Showing papers in "European thyroid journal in 2014"

2014 European Thyroid Association Guidelines for the Management of Subclinical Hypothyroidism in Pregnancy and in Children

Abstract: This guideline has been produced as the official statement of the European Thyroid Association guideline committee. Subclinical hypothyroidism (SCH) in pregnancy is defined as a thyroid-stimulating hormone (TSH) level above the pregnancy-related reference range with a normal serum thyroxine concentration. Isolated hypothyroxinaemia (defined as a thyroxine level below the 2.5th centile of the pregnancy-related reference range with a normal TSH level) is also recognized in pregnancy. In the majority of SCH the cause is autoimmune thyroiditis but may also be due to iodine deficiency. The cause of isolated hypothyroxinaemia is usually not apparent, but iodine deficiency may be a factor. SCH and isolated hypothyroxinaemia are both associated with adverse obstetric outcomes. Levothyroxine therapy may ameliorate some of these with SCH but not in isolated hypothyroxinaemia. SCH and isolated hypothyroxinaemia are both associated with neuro-intellectual impairment of the child, but there is no evidence that maternal levothyroxine therapy improves this outcome. Targeted antenatal screening for thyroid function will miss a substantial percentage of women with thyroid dysfunction. In children SCH (serum TSH concentration >5.5-10 mU/l) normalizes in >70% and persists in the majority of the remaining patients over the subsequent 5 years, but rarely worsens. There is a lack of studies examining the impact of SCH on the neuropsychological development of children under the age of 3 years. In older children, the evidence for an association between SCH and impaired neuropsychological development is inconsistent. Good quality studies examining the effect of treatment of SCH in children are lacking.

Thyroid Incidentalomas: Epidemiology, Risk Stratification with Ultrasound and Workup

Abstract: A thyroid incidentaloma is an unexpected, asymptomatic thyroid tumor fortuitously discovered during the investigation of an unrelated condition. The prevalence rate is 67% with ultrasonography (US) imaging, 15% with computed tomography (CT) or magnetic resonance imaging (MRI) of the neck, and 1-2% with fluorodeoxyglucose (FDG) positron emission tomography. In the absence of a history of external beam radiation or familial medullary thyroid cancer, the risk of malignancy ranges between 5 and 13% when discovered with US, CT or MRI, but is much higher if based on focal FDG uptake (30%). All patients with a thyroid incidentaloma, independent of the mode of detection, should undergo a dedicated neck US with risk stratification: US imaging allows a quantitative risk stratification of malignancy in thyroid nodules, named ‘reporting system’ or ‘TIRADs' (thyroid imaging reporting and data system). The reported sensitivity ranges from 87 to 95% for the detection of carcinomas and the negative predictive value from 88 to 99.8%. We suggest that the indications for fine-needle aspiration be based mainly on size and US risk stratification. However, the diagnosis and workup of thyroid incidentalomas leads to superfluous surgery for benign conditions, and excess diagnosis and treatment of papillary microcarcinomas, the vast majority of which would cause no harm. Recognizing this must form the basis of any decision as to supplementary investigations and whether to offer therapy, in a close dialogue between patient and physician. The current use of minimally invasive nonsurgical ablation options, as alternatives to surgery, is highlighted.

Iodine status in europe in 2014.

Abstract: Iodine deficiency has been recognised as a worldwide problem since the last century [1]. The International Council for Iodine Deficiency Disorders Global Network (ICCIDD GN) has underpinned remarkable progress in ameliorating this problem during the last nearly 30 years and especially during the last decade [2]. The number of iodine-deficient countries in the world has decreased from 54 in 2003 to 47 in 2007 and 32 in 2011 [3]. This remarkable rate of progress has been largely due to intensive work by the ICCIDD GN, UNICEF and WHO. Nevertheless, of these 32 countries, 11 (34%) are in Europe, the largest number from any continent [3]. West and Central Europe has a total population of about 600 million situated in 35 countries (table 1), with country populations ranging from 0.3 to 75 million. Attention was drawn to the iodine deficiency problem in this area more than 10 years ago [4]. In general, the iodine deficiency is mild, but nevertheless this may have an impact on childhood development. For example, mild-to-moderate iodine deficiency in the first trimester of pregnancy was associated with increased odds of the intelligence quotient of offspring being in the lowest quartile (odds ratio: 1.43; 95% CI: 1.04-1.98; p = 0.03), with the greatest negative impact observed with the verbal intelligence quotient (odds ratio: 1.66; 95% CI: 1.20-2.31; p = 0.002) [5]. A review of the current evidence indicates that a correction of mild-to-moderate iodine deficiency improves cognitive performance in school-age children, but there are insufficient data on developmental outcomes in early life [6]. There are 2 randomised studies of iodine supplementation in children with mild iodine deficiency in Albania [7] and New Zealand [8] showing improved cognition. However, large-scale controlled trials are now needed to clarify whether gestational iodine supplementation will benefit infant and childhood neurodevelopment in more European countries with marginal iodine deficiency.

