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Iodine supplementation during pregnancy in areas with mild-moderate deficiency is still a matter of debate. The present study aimed at systematically reviewing currently available evidences provided by meta-analyses with the aim to further clarify controversial aspects regarding the need of iodine supplementation in pregnancy as well as to provide guidance on clinical decision-making, even in areas with mild-moderate deficiency. Medline, Embase and Cochrane search from 1969 to 2022 were performed. For the purpose of this review, only studies containing meta-analytic data were selected. A total of 7 meta-analyses were retrieved. Four meta-analyses evaluated the relationship between iodine status during pregnancy and neonatal and maternal outcomes suggesting the existence of a U-shaped correlation between iodine status and several maternal and neonatal consequences, especially if iodine status is evaluated at the beginning of pregnancy. Three meta-analyses evaluating the results of intervention trials failed to provide straightforward conclusions on the benefits of iodine supplementation in pregnant women in areas with mild-moderate iodine deficiency. Although evidence coming from meta-analyses suggests a role of iodine status during pregnancy in determining maternal and child outcomes, results of meta-analyses of intervention trials are still controversial. Several factors including, degree of iodine deficiency, and pooling studies conducted in areas with different iodine intake, may account for the lack of benefits reported by meta-analyses of intervention trials. More high-quality, randomized, controlled trials including information on timing, dose and regimen of iodine supplementation are needed to further elucidate this issue.

Graves' orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves' disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves' patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate-to-severe forms of GO (traditionally, high-dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding the epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, Graves' orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH-receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. Recent studies suggest a secular trend toward a milder phenotype of GO. Standardized assessment at a thyroid eye clinic allows for a better general management plan. Treatment of active moderate-to-severe forms of GO still relies in most cases on high-dose systemic-mainly intravenous-glucocorticoids as monotherapy or in combination with other therapies-such as mycophenolate, cyclosporine, azathioprine, or orbital radiotherapy-but novel biological agents-including teprotumumab, rituximab, and tocilizumab-have achieved encouraging results.

BackgroundGraves’ orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves’ Orbitopathy (EUGOGO) tertiary referral centres and initial management over time.MethodsProspective observational multicentre study. All new referrals with diagnosis of GO within September–December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012.ResultsBesides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; pConclusionGO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Extra-pituitary ACTH secretion is associated with a variety of neoplastic conditions and may cause the so-called ectopic ACTH-dependent Cushing syndrome (CS). The clarification of the mechanisms of extra-pituitary ACTH expression would provide potential therapeutic targets for this complex and severe disease. In the adenohypophysis, the transcription factor TPIT, co-operating with other molecules, induces POMC expression and ACTH production. However, no data is currently available on the presence and role of TPIT expression in extra-pituitary ACTH-producing neoplasms. This study was designed to explore TPIT expression in a series of pulmonary and pancreatic ACTH-producing tumors, either CS-associated or not. 41 extra-pituitary ACTH-producing neuroendocrine tumors (NETs) were included in the study, encompassing 32 NETs of the lung (LuNETs), 7 of the pancreas (PanNETs) and 2 pheochromocytomas. Of these, 9 LuNETs, all PanNETs and the two pheochromocytomas were CS-associated. For comparison, 6 NETs the pituitary gland (PitNETs), and 35 ACTH-negative NETs (15 Lu-NETs and 20 PanNETs) were analyzed. Immunohistochemistry with specific anti-TPIT antibodies and quantitative real time PCR (qRT-PCR) were performed using standard protocols. TPIT expression was completely absent (protein and mRNA) in PanNETs, pheochromocytomas, and all ACTH-negative NETs. In contrast, it was expressed in 16/32 LuNETs, although with lower levels than in PitNETs. No definite relationship was found between immunohistochemistry TPIT expression and NET grade or the presence of Cushing syndrome. This study further highlights the clinical and biological heterogeneity of extrapituitary ACTH secretion and suggests that the differences between ACTH-secreting PanNETs and LuNETs may mirror distinct molecular mechanisms underlying POMC expression. Our results point towards the recognition of a real corticotroph-like phenotype of ACTH-producing LuNETs, that is not a feature of ACTH-producing PanNETs.

