Hypothyroidism.

Hypothyroidism, the deficiency of thyroid hormone, is a common condition worldwide. It affects almost all body systems and has a wide variety of clinical presentations from being asymptomatic to, in rare cases, life threatening. The classic symptoms of hypothyroidism include fatigue, lethargy, weight gain, and cold intolerance; however, these symptoms are non-specific and the diagnosis is typically made on biochemical grounds through serum thyroid function tests. The most common cause of hypothyroidism is chronic autoimmune thyroiditis (Hashimoto's thyroiditis), although other causes, including drugs (such as amiodarone, lithium, and immune checkpoint inhibitors), radioactive-iodine treatment, and thyroid surgery, are frequent. Historically, severe iodine deficiency was the most common cause. Reference ranges for thyroid function tests are based on fixed percentiles of the population distribution, but there is increasing awareness of the need for more individualised reference intervals based on key factors such as age, sex, and special circumstances such as pregnancy. Levothyroxine monotherapy is the standard treatment for hypothyroidism; it is safe and inexpensive, restores thyroid function tests to within the reference range, and improves symptoms in the majority of patients. However, 10% of patients have persistent symptoms of ill health despite normalisation of thyroid function tests biochemically and a substantial proportion of patients on levothyroxine have thyroid-stimulating hormone concentrations outside the reference range. Ongoing symptoms despite levothyroxine treatment has led to some patients using liothyronine or desiccated thyroid extract. Taken together, these factors have led to intense debate around the treatment thresholds and treatment strategies for hypothyroidism. In this Seminar, we review the epidemiology, genetic determinants, causes, and presentation of hypothyroidism; highlight key considerations and controversies in its diagnosis and management; and provide future directions for research.

Evaluation of US Elastography in Thyroid Nodule Diagnosis: The ElaTION Randomized Control Trial.

Background There is variable evidence and no randomized trials on the benefit of US elastography-guided fine-needle aspiration cytology (FNAC) over conventional US-guided FNAC alone for thyroid nodules. Purpose To compare the efficacy of US elastography-guided FNAC versus US-guided FNAC in reducing nondiagnostic rates for thyroid nodules. Materials and Methods A pragmatic, multicenter randomized controlled trial was performed at 18 secondary and tertiary hospitals across England between February 2015 and September 2018. Eligible adults with single or multiple thyroid nodules who had not previously undergone FNAC were randomized (1:1 ratio) to US elastography FNAC (intervention) or conventional US FNAC (control). The primary outcome was the proportion of patients who have a nondiagnostic cytologic Thy1 (British Thyroid Association system) result following the first FNAC. Results A total of 982 participants (mean age, 51.3 years ± 15 [SD] [IQR, 39-63]; male-to-female ratio, 1:4) were randomized. Of the 493 participants who underwent US elastography, 467 (94.7%) were examined with strain US elastography. There was no difference between the two arms in the nondiagnostic (Thy1) rate following the first FNAC (19% vs 16%; risk difference [RD], 0.03 [95% CI: -0.01, 0.07]; P = .11) or in the median time to reach the final definitive diagnosis (3.3 months [IQR, 1.5-6.4] for US elastography FNAC vs 3.4 months [IQR, 1.5-6.2] for US FNAC). All sensitivity analyses supported the primary analysis. Fewer participants in the US elastography FNAC arm underwent diagnostic hemithyroidectomy than in the US FNAC arm (183 of 493 [37%] vs 196 of 489 [40%]), but this was not statistically significant (adjusted RD, 0.02 [95% CI: -0.06, 0.01]; P = 0.15). There was no evidence of a difference in malignancy rates between the two arms: 70 of 493 (14%) in US elastography FNAC arm versus 79 of 489 (16%) in US FNAC arm (P = .39). There was also no difference in the rate of benign histologic findings between the groups (RD, -0.01 [95% CI: -0.04, 0.03]; P = .7). Conclusion Strain US elastography does not appear to have additional benefit over conventional US FNAC in the diagnosis of malignancy in thyroid nodules. Clinical trial registration no. ISRCTN18261857 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Isikbay and Harwin in this issue.