Spontaneous abortion, stillbirth and hyperthyroidism: a danish population-based study

Abstract: Objectives: Pregnancy loss in women suffering from hyperthyroidism has been described in case reports, but the risk of pregnancy loss caused by maternal hyperthyroidism in a population is unknown. We aimed to evaluate the association between maternal hyperthyroidism and pregnancy loss in a population-based cohort study. Study Design: All pregnancies in Denmark from 1997 to 2008 leading to hospital visits (n = 1,062,862) were identified in nationwide registers together with information on maternal hyperthyroidism for up to 2 years after the pregnancy [hospital diagnosis/prescription of antithyroid drug (ATD)]. The Cox proportional hazards model was used to estimate adjusted hazard ratio (aHR) with 95% confidence interval (CI) for spontaneous abortion (gestational age Results: When maternal hyperthyroidism was diagnosed before/during the pregnancy (n = 5,229), spontaneous abortion occurred more often both in women treated before the pregnancy alone [aHR 1.28 (95% CI 1.18-1.40)] and in women treated with ATD in early pregnancy [1.18 (1.07-1.31)]. When maternal hyperthyroidism was diagnosed and treated for the first time in the 2-year period after the pregnancy (n = 2,361), there was a high risk that the pregnancy under study had terminated with a stillbirth [2.12 (1.30-3.47)]. Conclusions: Both early (spontaneous abortion) and late (stillbirth) pregnancy loss were more common in women suffering from hyperthyroidism. Inadequately treated hyperthyroidism in early pregnancy may have been involved in spontaneous abortion, and undetected high maternal thyroid hormone levels present in late pregnancy may have attributed to an increased risk of stillbirth.

A Progress Report of the IFCC Committee for Standardization of Thyroid Function Tests.

Abstract: Background: The IFCC Committee for Standardization of Thyroid Function Tests aims at equivalence of laboratory test results for free thyroxine (FT4) and thyrotropin (TSH). Objectives: This report describes the phase III method comparison study with clinical samples representing a broad spectrum of thyroid disease. The objective was to expand the feasibility work and explore the impact of standardization/harmonization in the clinically relevant concentration range. Methods: Two sets of serum samples (74 for FT4, 94 for TSH) were obtained in a clinical setting. Eight manufacturers participated in the study (with 13 FT4 and 14 TSH assays). Targets for FT4 were set by the international conventional reference measurement procedure of the IFCC; those for TSH were based on the all-procedure trimmed mean. The manufacturers recalibrated their assays against these targets. Results: All FT4 assays were negatively biased in the mid- to high concentration range, with a maximum interassay discrepancy of approximately 30%. However, in the low range, the maximum deviation was approximately 90%. For TSH, interassay comparability was reasonable in the mid-concentration range, but worse in the pathophysiological ranges. Recalibration was able to eliminate the interassay differences, so that the remaining dispersion of the data was nearly entirely due to within-assay random error components. The impact of recalibration on the numerical results was particularly high for FT4. Conclusions: Standardization and harmonization of FT4 and TSH measurements is feasible from a technical point of view. Because of the impact on the numerical values, the implementation needs careful preparation with the stakeholders.

Structure and Function of Thyroid Hormone Plasma Membrane Transporters

Abstract: Thyroid hormones (TH) cross the plasma membrane with the help of transporter proteins. As charged amino acid derivatives, TH cannot simply diffuse across a lipid bilayer membrane, despite their notorious hydrophobicity. The identification of monocarboxylate transporter 8 (MCT8, SLC16A2) as a specific and very active TH transporter paved the way to the finding that mutations in the MCT8 gene cause a syndrome of psychomotor retardation in humans. The purpose of this review is to introduce the current model of transmembrane transport and highlight the diversity of TH transmembrane transporters. The interactions of TH with plasma transfer proteins, T3 receptors, and deiodinase are summarized. It is shown that proteins may bind TH owing to their hydrophobic character in hydrophobic cavities and/or by specific polar interaction with the phenolic hydroxyl, the aminopropionic acid moiety, and by weak polar interactions with the iodine atoms. These findings are compared with our understanding of how TH transporters interact with substrate. The presumed effects of mutations in MCT8 on protein folding and transport function are explained in light of the available homology model.

Selenium Supplementation for Hashimoto's Thyroiditis: Summary of a Cochrane Systematic Review

Abstract: Selenium supplementation in people with Hashimoto's thyroiditis might reduce antibody levels and result in a decreased dosage of levothyroxine (LT4) and may provide other beneficial effects (eg on mood and health-related quality of life) The aim of our systematic review was to assess the effects of selenium supplementation on Hashimoto's thyroiditis We searched The Cochrane Library, MEDLINE, EMBASE and Web of Science for randomized controlled trials Study selection, data extraction, assessment of risk of bias and analyses were carried out by two independent review authors We assessed the quality of the evidence of included studies using GRADE Four studies rated at unclear to high risk of bias comprising 463 participants were included One study at high risk of bias showed statistically significant improvement in subjective well-being with sodium selenite 200 μg plus titrated LT4 compared with placebo plus titrated LT4 (RR 467, 95% CI 161-1350) Selenomethionine 200 μg as a single treatment or combined with LT4 reduced the serum levels of anti-thyroid peroxidase antibodies compared with placebo (or placebo plus LT4) in three studies (p < 0001) Although the changes from baseline were statistically significant in these three studies, their clinical relevance is unclear In conclusion, the results of these four studies, assessed at unclear to high risk of bias, show that evidence to support or refute the efficacy of selenium supplementation in people with Hashimoto's thyroiditis is incomplete and not reliable to help inform clinical decision making

Anxiety and Depression Are More Prevalent in Patients with Graves' Disease than in Patients with Nodular Goitre

Abstract: Background and Objective: Graves' disease has been associated with an increased psychiatric morbidity. It is unclarified whether this relates to Graves' disease o

Clinical Consequences of Mutations in Thyroid Hormone Receptor-α1.