Purpose According to a few recent studies, the clinical phenotype of Graves’ disease (GD) at onset is becoming milder in recent years, in terms of prevalence and severity of hyperthyroidism, goiter and overt eye disease. The aim of this study was to assess the change in GD phenotype across the late twentieth and the early twenty-first centuries. Materials and methods We carried out a systematic search of studies published between 1/1/1980 and 12/31/2017 describing naïve GD patients at diagnosis. We collected epidemiological, clinical, biochemical and serological data reported in the selected studies, and (1) conducted a single-arm meta-analysis to compare clinical and biochemical characteristics of naïve GD patients before and after year 2000 and (2) performed a meta-regression to identify the trend of the observed clinical presentations. Results Eighty selected articles were related to the period before the year 2000, 30 to the years 2000–2017. According to demographics, the two defined populations were homogeneous at meta-analysis: overall estimated female prevalence was 81% [95% CI 79–82], mean estimated age of the entire population was 39.8 years [95% CI 38.4–41.1], with no significant differences between pre- and post-2000 groups (p > 0.05). The overall estimated prevalence of smokers was 40% [95% CI 33–46], with no significant difference between the two groups (p > 0.05). Mean estimated free thyroxine (FT4) and free triiodothyronine (FT3) levels at diagnosis were higher in the pre-2000 group: 4.7 ng/dl [95% CI 4.5–4.9] for FT4 and 14.2 pg/ml [95% CI 13.3–15.1] for FT3, as compared to the post-2000 group: 3.9 ng/dl [95% CI 3.6–4.2] for FT4 and 12.1 pg/ml [95% CI 11.0–13.3] for FT3 (all p p = 0.03). Accordingly, meta-regression adjusted for covariates showed an average annual reduction of FT4 (− 0.040 ± 0.008 ng/dl, p p p = 0.006), and goiter size (− 0.560 ± 0.031 ml, p Conclusions Our meta-analysis and meta-regression confirmed that GD phenotype at diagnosis is nowadays milder than in the past; we hypothesize that conceivable factors involved in this change are iodoprophylaxis, worldwide decrease in smoking habits, larger use of contraceptive pill and micronutrient supplementation, as well as earlier diagnosis and management.

Purpose Current treatment of acromegaly restores a normal life expectancy in most cases. So, the study of persistent complications affecting patients’ quality of life (QoL) is of paramount importance, especially motor disability and depression. In a large cohort of acromegalic patients we aimed at establishing the prevalence of depression, to look for clinical and sociodemographic factors associated with it, and to investigate the respective roles (and interactions) of depression and arthropathy in influencing QoL. Methods One hundred and seventy-one acromegalic patients (95 women and 76 men, aged 20–85 years) among those recruited in a cross-sectional Italian multicentric study were investigated. Each patient filled in three validated questionnaires: AcroQoL, WOMAC (measuring articular pain, stiffness and functionality), and AIMS (evaluating articular symptoms and depression). Results A very high (up to 28%) depression rate was detected in acromegalic subjects. Two patients showing pathological AIMS depression scores, committed suicide during the three years observational period. In our population poor psychological status was significantly associated with female sex. Furthermore, a significant strong correlation was found between AIMS depression score and WOMAC score. Both depression and arthropathy-related motor disability turned out to independently contribute with similar strength to the impairment of QoL. Conclusions We report a high prevalence of depression in acromegaly, which is associated with female sex and arthropathy. Both depression and arthropathy strongly and independently contribute to the impaired QoL of patients. Our study shows that assessment and monitoring of psychological status is mandatory in acromegaly, also suggesting an inexpensive tool for this assessment.