Consensus statement on the management of incidentally discovered FDG avid thyroid nodules in patients being investigated for other cancers.

With the widespread use of 18F-fluorodeoxyglucose positron emission tomography (FDG PET/CT) in the investigation and staging of cancers, incidental discovery of FDG-avid thyroid nodules is becoming increasingly common, with a reported incidence in the range 1%-4% of FDG PET/CT scans. The risk of malignancy in an incidentally discovered FDG avid thyroid nodule is not clear due to selection bias in reported retrospective series but is likely to be less than 15%. Even in cases where the nodule is found to be malignant, the majority will be differentiated thyroid cancers with an excellent prognosis even without treatment. If, due to index cancer diagnosis, age and co-morbidities, it is unlikely that the patient will survive 5 years, further investigation of an incidental FDG avid thyroid nodule is unlikely to be warranted. We provide a consensus statement on the circumstances in which further investigation of FDG avid thyroid nodules with ultrasound and fine needle aspiration might be appropriate.

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.

Sustained clinical knowledge improvements from simulation experiences with Simulation via Instant Messaging-Birmingham Advance.

BACKGROUND: Simulation via Instant Messaging-Birmingham Advance (SIMBA) delivers simulation-based learning through WhatsApp and Zoom, helping to sustain continuing medical education (CME) for postgraduate healthcare professionals otherwise disrupted by the coronavirus (COVID-19) pandemic. This study aimed to assess whether SIMBA helped to improve clinical knowledge and if this improvement in knowledge was sustained over time. METHODS: Two SIMBA sessions-thyroid and pituitary-were conducted in July-August 2020. Each session included simulation of various real-life cases and interactive discussion. Participants' self-reported confidence, acceptance, and knowledge were measured using surveys and multiple-choice questions pre- and post-simulation and in a 6- to 12-week follow-up period. The evaluation surveys were designed using Moore's 7 Levels of CME Outcomes Framework. RESULTS: A total of 116 participants were included in the analysis. Significant improvement was observed in participants' self-reported confidence in approach to simulated cases (thyroid, n = 37, P < .0001; pituitary, n = 79, P < .0001). Significant improvement in clinical knowledge was observed following simulation (thyroid, n = 37, P < .0001; pituitary, n = 79, P < .0001). For both sessions, retention of confidence and knowledge was seen at 6-12 weeks' follow-up. CONCLUSIONS: SIMBA increased participants' clinical knowledge on simulated cases and this improvement was retained up to 6-12 weeks after the session. Further studies are required to explore long-term retention and whether it translates to improved real-world clinical practice.

Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception.

BACKGROUND: Thyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes. METHODS: We conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 µg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation. RESULTS: The follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P = 0.74; absolute difference, -0.4 percentage points; 95% CI, -6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P = 0.14). CONCLUSIONS: The use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.).

Postradioiodine Graves' management: The PRAGMA study.

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.

Subclinical hypothyroidism and antithyroid autoantibodies in women with subfertility or recurrent pregnancy loss: Scientific Impact Paper No. 70 June 2022: Scientific Impact Paper No. 70 June 2022.