Abstract: Thyroid hormone (TH) exerts its biological activity via the TH receptors TRα1 and TRβ1/2, which are encoded by the THRA and THRB genes The first patients with mutations in THRB were identified decades ago These patients had a clinical syndrome of resistance to TH associated with high serum TH and nonsuppressed thyroid-stimulating hormone levels Until recently, no patients with mutations in THRA had been identified In an attempt to predict the clinical phenotype of such patients, different TRα1 mutant mouse models have been generated These mice have a variable phenotype depending on the location and severity of the mutation Recently, the first humans with mutations in THRA were identified Their phenotype consists of relatively low serum T4 and high serum T3 levels (and thus an elevated T3/T4 ratio), growth retardation, delayed mental and bone development, and constipation While, in retrospect, certain features present in humans can also be found in mouse models, the first humans carrying a defect in TRα1 were not suspected of having a THRA gene mutation initially The current review focuses on the clinical consequences of TRα1 mutations

Challenges in the evaluation of urinary iodine status in pregnancy: The importance of iodine supplement intake and time of sampling

Abstract: Objectives: Median urinary iodine concentration (UIC) is the recommended method to evaluate iodine status in pregnancy, but several factors may challenge the inte

Platelet-Derived Growth Factor: A Key Factor in the Pathogenesis of Graves' Ophthalmopathy and Potential Target for Treatment

Abstract: Activation of orbital fibroblasts resulting in excessive proliferation, cytokine and hyaluronan production and differentiation into adipocytes, is a main determinant of orbital tissue inflammation and tissue expansion in Graves' ophthalmopathy (GO). During the last years we have shown that the platelet-derived growth factor (PDGF) isoforms PDGF-AA, PDGF-AB and PDGF-BB are increased in orbital tissue from GO patients with active and inactive disease. These PDGF isoforms exhibit the capacity to stimulate proliferation, hyaluronan and cytokine/chemokine production by orbital fibroblasts. Moreover, PDGF-AB and PDGF-BB increase thyroid stimulating hormone receptor (TSHR) expression by orbital fibroblasts, which enhances the orbital fibroblast activating capacity of the THSR stimulatory autoantibodies present in Graves' disease (GD) patients. Of these PDGF isoforms PDGF-BB exhibits the strongest orbital fibroblast activating effects, which is likely related to its ability to bind both the PDGF-receptor (PDGF-R)α and PDGF-Rβ chains. Thus the PDGF-system fulfills important roles in orbital fibroblast activation in both active and inactive GO, which supports a therapeutic rationale for blocking PDGF signaling in GO. Tyrosine kinase inhibitors (TKIs) may be candidates to target PDGF signaling. Of several TKIs tested dasatinib exhibited the highest potency to block PDGF-R signaling in orbital fibroblasts and may represent a promising compound for the treatment of GO as it was effective at low dosage and is associated with less side effects compared to imatinib mesylate and nilotinib. In this review the contribution of PDGF to the pathophysiology of GO as well as therapeutic approaches to target this PDGF-system will be addressed.

Letter regarding the Paper by Pearce et al. Entitled '2013 ETA Guideline: Management of Subclinical Hypothyroidism'.

Abstract: Dear Editor, In this letter we would like to emphasize a specific part of the new ETA guideline which was explained in the paper by Pearce et al. [1], more specifically the part on thyroid hormone supplementation in the oldest old. In the guideline it is recommended that thyroid hormone supplementation ‘should generally be stopped’ in the oldest old with a TSH above the normal range but ≤10 mU/l, but the clinical evidence for this statement is graded as level 3 [i.e. low quality (case series, case reports, expert opinion)]. For this reason, it is also stated that appropriately powered randomized controlled trials of L-thyroxine in patients with subclinical hypothyroidism, examining hard cardiovascular endpoints in various classes of age, are clearly warranted [1]. This recommendation is in line with the latest Cochrane review on this subject [2]. The conservative treatment recommendation in those over 80 years with a TSH above the normal range but ≤10 mU/l is based on findings from the Leiden 85-Plus Study [3]. In this observational follow-up study comprising a population-based sample of 562 persons aged 85 years, those with subclinical hypothyroidism lived longer than those with normal thyroid function. However, the observational design of this study did not allow for definite conclusions about the effect of treatment. In the oldest old, for example, higher blood pressure [4] and high cholesterol [5] have been associated with lower mortality, whereas randomized trials nevertheless have shown that treatment with antihypertensives [6] and statins [7], respectively, remains beneficial up to the highest age groups. It is for this reason that the ETA guideline also states that since observational studies are subject to several limitations, clinical decisions based only on these data should be made with great caution. Furthermore, in a later meta-analysis including individual patient data of over 50,000 participants, no beneficial effect of subclinical hypothyroidism was seen in the total subgroup of patients ≥80 years [8]. Another argument against treatment would be the risk of overtreatment [9]. An argument in favor of treatment would be that in older patients, thyroid function testing is often requested because of symptoms concerning mood, fatigue, or cognition. There is no evidence that the effectiveness of thyroid hormone supplementation on complaints is different in older patients compared to younger patients, whereas in younger patients with TSH above the normal range but ≤10 mU/l, treatment is recommended in the presence of symptoms. Although a conservative approach to the treatment of older people is defendable, so is an approach to start treatment in case of complaints, which are likely to be present. This clinical equipoise has spurred us to initiate a much needed and clearly warranted [see Pearce et al. [1]] randomized controlled trial on supplementation of subclinical hypothyroidism in those over 80 years of age (IEMO 80-Plus Thyroid Trial, NTR3851, www.trialregister.nl), with an independent data safety monitoring board to monitor overtreatment and negative side effects. In a nationwide initiative in the Netherlands, we are currently recruiting 450 older adults with persistent subclinical hypothyroidism. The primary endpoints of the trial include a combined cardiovascular endpoint and thyroid-specific quality of life. Secondary endpoints include overall mortality, quality of life, functional capacity, and cognitive function. Analyses of this trial will include a preplanned pooled analysis of all endpoints in all 80-plus participants together with TRUST (Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial, ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01660126","term_id":"NCT01660126"}}NCT01660126). Clinical recommendations in the absence of solid evidence should be interpreted with caution. We would therefore like to emphasize the lack of evidence in this particular age group to readers of the guidelines, and to advise them to consider the lack of evidence when applying the recommendations to their individual older patients. It is important that the need for randomized controlled trials is underlined by this ETA guideline, and that despite arguments for a conservative treatment approach of subclinical hypothyroidism in those over 80 years of age, doctors see this as an encouragement to include these patients in relevant trials on the matter.