Context Patients with amiodarone-induced thyrotoxicosis (AIT) and severely reduced left ventricular ejection fraction (LVEF) have a high mortality rate that may be reduced by total thyroidectomy. Whether in this subset of patients thyroidectomy should be performed early during thyrotoxicosis or later after restoration of euthyroidism has not yet been settled. Objectives Mortality rates, including peritreatment mortality and 5-year cardiovascular mortality, and predictors of death, evaluated by Cox regression analysis. Methods Retrospective cohort study of 64 consecutive patients with AIT selected for total thyroidectomy from 1997 to 2019. Four groups of patients were identified according to serum thyroid hormone concentrations and LVEF: Group 1 (thyrotoxic, LVEF Results Among patients with low LVEF (Groups 1 and 3), mortality was higher in patients undergoing thyroidectomy after restoration of euthyroidism (Group 3) than in those submitted to surgery when still thyrotoxic (Group 1): peritreatment mortality rates were 40% versus 0%, respectively (P = .048), whereas 5-year cardiovascular mortality rates were 53.3% versus 12.3%, respectively (P = .081). Exposure to thyrotoxicosis was longer in Group 3 than in Group 1 (112 days, interquartile range [IQR] 82.5-140, vs 76 days, IQR 24.8-88.5, P = .021). Survival did not differ in patients with LVEF ≥40% submitted to thyroidectomy irrespective of being thyrotoxic (Group 2) or euthyroid (Group 4): in this setting, peritreatment mortality rates were 6.3% versus 4% (P = .741) and 5-year cardiovascular mortality rates were 12.5% and 20% (P = .685), respectively. Age (hazard ratio [HR] 1.104, P = .029) and duration of exposure to thyrotoxicosis (HR 1.004, P = .039), but not presurgical serum thyroid hormone concentrations (P = .577 for free thyroxine, P = .217 for free triiodothyronine), were independent predictors of death. Conclusions A prolonged exposure to thyrotoxicosis resulted in increased mortality in patients with reduced LVEF, which may be reduced by early thyroidectomy.

Summary Brown tumors are osteoclastic, benign lesions characterized by fibrotic stroma, intense vascularization and multinucleated giant cells. They are the terminal expression of the bone remodelling process occurring in advanced hyperparathyroidism. Nowadays, due to earlier diagnosis, primary hyperparathyroidism keeps few of the classical manifestations and brown tumors are definitely unexpected. Thus, it may happen that they are misdiagnosed as primary or metastatic bone cancer. Besides bone imaging, endocrine evaluation including measurement of serum parathyroid hormone and calcium (Ca) levels supports the pathologist to address the diagnosis. Herein, a case of multiple large brown tumors misdiagnosed as a non-treatable osteosarcoma is described, with special regards to diagnostic work-up. After selective parathyroidectomy, treatment with denosumab was initiated and a regular follow-up was established. The central role of multidisciplinary approach involving pathologist, endocrinologist and oncologist in the diagnostic and therapeutic work-up is reported. In our opinion, the discussion of this case would be functional especially for clinicians and pathologists not used to the differential diagnosis in uncommon bone disorders. Learning points: Brown tumors develop during the remodelling process of bone in advanced and long-lasting primary or secondary hyperparathyroidism. Although rare, they should be considered during the challenging diagnostic work-up of giant cell lesions. Coexistence of high parathyroid hormone levels and hypercalcemia in primary hyperparathyroidism is crucial for the diagnosis. A detailed imaging study includes bone X-ray, bone scintiscan and total body CT; to rule out bone malignancy, evaluation of bone lesion biopsy should include immunostaining for neoplastic markers as H3G34W and Ki67 index. If primary hyperparathyroidism is confirmed, selective parathyroidectomy is the first-line treatment. In advanced bone disease, treatment with denosumab should be considered, ensuring a strict control of Ca levels.

Hypertension is a frequent finding in elderly patients. Hypertension in older age can be both associated with frailty and represent a risk factor for frailty. Hypertension is recognized as a main risk factor for cardiovascular diseases such as heart failure, atrial fibrillation, and stroke and the occurrence of these diseases may provoke a decline in health status and/or worsen the degree of frailty. Blood pressure targets in hypertensive older and frail patients are not completely defined. However, specific evaluations of individual patients and their co-morbidities and assessment of domains and components of frailty, together with weighted consideration of drug use, may help in finding the appropriate therapy.