The thyroid is a gland located in the neck and is important for many processes in the body. Problems with the thyroid gland are common in women of reproductive age. It is essential to have a normal working thyroid gland in order to achieve a successful pregnancy. One of the most common problems with the thyroid is underactivity (known as hypothyroidism). An early, mild form of an underactive thyroid is called subclinical hypothyroidism. Often people with this condition do not have any symptoms. Another common problem is thyroid autoimmunity. Here, the immune system attacks the thyroid gland, sometimes leading to the development of abnormal thyroid function. This can be diagnosed by the presence of proteins in the bloodstream called antibodies. Mild thyroid problems and the presence of high levels of thyroid antibodies have been linked to miscarriage and premature birth. There is debate in medicine about whether there should be routine testing of thyroid function both in the general population and in individuals who are trying for a baby. In addition, the strategies used to manage certain thyroid problems are questioned. Discussions around testing and subsequent management particularly relate to women with a history of subfertility or repeated miscarriages. This Scientific Impact Paper provides information on thyroid testing and the management of mild thyroid problems and thyroid antibodies in women with a history of subfertility or recurrent miscarriages, using the latest evidence and guidelines. It concludes that there may be a role for treating these women with thyroxine tablets (the hormone produced by the thyroid gland) when subclinical hypothyroidism is present, and gives guidance on the cut-off levels for treatment.

Risk of incident circulatory disease in patients treated for differentiated thyroid carcinoma with no history of cardiovascular disease.

CONTEXT: The incidence of differentiated thyroid cancer (DTC) is increasing, yet the prognosis is favourable and long-term survival is expected. Exogenous TSH suppression has been used for many years to prevent DTC recurrence and may be associated with increased risks of circulatory diseases. DESIGN: Risks of circulatory disease in patients treated for DTC were compared to randomly matched patients without DTC (controls) up to a 1:5 ratio using age, sex, body mass index (BMI) and smoking as the matching parameters in a population-based, open cohort study using The Health Improvement Network. PATIENTS: A total of 3009 patients treated for DTC with no pre-existing cardiovascular disease were identified and matched to 11 303 controls, followed up to median of 5 years. RESULTS: A total of 1259 incident circulatory events were recorded during the observation period. No difference in the risk of ischaemic heart disease (IHD) (adjusted hazards ratio [aHR]: 1.04, 95% CI: 0.80-1.36) or heart failure (HF) (aHR: 1.27, 95% CI: 0.89-1.81) was detected. The risk of atrial fibrillation (AF) and stroke was significantly higher in patients with DTC (aHR: 1.71, 95% CI: 1.36-2.15 and aHR: 1.34, 95% CI: 1.05-1.72, respectively). In a sensitivity analysis limited to newly diagnosed patients with DTC, only the risk of AF was consistently elevated (aHR: 1.86, 95% CI: 1.33-2.60). CONCLUSIONS: The increased risk of AF in patients who have undergone treatment for DTC but without pre-existing CVD may warrant periodic screening for this arrhythmia. Whereas no evidence of increased risk of IHD or HF was observed, the increased risk of stroke/TIA warrants further investigation.

Glucocorticoid induced adrenal insufficiency is common in steroid treated glomerular diseases - proposed strategy for screening and management.

BACKGROUND: Glucocorticoids (GCs) are frequently used to treat glomerular diseases but are associated with multiple adverse effects including hypothalamic-pituitary-adrenal axis inhibition that can lead to adrenal insufficiency (AI) on withdrawal. There is no agreed GC tapering strategy to minimise this risk. METHODS: This is a single centre retrospective study, between 2013 to 2016, of patients with glomerular disease on GC therapy for more than 3 months screened for GC induced AI with short synacthen stimulation tests (SSTs) done prior to complete GC withdrawal. We investigated the prevalence of AI, predictors, choice of screening tool and recovery. RESULTS: Biochemical evidence of GC induced AI was found in 57 (46.3%) patients. Total duration of GC did not differ between those with and without AI (p = 0.711). Patients with GC induced AI had a significantly lower pre-synacthen baseline cortisol as compared to patients without AI. A cut off pre-synacthen baseline cortisol of ≥223.5 nmol/l had a specificity of 100% for identifying individuals without biochemical AI. Patients with GC induced AI took a mean of 8.7 ± 4.6 months (mean ± SD) to recover. Patients with persistent AI had a significantly lower index post-synacthen cortisol measurement. CONCLUSIONS: We demonstrate that biochemically proven GC induced AI is common in patients with glomerular diseases, is not predicted by daily dose or duration and takes a considerable time to recover. The study supports the use of morning basal cortisol testing as an appropriate means to avoid the need for SSTs in all patients and should be performed in all patients prior to consideration of GC withdrawal after 3 months duration.