Coexistence of thyroid-stimulating hormone-secreting pituitary adenoma and graves' hyperthyroidism.

Abstract: Background: Coexistence of thyroid-stimulating hormone (TSH)-secreting pituitary adenoma (TSHoma) with Graves' disease has been rarely reported. We describe a female patient displaying TSHoma with Graves' disease and who presented initially with inappropriate TSH values. Case Report: A 36-year-old woman presented with signs of thyrotoxicosis, small and vascular goiter and mild bilateral exophthalmos. Thyroid function tests showed hyperthyroxinemia and normal TSH values despite the use of different assays. Heterophile antibody testing result was negative. The patient underwent total right lobectomy with partial left lobectomy after 18 months of carbimazole treatment. Histology confirmed Graves' disease. Symptoms of thyrotoxicosis recurred 2 months later. Thyroid function tests showed hyperthyroxinemia and elevated TSH values. Investigations were consistent with a 10-mm TSHoma. The patient underwent a trans-sphenoidal tumor resection following preoperative lanreotide preparation. Histological examination and immunocytochemistry concluded to a pure TSH-producing tumor. There was no evidence of tumor recurrence after 18 years of follow-up. Conclusion: Association of TSHoma with Graves' disease should be carefully taken into account, especially when TSH values are not compatible with either the clinical history or other thyroid functions tests.

Environmental, Lifestyle, and Anthropometric Risk Factors for Differentiated Thyroid Cancer in Cuba: A Case-Control Study

Abstract: Background: The incidence of differentiated thyroid carcinoma (DTC) is low in people of African origin and higher in populations living on islands, but there is no well-established explanation for these differences. Cuba is a multiethnic nation with people of African and Spanish descent. Until now, no study on the risk factors of DTC has focused on the Cuban population. Our aim is to establish the role of environmental and lifestyle factors and to relate anthropometric measurements to the risk of developing DTC in Cuba. Methods: We performed a case-control study of 203 DTC patients treated in two hospitals in Havana and 212 controls living in the area covered by these hospitals (i.e. parts of Havana and the municipality of Jaruco). Risk factors were analyzed using conditional logistic regression. Results: As has been shown by other studies, we found that non-African ethnicity, never smoking, parity, and high body mass index are risk factors significantly associated with DTC, whereas a history of exposure to ionizing radiation and level of education were not significantly related with disease development. Being rhesus factor-positive, having a personal history of benign thyroid disorder, agricultural occupation, and consumption of artesian well water were also associated with a significantly increased risk of developing DTC. Conclusions: The original findings reported here concern the risk of DTC that was associated with non-African ethnicity, positive rhesus factor, farming, and drinking water from an artesian well.

Patient Knowledge of Antithyroid Drug-Induced Agranulocytosis

Abstract: Background: Agranulocytosis is a serious side effect of antithyroid drugs. Objective: To ascertain the knowledge of patients and review the quality of information available on the internet. Methods: A questionnaire survey was performed for patients receiving antithyroid drugs. Patients attending endocrine clinics who were receiving antithyroid drug treatment (group A, n = 33) were interviewed. A further national cohort of patients (group B, n = 100) treated with antithyroid drugs, participated in an online survey. Results: 60.9% of responders were not aware of the common symptoms of agranulocytosis. 18.6% had never received any information about side effects. Of the 108 patients who recalled receiving information, 30% rated the quality as ‘poor' or ‘not good at all'. Structured interviews of group A patients revealed that almost half (45.5%, 15/33) had experienced symptoms that could be indicative of agranulocytosis, but only 53.3% (8/15) had a blood count checked. A review of 20 selected patient information internet sites revealed a significant variation in advice given to patients. Conclusions: Inadequate knowledge about agranulocytosis among patients receiving antithyroid drug treatment is common. The available information on the internet is variable and inconsistent.

Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism.