Whether differentiated thyroid cancer (DTC) occurring concomitantly with Graves’ disease (GD) is more aggressive and bound to a less favorable outcome is controversial. Aim of this multicenter retrospective study was to compare baseline features and outcome of DTC patients with GD (DTC/GD+) or without GD (DTC/GD−). Enrolled in this study were 579 patients referred to five endocrine units (Cagliari, Pavia, Pisa, Siena, and Varese) between 2005 and 2014: 193 patients had DTC/GD+ , 386 DTC/GD−. Patients were matched for age, gender and tumor size. They underwent surgery because of malignancy, large goiter size, or relapse of hyperthyroidism in GD. Baseline DTC features (histology, lymph node metastases, extrathyroidal extension) did not differ in the two groups, except for multifocality which was significantly more frequent in DTC/GD+ (27.5% vs. 7.5%, p

Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves’ hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.

Objective We compared demographic and clinic-pathological variables related to the number of surgeries for thyroid conditions or for cancer, morbidity, and fine needle aspiration (FNA) practices among Covid19 pandemic phases I, II, III and the same seasonal periods in 2019. Methods The prospective database of the Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Changchun, China was used for this study. Covid19 emergency levels were stratified according to the World Health Organization: phase I (January 25–February 25, 2020), phase II (February 26–March 19), phase III (March 20–April 20). Results There were fewer outpatient FNAs and surgeries in 2020 than in 2019. There were no thyroid surgeries during phase I. There were also fewer surgeries for cancer with a significant reduction of advanced stage cancer treatments, mainly stage T1b N1a in phase II and T3bN1b in phase III. Operative times and postoperative stays were significantly shorter during the pandemic compared to our institutional baseline. In phase III, vocal cord paralysis (VCP) increased to 4.3% of our baseline numbers (P = 0.001). There were no cases of Covid19-related complications during the perioperative period. No patients required re-admission to the hospital. Conclusion The Covid19 outbreak reduced thyroid surgery patient volumes. The decrease of Covid19 emergency plans contributed to unexpected outcomes (reduction of early stage cancer treatment, decreased operative times and hospital stays, increased VCP rate). Electronic supplementary material The online version of this article (10.1007/s40618-020-01407-1) contains supplementary material, which is available to authorized users.

GO is the most frequent extrathyroidal manifestation of Graves’ disease, although it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. It is a relatively infrequent disorder, and men tend to have more severe ocular involvement at an older age. The prevalence of GO is lower than in the past among patients with recent onset Graves’ hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5–6% of all cases of GO. After an initial inflammatory (active) phase and a phase of stabilization (plateau phase), GO tends to improve and eventually inactivates (inactive or burnt-out phase). Minimal-to-mild GO often remits spontaneously, but complete restitutio ad integrum almost never occurs when GO is more than mild. Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them. Early diagnosis, control and removal of modifiable risk factors, early treatment of mild forms of GO may effectively limit the risk of progression to more severe forms, which have a profound and dramatic impact on the quality of life of affected individuals, and remain a therapeutic challenge, often requiring long-lasting and multiple medical and surgical therapies.

Osteoporosis and fractures are important comorbidities in patients with differentiated thyroid cancer (DTC), with potential negative impact on quality of life and survival. The main determinant of skeletal fragility in DTC is the thyrotropin (TSH)-suppressive therapy, which is commonly recommended to prevent disease's recurrence, especially in patients with structural incomplete response after thyroid surgery and radio-iodine therapy. TSH-suppressive therapy can stimulate bone resorption with consequent bone loss, deterioration of bone microstructure and high risk of fragility fractures. The skeletal effects of TSH-suppressive therapy may be amplified when thyroid cancer cells localize to the skeleton inducing alterations in bone remodelling, impairment of bone structure and further increase in risk of fractures. The management of skeletal fragility in DTC may be challenging, since prediction of fractures is a matter of uncertainty and data on effectiveness and safety of bone-active agents in this clinical setting are still scanty. This review deals with pathophysiological, clinical and therapeutic aspects of skeletal fragility of patients with DTC.

