GO. Bacteroides displayed positive and negative correlations with TSH and free thyroxine, respectively, and was also significantly associated with smoking in GO; smoking is a risk factor for GO but not GD. Longitudinal analyses revealed that the presence of certain bacteria (Clostridiales) at diagnosis correlated with the persistence of TRAb more than 200 days after commencing antithyroid drug treatment. CONCLUSION: The increased F:B ratio observed in GD/GO mirrors our finding in a murine model comparing TSHR-immunized with control mice. We defined a microbiome signature and identified changes associated with autoimmunity as distinct from those due to hyperthyroidism. Persistence of TRAb is predictive of relapse; identification of these patients at diagnosis, via their microbiome, could improve management with potential to eradicate Clostridiales.