Abstract: Resistance to thyroid hormone (RTH) was first described in 1967 [1], and the first mutations in the THRB gene were identified in 1989 [2,3], only 3 years after the cloning of the THR genes [4,5]. The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed TSH, often with goiter and no clear symptoms and signs of thyrotoxicosis [6]. In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH [7], as defined above. In the ensuing years more than 3,000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced cellular access of the biologically active thyroid hormone, T3, were identified. These are caused by defects of thyroid hormone cell membrane transport [8,9] and a defect reducing the intracellular metabolism generating T3 from T4[10]. To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term ‘reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts'. Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (table ​(table1).1). The term ‘impaired’ was to substitute for ‘reduced’ because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications ‘RTH’ is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype [11,12], we propose using the term ‘RTH α’, and in new publications to use ‘RTH β’ when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation ‘THR’ as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20,000 references, only a few related to resistance to thyroid hormone. Table 1 Inheritable forms of impaired sensitivity to thyroid hormone

Thyroid Tubercle of Zuckerkandl Is More Consistently Present and Larger on the Right: A Prospective Series

Abstract: Objective: The tubercle of Zuckerkandl (TZ) is a lateral projection from the thyroid lobe in the vicinity of the extralaryngeal termination of the recurrent laryngeal nerve (RLN), which is a very useful landmark for identification of the RLN during thyroidectomy. The purpose of the present study was to test our hypothesis that the TZ is more consistently found and is larger on the right than on the left side, and to investigate the frequency of anatomic variations of the TZ. Study Design: Prospective cohort study of 156 consecutive patients undergoing primary total thyroidectomy at an academic teaching hospital. Thyroidectomy was performed using a capsular dissection technique, with identification of the RLN only at its entry point into the larynx, using the TZ as a landmark. In vivo recording of size of right and left TZ was performed. The size of the right and left TZ was compared. Results: Identification of the TZ was 72.6% right side and 53.9% left side (p = 0.003). The mean size of the TZ, when present, was 11.2 mm on the right and 7.5 mm on the left (p = 0.0002). In matched-pair analysis, the right TZ was significantly larger than the left TZ (p -7). The TZ overlay the RLN in nearly all cases; however, there were 2 cases (0.8%) of a TZ extending medial to the RLN. In 12 cases (4.7%), the TZ appeared as a bilobed structure. Conclusion: The right TZ is consistently larger and more often identified than the left.

Thyrotoxicosis followed by Hypothyroidism due to Suppurative Thyroiditis Caused by Nocardia brasiliensis in a Patient with Advanced Acquired Immunodeficiency Syndrome

Abstract: Acute thyroiditis is an extremely rare complication of nocardiosis. We report a patient with hyperthyroidism due to suppurative thyroiditis caused by Nocardia brasiliensis. A 38-year-old Black male presented with features of thyrotoxicosis, sepsis and airway obstruction. He had no evidence of underlying thyroid disease, but was severely immunocompromised as a result of acquired immunodeficiency syndrome. He had previously been diagnosed with pulmonary nocardiosis and also had nocardial abscesses on his anterior chest wall. Investigations revealed thyrotoxicosis, with a FT4 of 43.2 pmol/l and a suppressed TSH <0.01 mIU/l. Serum anti-thyroperoxidase and anti-thyroglobulin antibodies were absent. Computed tomography scan showed a large abscess in the anterior neck involving the left lobe and isthmus, as well as inhomogeneous changes in the right lobe of the thyroid. The radioisotopic scan showed absent uptake of tracer in keeping with thyroiditis. Although the initial presentation was that of hyperthyroidism, destruction of the gland later resulted in sustained hypothyroidism, necessitating thyroid hormone supplementation. The hyperthyroidism can be explained by the release of presynthesized and stored thyroid hormone into the circulation as a result of inflammation and disruption of the thyroid follicles, and the subsequent hypothyroidism by the fact that much of the gland was destroyed by the abscess and the extensive inflammatory process. This is the first documented case of hyperthyroidism in a patient with acute suppurative thyroiditis caused by Nocardia.

Basal serum thyroglobulin measured by a second-generation assay is equivalent to stimulated thyroglobulin in identifying metastases in patients with differentiated thyroid cancer with low or intermediate risk of recurrence.

Abstract: Background: Guidelines for the follow-up of differentiated thyroid cancer (DTC) recommend the measurement of TSH-stimulated thyroglobulin (s-Tg) instead of basal

Historical Note: Many Steps Led to the ‘Discovery’ of Thyroid-Stimulating Hormone

Abstract: Finding thyroid-stimulating hormone was a process rather than a circumscribed event, and many talented persons participated over many years. Key early participants were Bennet M. Allen and Philip E. Smith who had the misfortune just prior to World War I of independently and simultaneously starting very similar experiments with tadpoles. This led to a series of back and forth publications attempting to establish priority for finding evidence of a thyrotropic factor in the anterior pituitary. Decades of work by others would be required before sophisticated biochemical techniques would bring us to our modern understanding.

Novel NKX2-1 Frameshift Mutations in Patients with Atypical Phenotypes of the Brain-Lung-Thyroid Syndrome.