Background: Laparoscopic sleeve gastrectomy (LSG) progressively became the preferred procedure worldwide for the treatment of morbid obesity. Occasionally, unknown gastrointestinal diseases may be incidentally discovered during the procedure or on the histologic gastric specimen. Gastric xanthomas are uncommon lesions of the lamina propria, composed by foamy macrophages and mixed inflammatory infiltrate. Rarely, xanthoma cells develop within a gastric hyperplastic polyp. Although usually benign, they may be associated with pre-malignant conditions or even gastric cancer, making advisable an appropriate workup. Case Presentation: A hyperplastic polyp with xanthomatous proliferation was discovered in the gastric specimen of a young man, suffering from severe obesity and metabolic syndrome. The patient had been treated with proton pump inhibitors for gastric discomfort for years. After the surgical procedure, the gastric discomfort rapidly disappeared. Conclusion: Obesity is often complicated by gastrointestinal abnormalities discovered during ultrasound or endoscopic procedures. Incidental findings of unknown gastric lesions are common occurrences during sleeve gastrectomy. Although xanthelasmas per se are harmless, they might coexist with pre-malignant/ malignant lesions, especially when associated with gastric polyps. Thus, prompt intra-operative recognition and adequate work-up are mandatory. Although cases of gastric polyps or xanthomas are not a novelty, to our knowledge, this is the first case reporting about the discovery of a gastric hyperplastic polyp with xanthomatous proliferation on gastric histological piece. From the discussion of this case and of similar reports in the literature, we advocated for the importance of endoscopic screening in obese patients admitted for bariatric surgery to address the proper surgical approach and follow-up.

Graves' disease (GD) is a common autoimmune cause of hyperthyroidism, which is eventually related to the generation of IgG antibodies stimulating the thyrotropin receptor. Clinical manifestations of the disease reflect hyperstimulation of the gland, causing thyrocyte hyperplasia (goiter) and excessive thyroid hormone synthesis (hyperthyroidism). The above clinical manifestations are preceded by still partially unraveled pathogenic actions governed by the induction of aberrant phenotype/functions of immune cells. In this review article we investigated the potential contribution of natural killer (NK) cells, based on literature analysis, to discuss the bidirectional interplay with thyroid hormones (TH) in GD progression. We analyzed cellular and molecular NK-cell associated mechanisms potentially impacting on GD, in a view of identification of the main NK-cell subset with highest immunoregulatory role.

Introduction: Intrathoracic goiters are associated with compression of nearby structures, triggering severe compressive symptoms. Total thyroidectomy is the gold standard to treat these cases. Case Presentation: A patient with a huge intrathoracic goiter suffering from compressive symptoms underwent a thorough clinical, functional and imaging assessment and underwent total thyroidectomy in an Endocrino-Metabolic surgical referral center; after the surgery she suffered from transient hypocalcaemia but was discharged without major complications and continued periodical endocrinological follow-up. Conclusion: Management of intra-thoracic goiter requires a multidisciplinary approach of a skilled team both pre, during and after surgery to maximize the safety and efficacy of the procedure and reduce or promptly manage surgical or medical complications.

Objective Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation. Design Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals. Methods We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8). Results 90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH. Conclusions Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.

Objective The aim of this observational study was to clarify the link between vitamin D status and metabolic syndrome (MetS) in people with visceral obesity. Design and methods One hundred ninety-six consecutive patients (152 women; mean age 51 ± 13 years) with visceral obesity (mean body weight 103 ± 20 kg, mean waist circumference (WC) 119 ± 13 cm) were enrolled at the Obesity Outpatient Clinic of the University of Insubria in Varese. Anthropometric measurements were recorded. Laboratory tests, including vitamin D (25(OH)D)), fasting blood glucose (FBG), lipid profile, liver and kidney function tests were assessed. Vitamin D status was defined according to the European Society of Endocrinology guidelines, MetS to the 2009 harmonized definition. Results An inverse association emerged among 25(OH)D, body mass index (BMI) (P = 0.001) and WC (all P = 0.003). Serum 25(OH)D levels were inversely related to FBG and systolic blood pressure (SBP) (respectively, P = 0.01 and 0.02). Median serum 25(OH)D levels were 13.3 ng/mL (CI 95% 12; 15) in MetS and 16 ng/mL (CI 95% 14; 18) (P = 0.01) in non-MetS patients. Among patients with MetS, lower 25(OH)D concentrations were related to higher risk of hypertension (HT) (odds ratio (OR) 1.7, CI 95%, 0.7;4) and hyperglycemia (IFG)/type 2 diabetes (OR 5.5, CI 95% 2; 14). Conclusion Vitamin D status and MetS are inversely correlated in visceral obesity, particularly with regard to glucose homeostasis and BP. More extensive studies are required to investigate the potential for causality.

