Bijay Vaidya

Background: The rise in serum thyroid stimulating hormone (TSH) in healthy older adults is well established. However, age-related reference intervals are not widely used. We aimed to establish all-adult and age-related reference intervals for TSH, free thyroxine (FT4) and free triiodothyronine (FT3) and determine their impact on primary care thyroid testing results. Methods: We measured TSH, FT4 and FT3 by Roche Cobas assays in a reference cohort of 1364 anti-thyroid peroxidase antibody negative adults with no self-reported medical conditions or medications. Reference intervals were generated for all-adult, 18–60 and over 60 years. Reference intervals were applied to 21,286 primary care tests with no known thyroid disease to assess effect on test interpretation. Results: In the reference cohort, 23.2% were over 60 years compared to 50.4% of those undergoing thyroid testing in primary care. With an all-adult reference interval, 8.2% of over 60s had an elevated TSH, 7.0% were classified as subclinical hypothyroid and 0.8% as overt hypothyroid. With age-related reference intervals, this fell to 4.4% with an elevated TSH, 3.7% subclinical hypothyroid and 0.4% overt hypothyroid. Minimal changes were seen in the 18–60 years group. Conclusions: An all-adult reference interval derived from healthy and therefore younger individuals is less appropriate for the older subset of the population being tested. Application of an age-related reference interval for over 60s would reduce the proportion of patients with abnormal thyroid test results. In turn, this would decrease potentially unnecessary cascade and repeat testing as well as regular follow-up in primary care.

Thyroid eye disease (TED) is an autoimmune disease, most commonly occurring in association with Graves’ hyperthyroidism although it can rarely occur in people with autoimmune hypothyroidism or normal thyroid function. There is a link between thyroid function abnormalities and poorer outcome of TED, therefore the restoration and maintenance of optimal thyroid function is essential in the management of TED. Different treatment modalities for hyperthyroidism have variable impact on the natural history of TED, with radioiodine treatment increasing the risk of new onset or worsening of TED. The risk is particularly high in patients with risk factors such as smoking, short duration of Graves’ hyperthyroidism, severe hyperthyroidism, untreated post-radioiodine hypothyroidism and pre-existing TED. A careful selection of patients, counselling the patients about the risk and symptoms of TED, providing smoking cessation advice and support, and the use of concomitant prophylactic steroid if indicated will reduce the risk of TED following radioiodine.

Background: Recent years have seen changes and uncertainties in evidence and guideline recommendations in Graves' disease treatment. To understand the impact of these developments on current practice, we undertook a survey of Graves' disease management in the United Kingdom and compared this to other national and international surveys.Method: Members of the British Thyroid Association, the UK Society for Endocrinology and regional endocrinology networks, were invited by e‐mail to complete a 15‐min online survey (October 2022 to March 2023).Results: Out of 158 eligible respondents, 99% were endocrinologists. For a 40‐year‐old female with a first presentation of Graves' hyperthyroidism, TSH‐receptor antibodies (TRAb) were requested at diagnosis and at follow‐up by 95% and 76%, respectively. Isotope scans and ultrasound were rarely requested (< 5%). Majority (95%) would treat with antithyroid drugs (ATD), predominantly Carbimazole (CMZ), while radioactive iodine (RAI) was preferred for recurrent disease (81%). Common reasons for avoiding RAI were thyroid eye disease, pregnancy intention, or contact with young children whereas biochemical severity, goitre, or male sex did not influence decision to use RAI. Propylthiouracil (PTU) was preferred in preconception and early pregnancy, but after the first‐trimester, 50% would continue PTU while 50% switch back to CMZ.Conclusions: The survey confirms a growing application of TRAbs, both for diagnostic and prognostic purposes. ATDs remain the preferred first‐line therapy for Graves' disease, which is consistent with global trends but contrary to National Institute of Health and Care Excellence (NICE) guidance. Further studies are required to explore the clinical and pragmatic determinants of current treatment approaches.

Multiple endocrine neoplasia (MEN) type 2B is an autosomal dominant condition, typically associated with an early onset aggressive form of medullary thyroid carcinoma (MTC), phaeochromocytoma and distinctive phenotypic features including marfanoid habitus, mucosal neuroma and corneal nerve thickening (CNT). In contrast, MEN2A is associated with MTC, phaeochromocytoma and primary hyperparathyroidism but the additional phenotypic features seen in MEN2B are characteristically absent. ¹ We report a case presented to a local optician with CNT whose investigations led to the identification of a new lineage of MEN2A.

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.

Context: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. Objective: (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. Methods: (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. Results: (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody–positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from –10.8% to –21.8% for TSH and –1.2% to –13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. Conclusion: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.

Objective: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post‐RI and compare effectiveness of common management strategies.Design: Retrospective, multicentre and observational study.Patients: Adult patients with Graves' disease treated with RI with 12 months' follow‐up.Measurements: Euthyroidism was defined as both serum thyrotropin (thyroid‐stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo‐ and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4.Results: Of 812 patients studied post‐RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post‐RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%–28.7%). No negative outcomes (new‐onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres.Conclusions: Dysthyroidism in the 12 months post‐RI was common. Differences between post‐RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.

Preterm birth complicates 5% to 15% of births worldwide. It is the most important direct cause of morbidity and mortality in children younger than 5 years,¹ and is an important risk factor for psychiatric, metabolic, cardiovascular, and renal disease later in life.^2,3 However, in the majority of cases, no known risk factors can be identified.^4,5

Background: The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC.Methods: MEDLINE and Embase databases were searched using the MeSH terms “medullary carcinoma”, “epigenetics”, “molecular genetics”, “microRNAs”; and free text terms “medullary carcinoma”, “sporadic medullary thyroid cancer”, “sMTC”, “RET”, “RAS” and “miR”. Articles containing less than ten subjects, not focussing on sMTC, or not reporting clinical outcomes were excluded. Risk of bias was assessed using a modified version of the Newcastle‐Ottawa Scale.Results: Twenty‐three studies met the inclusion criteria, and key findings were summarized in themes according to the genetic and epigenetic markers studied. There is good evidence that somatic RET mutations predict higher rates of lymph node metastasis and persistent disease, and worse survival. There are also several good quality studies demonstrating associations between certain epigenetic markers such as tumour miR‐183 and miR‐375 expression and higher rates of lymph node and distant metastasis, and worse survival.Conclusions: There is a growing body of evidence that tumour genetic and epigenetic profiles can be used to risk stratify patients with sMTC. Further research should focus on the clinical applicability of these findings by investigating the possibility of tailoring management to an individual's tumour mutation profile.