Abstract: Objectives: To verify the involvement of NKX2-1 gene in infants with brain-lung-thyroid (BLT) syndrome and hypothyroid phenotypes variable amon

A Rare Case of Dyshormonogenetic Fetal Goiter Responding to Intra-Amniotic Thyroxine Injections

Abstract: Fetal goiter was detected by routine ultrasound in early pregnancy, gestational week (GW) 18, in a 28-year-old woman with no thyroid history, normal thyroid hormone levels and no TSH receptor or thyroid peroxidase antibodies. An umbilical cord blood sample was drawn in GW 23. The analysis indicated fetal hypothyroidism with TSH >100 mU/l (reference value 6.8 ± 2.9, mean ± SD), fT4 3.8 pmol/l (reference value 16.5 ± 5.3, mean ± SD). Intra-amniotic injections of thyroxine were given in conjunction with ultrasound every 7-10 days, in total nine times during GW 24-33. A dose of 10 µg thyroxine/kg of estimated fetal weight per day was administered on six occasions, and 5 µg/kg/day the last three times. Upon injections of thyroxine further growth of the goiter was reduced. Elevated amniotic TSH levels fell from 13 to 2.5 mU/l (reference range 0.04-0.51). Throughout pregnancy, fetal heart rate and skeletal maturation were within normal limits. In week 34, chorioamnionitis was suspected and the child was delivered by cesarean section. Cord blood revealed TSH 596 mU/l (reference value 8.0 ± 5.12, mean ± SD), fT4 4.4 pmol/l (reference value 19.3 ± 4.3, mean ± SD) and total T3 1.18 nmol/l (reference value 0.5 ± 0.3, mean ± SD); the newborn was put on thyroxine supplementation. Psychomotor development of the child, now 3 years old, has been uneventful. The reported experience of treating dyshormonogenetic fetal goiter is limited but growing, creating a need for guidelines on administration of intra-amniotic thyroxine and monitoring treatment.

Simple core-needle biopsy for thyroid nodule, complicated tinnitus.

Abstract: Background: Fine-needle aspiration is the procedure of choice for evaluating thyroid nodules. Core-needle biopsy (CNB) is not included in the American Thyroid Association recommendations for evaluating such nodules. CNB complications are classically bleeding and hematomas. To our knowledge, no case of arteriovenous fistula (AVF) secondary to a CNB has been reported, nor has any case of tinnitus secondary to a post-CNB AVF. Objectives: To make the clinician aware of possible vascular complications caused by CNB and the possibility of difficult pathology reading caused by previous CNB. Methods: A 44-year-old female is described who was referred to our tertiary care center for left-sided pulsatile tinnitus. She did report having had a CNB right before the tinnitus appeared. Conventional angiography demonstrated a focal AVF originating from the left vertebral artery, with reflux to the left vertebral venous plexus. A 6-mm stent was placed over the site of the fistula via an endovascular approach, which solved both the radiological and clinical documented problems. Moreover, CNB greatly complicated pathology reading once total thyroidectomy was later performed. The suspected area of invasion was an artifact due to the previous biopsies. Conclusion: Although many authors recommend a CNB as an alternative modality in cases of inconclusive cytology with fine-needle aspiration, it is not in the American Thyroid Association recommendations. In cases of iatrogenic AVFs caused by a CNB, angiography is recommended both as a diagnostic and therapeutic modality. Stenting the fistula with an endoprosthesis can correct the problem immediately.

Retrospective Analysis of 255 Papillary Thyroid Carcinomas ≤2 cm: Clinicohistological Features and Prognostic Factors.

Abstract: Background: Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. The widespread use of neck ultrasound (US) and US-guided fine-needle aspiration cytology is triggering an overdiagnosis of PTC. Objective: To evaluate clinical behavior and outcomes of patients with PTCs ≤2 cm, seeking for possible prognostic factors. Methods: Clinical records of cases with histological diagnosis of PTC ≤2 cm followed at the Endocrine Department of Instituto Portugues de Oncologia, Lisbon between 2002 and 2006 were analyzed retrospectively. Results: We identified 255 PTCs, 111 were microcarcinomas. Most patients underwent near-total thyroidectomy, with lymph node dissections in 55 cases (21.6%). Radioiodine therapy was administered in 184 patients. At the last evaluation, 38 (14.9%) had evidence of disease. Two deaths were attributed to PTC. Median (±SD) follow-up was 74 (±23) months. Multivariate analysis identified vascular invasion, lymph node and systemic metastases significantly associated with recurrence/persistence of disease. In addition, lymph node involvement was significantly associated with extrathyroidal extension and angioinvasion. Median (±SD) disease-free survival (DFS) was estimated as 106 (±3) months and the 5-year DFS rate was 87.5%. Univariate Cox analysis identified some relevant parameters for DFS, but multivariate regression only identified lymph node and systemic metastases as significant independent factors. The median DFS estimated for lymph node and systemic metastases was 75 and 0 months, respectively. Conclusions: In the setting of small PTCs, vascular invasion, extrathyroidal extension and lymph node and/or systemic metastases may confer worse prognosis, perhaps justifying more aggressive therapeutic and follow-up approaches in such cases.

The TRHR Gene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine

Abstract: Background: Thyroidectomized patients need variable doses of levothyroxine (LT4) to obtain target thyroid-stimulating hormone (TSH) levels. Individual feedback set-points have been hypothesized and the influence of several genes in the regulation of the pituitary-thyroid axis has been demonstrated. Objectives: We hypothesized that genetic variants of the TRHR gene could be associated with a different hypothalamo-pituitary sensitivity to thyroid hormone feedback. Methods: We retrospectively analyzed 84 thyroidectomized patients with no residual thyroid function and undetectable thyroglobulin levels. Patients were evaluated under LT4 resulting in TSH levels detectable but TRHR gene. Genotyping was performed using high-resolution melting technology. Genotype distribution was compared between the patients and 99 euthyroid controls. Results: The selected SNPs were in linkage disequilibrium and only rs3134105 was further considered. A significant difference between the three possible genotypes for rs3134105 was found for TSH (p = 0.04) and free thyroxine (fT4)/TSH ratio (p = 0.02). Moreover, despite similar serum concentrations of free triiodothyronine (fT3) and fT4, carriers of at least one A allele of rs3134105 had significantly lower serum TSH levels (p = 0.01) as well as higher fT3/TSH (p = 0.01) and fT4/TSH ratios (p Conclusions: We demonstrated an association between serum TSH levels and discrete alleles of the TRHR gene in totally thyroidectomized patients under LT4 therapy. Therefore, the TRHR gene seems to be a determinant of hypothalamo-pituitary sensitivity to LT4.