We review the clinical and pathologic features of seven cases of papillary carcinoma of the thyroid that invaded the trachea and were treated by thyroidectomy, airway resection with reconstructive surgery over an interval of 15 years. We depicted the peculiarity of invasion of well differentiated papillary thyroid carcinoma (PTC) cells is perpendicularly oriented to the tracheal lumen, in between cartilaginous rings, along blood vessels and collagen fibers. Tracheal rings appear non-infiltrated in all histological sections of well differentiated PTC infiltrating the trachea. Similar description of inter-cartilage PTC infiltration into the trachea was first provided by Shin et al. in 1993. Interestingly, our pathological revision support the estimation by Shin et al., though that cartilage rings infiltration did occur in poorly differentiated thyroid cancers with exiguous prognosis.

Purpose: Papillary thyroid carcinomas (PTCs) and medullary thyroid carcinomas (MTCs) have always been considered different in terms of their incidence rates, cell origins, and histopathological features. Simultaneous occurrence of both disease entities is very rare. Methods: We describe a series of cases with simultaneous MTC and PTC occurrences in the thyroid gland. Results: From 2,897 patients (mean age, 49.2±12.5; 81% women) who underwent thyroidectomy for cancer between 2000 and 2015, we reviewed 11 cases of simultaneous occurrence of MTCs and PTCs. Multifocal PTC with simultaneous MTC was detected in 5 of the 11 cases (45%). Of these PTC patients, 2 had 2 foci, 2 had 3 foci, and 1 had 4 foci. There was 1 case of multifocal MTC with solitary PTC. One patient presented with “composite thyroid carcinoma” with mixed features of MTCs and PTCs. Eight patients (72%) presented an association with diffuse lymphocytic thyroiditis. The sizes of the tumors were 1.95±0.23 cm vs. 1.20±0.20 cm for PTCs and MTCs, respectively (P=0.531). The prevalence of extrathyroidal extension was 33.1% vs. 30.2% for PTCs and MTCs, respectively (P=0.282). All patients underwent total thyroidectomy and central neck node dissection. Radio iodine was delivered to 44% of patients. Follow-up review revealed 9 disease-free patients and 1 with local neck recurrence, while 1 patient died due to non-thyroid reasons. Conclusion: There are only 30 reports describing a total of 50 cases in the English literature regarding concurrent PTC and MTC in the same gland. This study represents one of the largest case series. Whether the incidence of another cancer in these patients is coincidental, or due to the possible activation of a common tumorigenic pathway for both follicular and parafollicular thyroid cells, remains to be elucidated.

Thyroid diseases, both benign and malignant, are the most common manifestation of endocrine disease and represents the most frequent endocrinopathy of surgical interest as well as the first cause of interventions on the neck.

Cancer screening is aimed primarily at reducing deaths from the specific cancer. Thyroid-specific cancer mortality may be the most ambitious endpoint for obtaining estimates of screening effect. Numerous observations have accumulated over the years, indicating that thyroid cancer mortality endpoint has been difficult to study and is confounded by population heterogeneity, provision of randomization, and requirement of large cohorts with sufficiently long follow-up due to the excellent prognosis of the cancer. Accordingly, it may be important to reconsider how to best measure thyroid cancer screening efficacy. Recommendations against thyroid cancer screening should be based upon trials designed to evaluate its effectiveness not only in significant reduction in cancer mortality, but also of other distinct endpoints. It is desirable to evaluate derivative endpoints that can reliably predict reductions in mortality. The term "derivative" means a variable that is related to the true endpoint and is likely to be observable before the primary endpoint. Derivative endpoints may include thyroid cancer incidence, the proportion of early-stage tumors detected, more treatable stage, the identification of small tumors (to maintain in observation), decrease in the number of people who develop metastatic disease, the increased chance of lesser extent surgery, and the application of minimally invasive approaches, as well as no need for lifelong thyroid replacement therapy, a consistent follow-up, low-dose or no RAI administration and risk factor assessments where case findings should be continuous. The Korean guidelines for thyroid cancer national-level screening were published by a relevant group of multidisciplinary thyroid experts. It was concluded that the evidence is insufficient to balance the benefits and harms of thyroid cancer screening. However, the paper seems to raise the necessary investments in future research and demand a complete analysis for derivative endpoints, and offer screening participants with complete information necessary to make decisions that will provide them with the most value when a small thyroid cancer is screen-identified.