The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer.

The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P = 0.009) and protein (P < 0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (Δ126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (> 90%; P < 0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P < 0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.

Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee.

The management of primary hypothyroidism with levothyroxine (L-T4) is simple, effective and safe, and most patients report improved well-being on initiation of treatment. However, a proportion of individuals continue to suffer with symptoms despite achieving adequate biochemical correction. The management of such individuals has been the subject of controversy and of considerable public interest. The American Thyroid Association (ATA) and the European Thyroid Association (ETA) have recently published guidelines on the diagnosis and management of hypothyroidism. These guidelines have been based on extensive reviews of the medical literature and include sections on the role of combination therapy with L-T4 and liothyronine (L-T3) in individuals who are persistently dissatisfied with L-T4 therapy. This position statement by the British Thyroid Association (BTA) summarises the key points in these guidelines and makes recommendations on the management of primary hypothyroidism based on the current literature, review of the published positions of the ETA and ATA, and in line with best principles of good medical practice. The statement is endorsed by the Association of Clinical Biochemistry, (ACB), British Thyroid Foundation, (BTF), Royal College of Physicians (RCP) and Society for Endocrinology (SFE).

Optimal management of hypothyroidism, hypothyroxinaemia and euthyroid TPO antibody positivity preconception and in pregnancy.

Normal physiological changes of pregnancy warrant the need to employ gestation specific reference ranges for the interpretation of thyroid function tests. Thyroid hormones play crucial roles in foetal growth and neurodevelopment which are dependent on adequate supply of maternal thyroid hormones from early gestation onwards. The prevention of significant adverse obstetric and neurodevelopmental outcomes from hypothyroidism requires a strategy of empirical levothyroxine dose increases and predictive dose adjustments in pregnancy combined with regular thyroid function testing, starting before pregnancy and until the postpartum period. Subclinical hypothyroidism has been associated with an increased risk of pregnancy loss and neurocognitive deficits in children, especially when diagnosed before or during early pregnancy. Whilst trials of levothyroxine replacement for mild hypothyroidism in pregnancy have not indicated definite evidence of improvements in these outcomes, professional guidelines recommend treatment, especially if evidence of underlying thyroid autoimmunity is present. Studies of isolated hypothyroxinaemia in pregnancy have shown conflicting evidence with regards to adverse obstetric and neurodevelopmental outcomes and no causative relationships have been determined. Treatment of this condition in pregnancy may be considered in those with underlying thyroid autoimmunity. Whilst the evidence for a link between the presence of anti-TPO antibodies and increased risks of pregnancy loss and infertility is compelling, the results of ongoing randomized trials of levothyroxine in euthyroid women with underlying autoimmunity are currently awaited. Further studies to define the selection of women who require levothyroxine replacement and to determine the benefits of a predictive dose adjustment strategy are required.

The Endocrinology of Ageing: A Mini-Review.

Significant advances in health and social wellbeing have led to linear gains in life expectancy and an accompanying increase in the burden imposed by age-related morbidities. Complex alterations in hormonal networks which regulate homeostasis and survival may underlie this poor adaptation to later life, as exemplified by an increased fracture risk amongst post-menopausal women. Beyond overt under- or overactivity of hormonal axes, changes in the concentrations of regulatory hormones may also impact on health and disease. Subclinical hyperthyroidism, a disorder characterised by normal thyroxine levels in the presence of decreased thyroid-stimulating hormone, is, for instance, independently associated with an increased risk of atrial fibrillation amongst elderly populations. Both the menopause and subclinical thyroid disease demonstrate the difficulty in reversing endocrine changes in later life, with minimal impact from thyroxine therapy in subclinical hypothyroidism and multiple reports of harm resulting from hormone replacement therapy in peri- and post-menopausal women. Given these findings, strategies to locally regulate hormone bioavailability by altering pre-receptor metabolism may offer greater therapeutic potential in the fight against age-related disease. This review aims to provide an overview of the ageing endocrine system and its potential impact on health and disease in the elderly. It will postulate that strategies to coordinate pre-receptor hormone metabolism and a greater understanding of putative hormonal longevity pathways may offer key new drug targets in the fight against ageing, and will argue against applying the conventional endocrine maxim of 'block and replace' to hormonal changes seen during ageing.