The Dilemma of Treating Subclinical Hypothyroidism: Risk that Current Guidelines Do More Harm than Good.

Abstract: Dear Editor, The recent European Thyroid Association (ETA) guideline on the treatment of subclinical hypothyroidism (SCH) [1] will potentially be widely used by clinicians faced with this common condition. Although the report includes much useful background and guidance, we suggest that the approach recommended there carries potential risks, with the likely outcome of an increase in the proportion of ‘younger’ elderly patients treated for SCH and the withholding of thyroxine treatment in the very elderly, in the absence of any good evidence that this will give net clinical gain. We suggest that the current uncertain state of evidence merits a very simple approach and that watchful waiting with repeat thyroid function tests is the appropriate strategy for most patients with persisting subclinical hypothyroidism. The exception to this are patients with biochemical SCH who have one or more symptoms that cannot be explained otherwise, particularly tiredness or fatigue, affecting quality of life and expected to improve with thyroid hormone replacement. Such patients may not be truly ‘subclinical’ and a ‘trial’ of thyroxine treatment is warranted, as suggested in the ETA guidelines. When biochemical SCH is identified, the ETA guideline suggests a repeat measurement of both serum thyroid-stimulating hormone (TSH) and free thyroxine along with thyroid peroxidase antibodies after a 2- to 3-month interval. We agree that repeating thyroid function tests is important as many patients will normalise their TSH results and should not be treated with levothyroxine. Some will show progression to overt biochemical hypothyroidism where treatment is no doubt warranted. However, the usefulness of auto-antibodies in supporting the decision whether to start thyroxine is less clear, since although antibody-positive subjects have an increased risk of developing biochemical hypothyroidism over a prolonged follow-up [2], the decision whether to treat is based on thyroid function status and symptoms rather than on the presence of auto-antibodies. After repeat thyroid function tests, the ETA guideline then recommends that when TSH is persistently elevated, patients should be categorised by TSH level (mild increase 4.0-10.0 mU/l, severer increase >10 mU/l) and by age (<70 years categorised as ‘younger’ and over 80 or 85 years as ‘oldest old’). It is stated that ‘age-specific local reference ranges for serum TSH should be considered in order to establish a diagnosis of SCH in older people’ [1]. We believe this advice is premature and overly complex. It is also difficult to implement, as most laboratories do not offer age-specific ranges. The rationale underpinning the ETA recommendations comes from clinical associations of SCH in observational data sets. Cohort studies in predominantly middle-aged or young elderly subjects show increased cardiovascular mortality associated with TSH concentrations of 10.0-19.9 mU/l (adjusted hazard ratio 1.58, 95% confidence interval 1.10-2.27; compared with TSH 4.5-6.9 mU/l); however, there is no epidemiological association of SCH with increased total mortality [3]. Furthermore the epidemiological associations may be reversed in later life; SCH in those older than 80 years may be associated with improved health and survival compared with the euthyroid state [4]. This raises the possibility that thyroxine replacement for subclinical hypothyroidism could be harmful, particularly in the ‘oldest old’. There is an association of lower TSH levels with an increased risk of atrial fibrillation; subjects with SCH have a reduced risk of this arrhythmia [5]. Thyroxine treatment is also associated with an increased risk of fracture with a dose-dependent relationship [6]. Lower TSH and higher thyroid hormone levels are also associated with a reduced bone density and increased risk of fractures [7]. Therefore there is the potential for thyroxine treatment of SCH to cause harm due to atrial fibrillation and also to increase the risk of osteoporotic fractures. However, the associations demonstrated in observational studies are not sufficient to prove causality and cannot fully inform decisions whether or not to initiate thyroxine treatment in clinical practice. For that we need good-quality randomised controlled trials. The Cochrane review of thyroxine replacement for subclinical hypothyroidism found 12 trials with 350 patients [8]; there was insufficient evidence to allow definitive advice for prescribing (or avoiding) treatment, including in subgroups of those with TSH concentrations above 10 mU/l or in very elderly people. The decision on whether to initiate thyroid hormone replacement for SCH is therefore currently finely balanced given the lack of good randomised clinical trial evidence to support decision making. As well as the possibility of benefit from treatment, there is the possibility of harm. We strongly endorse recommendations that further trials are required. Funded by the EU, we are currently recruiting subjects to the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial (TRUST) – a multicentre randomised placebo-controlled trial of levothyroxine in subclinical hypothyroidism with cardiovascular events and quality of life the coprimary outcomes (ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01660126","term_id":"NCT01660126"}}NCT01660126). An additional parallel study is recruiting subjects over the age of 80, with the aim of determining whether this subgroup benefits from treatment. It is expected that the TRUST-IEMO (Institute for Evidence-Based Medicine in Old Age) collaboration will report by late 2016 and will generate data that properly informs future evidence-based guidelines. Until then definitive guidance on initiation (or withholding) of levothyroxine will carry the risk of causing harm. Furthermore by inferring that the best process of care is already known, such guidance may negatively affect recruitment to trials such as TRUST-IEMO that are required to determine whether treatment gives net clinical benefit.

Major Haemorrhage during Vitamin K Antagonist Treatment: The Influence of Thyroid Hormone Levels

Abstract: Background: Annually, approximately 1-3% of patients treated with vitamin K antagonists (VKA) suffer from major haemorrhage. Since high levels of free thyroxine (fT4) are associated with increased thrombosis risk, the aim was to assess whether low levels of fT4 contribute to major haemorrhage in patients under VKA treatment. Methods: The FACTORS (Factors in Oral Anticoagulant Safety) study is a case-control study on patients receiving VKA treatment, including 110 cases with major haemorrhage. Controls were 220 matched participants treated with VKA without major haemorrhage. Odds ratios (OR) and 95% confidence intervals (95% CI) for the association of fT4 levels with major haemorrhage were calculated for different fT4 cutoffs by conditional logistic regression. Results: In patients with an fT4 level below 13 pmol/l, the risk of major haemorrhage was 5-fold increased (OR = 5.1; 95% CI: 0.9-28.6) compared with patients with an fT4 level above 13 pmol/l. At a cutoff of 14 pmol/l, the risk was 3-fold increased (OR = 2.9; 95% CI: 1.0-8.5). High levels of fT4 did not affect bleeding risk. No clear effect of thyroid-stimulating hormone and thyroid peroxidase antibodies was seen on the risk of major haemorrhage. Conclusions: These results indicate that fT4 levels below 14 pmol/l play a role in the aetiology of major haemorrhage in VKA users.

Concurrent Medullary, Papillary, and Follicular Thyroid Carcinomas and Simultaneous Cushing's Syndrome

Abstract: Background: Papillary thyroid carcinoma is the most common thyroid cancer (85%). Follicular thyroid carcinoma is the second most common type of thyroid cancer, accounting for up to 10% of all thyroid cancers. Medullary thyroid carcinoma accounts for only 5-8% of thyroid cancers. Concurrent medullary, follicular, and papillary carcinomas of the thyroid gland are extremely rare and reported scarcely. Case Report: A 72-year-old male presented with nonspecific neck pain. The workup revealed a nodular thyroid gland with a follicular lesion on fine-needle aspiration. Total thyroidectomy was performed and pathological examination identified a 25-mm follicular carcinoma, two papillary microcarcinomas, and two medullary microcarcinomas. The genetic workup was negative and no other family members were diagnosed with any endocrinopathy. Two months after surgery, the patient was diagnosed with Cushing's syndrome that was treated with laparoscopic left adrenalectomy. On 3-year follow-up, the patient is asymptomatic with no evidence of recurrent disease. Conclusion: We present a rare case of a patient with follicular, papillary, and medullary thyroid carcinoma, and Cushing's syndrome. To date, no known genetic mutation or syndrome can account for this combination of neoplastic thyroid and adrenal pathologies, although future research may prove differently.

CBX7 Expression in Oncocytic Thyroid Neoplastic Lesions (Hürthle Cell Adenomas and Carcinomas).

Abstract: Background: Previous analysis of CBX7 expression in a large number of thyroid adenoma and carcinoma samples revealed a progressive reduction of CBX7 levels that was well related with the malignant grade of thyroid neoplasias. Hurthle cell tumors are unusual thyroid neoplasms characterized by the presence of particular cells called oncocytes. Objectives: In order to develop new tools for a more accurate diagnosis of Hurthle cell tumors of the thyroid, we evaluated CBX7 protein levels to verify the possible presence of an expression signature. Methods: CBX7 expression was evaluated by immunohistochemistry in a panel of thyroid tissue sections including normal thyroids, goiters, follicular adenomas and oncocytic lesions. Results: CBX7 expression was low or null in 68% of Hurthle adenomas, whereas it was comparable to normal thyroid tissue in Hurthle hyperplasias and follicular adenomas. Conclusions: Reduced expression of CBX7 suggests a more aggressive identity of Hurthle adenomas with respect to non-Hurthle ones.

Anaplastic carcinoma and toxic multinodular goiter: an unusual presentation.

Abstract: A 70-year-old male was referred with hyperthyroidism and multinodular goiter (MNG). Thyroid ultrasonography showed 2 nodules, one in the isthmus and the other in the left lobe, 51 and 38 mm in diameter, respectively. Neck CT showed a large MNG, thyroid scintigraphy showed increased uptake in the nodule in the left lobe, and fine-needle aspiration biopsy showed a benign cytology of the nodule in the isthmus. The patient declined surgery and was treated with methimazole. After being lost to follow-up for 3 years, the patient returned with complaints of dyspnea, dysphagia, and hoarseness; he was still hyperthyroid. Cervical CT showed a large mass in the isthmus and left lobe with invasion of surrounding tissues, the trachea, the esophagus, and the recurrent laryngeal nerve. Bronchoscopy showed extensive infiltration and compression of the trachea to 20% of its caliber. A tracheal biopsy revealed an anaplastic thyroid carcinoma. The tumor was considered unresectable, and radiotherapy was given. One month later, the patient died. The association between a toxic thyroid nodule and anaplastic thyroid carcinoma has apparently not been reported so far.