A truncating TPO mutation (Y55X) in patients with hypothyroidism and total iodide organification defect.

UNLABELLED: Absract Purpose: Mutations in the TPO gene have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of congenital hypothyroidism in two affected children coming from a consanguineous family. METHODS: Since CH is usually inherited in autosomal recessive manner in consanguineous/multi case-families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked-gene by Sanger sequencing. RESULTS: The family showed potential linkage to the TPO gene and we detected a non-sense mutation (Y55X) in both cases that had total iodode organification defect (TIOD). The mutation segregated with disease status in the family. Y55X is the only truncating mutation in the exon 2 of the TPO gene reported in the literature and results in the earliest stop codon known in the gene to date. CONCLUSIONS: This study confirms the pathogenicity of Y55X mutation and demonstrates that a nonsense mutation in the amino-terminal coding region of the TPO gene could totally abolish the function of the TPO enzyme leading to TIOD. Thus it helps to establish a strong genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH.

Real-time ultrasound elastography in the diagnosis of newly identified thyroid nodules in adults: the ElaTION RCT.

Background: Strain and shear wave elastography which is commonly used with concurrent real-time imaging known as real-time ultrasound shear/strain wave elastography is a new diagnostic technique that has been reported to be useful in the diagnosis of nodules in several organs. There is conflicting evidence regarding its benefit over ultrasound-guided fine-needle aspiration cytology alone in thyroid nodules. Objectives: To determine if ultrasound strain and shear wave elastography in conjunction with fine-needle aspiration cytology will reduce the number of patients who have a non-diagnostic first fine-needle aspiration cytology results as compared to conventional ultrasound-only guided fine-needle aspiration cytology. Design: A pragmatic, unblinded, multicentre randomised controlled trial. Setting: Eighteen centres with a radiology department across England. Participants: Adults who had not undergone previous fine-needle aspiration cytology with single or multiple nodules undergoing investigation. Interventions: Ultrasound shear/strain wave elastography-ultrasound guided fine-needle aspiration cytology (intervention arm) - strain or shear wave elastography-guided fine-needle aspiration cytology. Ultrasound-only guided fine-needle aspiration cytology (control arm) - routine ultrasound-only guided fine-needle aspiration cytology (the current standard recommended by the British Thyroid Association guidelines). Main outcome measure: The proportion of patients who have a non-diagnostic cytology (Thy 1) result following the first fine-needle aspiration cytology. Randomisation: Patients were randomised at a 1 : 1 ratio to the interventional or control arms. Results: A total of 982 participants (80% female) were randomised: 493 were randomised to ultrasound shear/strain wave elastography-ultrasound guided fine-needle aspiration cytology and 489 were randomised to ultrasound-only guided fine-needle aspiration cytology. There was no evidence of a difference between ultrasound shear/strain wave elastography and ultrasound in non-diagnostic cytology (Thy 1) rate following the first fine-needle aspiration cytology (19% vs. 16% respectively; risk difference: 0.030; 95% confidence interval -0.007 to 0.066; p = 0.11), the number of fine-needle aspiration cytologies needed (odds ratio: 1.10; 95% confidence interval 0.82 to 1.49; p = 0.53) or in the time to reach a definitive diagnosis (hazard ratio: 0.94; 95% confidence interval 0.81 to 1.10; p = 0.45). There was a small, non-significant reduction in the number of thyroid operations undertaken when ultrasound shear/strain wave elastography was used (37% vs. 40% respectively; risk difference: -0.02; 95% confidence interval -0.06 to 0.009; p = 0.15), but no difference in the number of operations yielding benign histology - 23% versus 24% respectively, p = 0.70 (i.e. no increase in identification of malignant cases) - or in the number of serious adverse events (2% vs. 1%). There was no difference in anxiety and depression, pain or quality of life between the two arms. Limitations: The study was not powered to detect differences in malignancy. Conclusions: Ultrasound shear/strain wave elastography does not appear to have additional benefit over ultrasound-guided fine-needle aspiration cytology in the diagnosis of thyroid nodules. Future work: The findings of the ElaTION trial suggest that further research into the use of shear wave elastography in the diagnostic setting of thyroid nodules is unlikely to be warranted unless there are improvements in the technology. The diagnostic difficulty in distinguishing between benign and malignant lesions still persists. Future studies might examine the role of genomic testing on fine-needle aspiration samples. There is growing use of targeted panels of molecular markers, particularly aimed at improving the diagnostic accuracy of indeterminate (i.e. Thy3) cytology results. The application of these tests is not uniform, and their cost effectiveness has not been assessed in large-scale trials. Study registration: This study is registered as ISRCTN (ISRCTN18261857). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/19/04) and is published in full in Health Technology Assessment; Vol. 28, No. 46. See the NIHR Funding and Awards website for further award information.

About half the population will have lumps in their thyroid if examined by an ultrasound scan but may not know they have one. About one in twenty people will feel a thyroid lump in their neck at some time in their life, with about one in twenty of those being malignant. Currently, the recommended way of getting a diagnosis of thyroid nodules is by using ultrasound to guide a needle to get cells from the lump, called ultrasound-guided fine-needle aspiration cytology. These cells are examined to determine the cause of the lump. If there are enough cells, Doctors can then make a diagnosis of whether the lump is benign or malignant. If not, patients will undergo another ultrasound-guided fine-needle aspiration cytology. One in five ultrasound-guided fine-needle aspiration cytologies are non-diagnostic with an overall false-positive rate of approximately 24%. This means one in five patients, with benign disease, may undergo unnecessary diagnostic operations. Thyroid surgery carries risks of complications, which could be avoided if we had better ways to diagnose which patients actually need an operation. We conducted a randomised trial, ElaTION, to determine if a new technology called strain and shear wave elastography, commonly known as real-time elastography, would be better at helping the radiologist take a sufficient sample of cells and reduce the number of non-diagnostic results, reducing the number of fine-needle aspiration cytologies required to make a definitive diagnosis. Nine hundred eighty-two patients were recruited between 2015 and 2018 and followed up until the end of the trial. Patients were randomised into two groups: 489 patients received the standard ultrasound-guided fine-needle aspiration cytology alone, and 493 patients received ultrasound-guided fine-needle aspiration cytology + shear wave elastography. Ultrasound shear/strain wave elastography did not reduce non-diagnostic cytology at first fine-needle aspiration cytology or improve the likelihood of determining whether the lump is benign or malignant. The results of ElaTION do not support the use of shear wave elastography-fine-needle aspiration cytology in the diagnosis of thyroid nodules.

Diagnostic performance of ultrasound vs. ultrasound-guided FNAc in thyroid nodules: data from the ElaTION trial.

INTRODUCTION: ElaTION is a large multi-centre pragmatic randomised controlled trial, performed in 18 secondary/tertiary hospitals across England, comparing elastography ultrasound-guided fine needle aspiration cytology (EUS-FNAC) with ultrasound-guided FNAC (US-FNAC) alone in the diagnostic assessment of thyroid nodules. Secondary trial outcomes, reported here, assessed the accuracy of ultrasound-alone (US) compared with US-guided FNAC to inform and update current practice guidelines. METHODS: Adults with single or multiple thyroid nodules who had not undergone previous FNAC were eligible. Radiologists assessed all thyroid nodules using US alone, thereby enabling assessment of its accuracy (sensitivity and specificity) versus US-FNAC. RESULTS: Of the 982 participants, a final definitive diagnosis was obtained in 688, who were included in the final analyses. The sensitivity of US-alone was the same as US-FNAC (0.91, [95% CI 0.85, 0.97] vs 0.87 [95%CI 0.80-0.95], p=0.37). US alone had statistically significant lower specificity than US-FNAC alone (0.48 vs 0.67 respectively, p<0.0001). The malignancy rate on histology in a nodule classified as benign on ultrasound (U2) was 9/263 (3.42%) and on cytology (Thy2) was 15/353 (4.25%), whereas the malignancy rate in a nodule that was benign on both (U2, Thy2) was 3/210 (1.43%). Malignancy risk for U3, U4, and U5 nodules was 68/304 (22.4%), 43/83 (51.8%), and 29/38 (76.3%) respectively (p<0.0001). Yet 80/982 (8%) patients were discharged despite having U3-U5 scans with Thy1 (non-diagnostic) FNAC and no definitive diagnosis.Malignancy risk was higher in smaller nodules: <10mm 23/60 (38.3%), 10-20mm 46/162 (28.4 %), and >20mm 80/466 (17.2%) (p<0.0001). Nodules with indeterminate cytology with atypical features (Thy3a) carried a similar malignancy risk to those with indeterminate cytology (Thy3/3f): 27/95 (28.4%) versus 42/113 (37.2%) respectively (p=0.18). CONCLUSION: Ultrasound alone appears to be an effective diagnostic modality in thyroid nodules, confirming the recommendations of recent guidelines and the BTA classification. However, findings also suggest caution regarding existing recommendations for conservative management of non-diagnostic (Thy1/Bethesda I) and atypical (Thy3a/Bethesda III) nodules. In those cases, ultrasound (U3-5) features may help identify high-risk subgroups for more proactive management.

Combined Vorinostat and Chloroquine Inhibit Sodium-Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo.

PURPOSE: Patients with aggressive thyroid cancer are frequently failed by the central therapy of ablative radioiodide (RAI) uptake, due to reduced plasma membrane (PM) localization of the sodium/iodide symporter (NIS). We aimed to understand how NIS is endocytosed away from the PM of human thyroid cancer cells, and whether this was druggable in vivo. EXPERIMENTAL DESIGN: Informed by analysis of endocytic gene expression in patients with aggressive thyroid cancer, we used mutagenesis, NanoBiT interaction assays, cell surface biotinylation assays, RAI uptake, and NanoBRET to understand the mechanisms of NIS endocytosis in transformed cell lines and patient-derived human primary thyroid cells. Systemic drug responses were monitored via 99mTc pertechnetate gamma counting and gene expression in BALB/c mice. RESULTS: We identified an acidic dipeptide within the NIS C-terminus that mediates binding to the σ2 subunit of the Adaptor Protein 2 (AP2) heterotetramer. We discovered that the FDA-approved drug chloroquine (CQ) modulates NIS accumulation at the PM in a functional manner that is AP2 dependent. In vivo, CQ treatment of BALB/c mice significantly enhanced thyroidal uptake of 99mTc pertechnetate in combination with the histone deacetylase (HDAC) inhibitor vorinostat/SAHA, accompanied by increased thyroidal NIS mRNA. Bioinformatic analyses validated the clinical relevance of AP2 genes with disease-free survival in RAI-treated DTC, enabling construction of an AP2 gene-related risk score classifier for predicting recurrence. CONCLUSIONS: NIS internalization is specifically druggable in vivo. Our data, therefore, provide new translatable potential for improving RAI therapy using FDA-approved drugs in patients with aggressive thyroid cancer. See related commentary by Lechner and Brent, p. 1220.

Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.