Amiodarone-induced thyrotoxicosis (AIT) resulting from destructive thyroiditis (type 2) is commonly treated with glucocorticoids, but time needed to restore euthyroidism may be unacceptable for patients with underlying cardiac disorders.The objective of this prospective study was to identify factors affecting the response to glucocorticoids in a large cohort of patients with type 2 AIT followed prospectively.This study was conducted at university centers.Sixty-six untreated patients with type 2 AIT were enrolled in the study.All patients were treated with prednisone (initial dose, 0.5 mg/kg.d) as long as needed to restore euthyroidism, defined as cure of AIT.The main outcome measure was cure time.The median cure time was 30 d (95% confidence interval, 23-37 d). Serum free T4 concentration (picograms per milliliter) and thyroid volume (milliliters per square meter) (and, to a lesser extent, serum free T3 concentration) at diagnosis were the main determinants of response to glucocorticoids, with a cure hazard ratio of 0.97 (95% confidence interval, 0.95-0.99; P = 0.005) and 0.84 (95% confidence interval, 0.77-0.91; P = 0.000) for unit of increment, respectively. AIT was cured in all patients with a complete follow-up; euthyroidism was reached in 30 d or less in 60% of patients but in more than 90 d in 16%. A prompt control of thyrotoxicosis (or=30 d of treatment) was more frequent (77%) in patients with serum basal free T4 concentration no greater than 50 pg/ml and thyroid volume (normalized for body surface area) no greater than 12 ml/m2. The cure probability and the mean cure time in an individual patient can be obtained using a formula generated by multiple regression models.Baseline serum thyroid hormone concentrations and thyroid volume help identify patients with type 2 AIT at risk of a delayed response to glucocorticoids.

This paper aims to review controversies in the management of minimally invasive follicular thyroid carcinoma (MIFTC) and to reach an evidence-based consensus.MEDLINE search of the literature was conducted using keywords related to MIFTC. The search term was identified in the title, abstract, or medical subject heading. Available literature meeting the inclusion criteria were assigned the appropriate levels of evidence and recommendations in accordance with accepted international standards. Results were discussed at the 2013 Workshop of the European Society of Endocrine Surgeons devoted to MIFTC.Published papers on MIFTC present inadequate power with a III–IV level of evidence and C grade of recommendation. Several issues demanded a comparison of published studies from different medical reports regarding MIFTC definition, specimen processing, characteristics, diagnosis, prognoses, and therapy. As a consequence, it is difficult to make valuable statements on MIFTC with a sufficient recommendation rating. MIFTC diagnosis requires clearer, unequivocal, and reproducible criteria for pathologist, surgeons, and endocrinologists to use in the management of these patients. If the distinction between MIFTC and WIFTC cannot be made, an expert in thyroid pathologist should be consulted.According to published papers, the following conclusions can be drawn. (a) Candidates for hemithyroidectomy are MIFTC with exclusive capsular invasion, patients45 years old at presentation, tumor size40 mm, without vascular invasion, and without any node or distant metastases. (b) Candidates for total thyroidectomy are MIFTC in patients ≥45 years at presentation, tumor size ≥40 mm, vascular invasion present, positive nodes, and positive distant metastases. (c) In the absence of clinical evidence for lymph node metastasis, patients with MIFTC do not require prophylactic lymph node dissection. (d) Radio iodine ablation is indicated in elderly patients (45 years), large tumor size (40 mm), extensive vascular invasion, presence of distant synchronous or metachronous metastasis, positive nodes, and if recurrence is noted at follow-up.

______________________________________________________________________ Correspondence: Professor Luigi Bartalena, Dept. of Clinical Medicine, University of Insubria, Division of Endocrinology, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy. Phone & Fax: +39-0332-278561; e-mail: l.bartalena@libero.it or luigi.bartalena@uninsubria.it . Page 1 of 8 Accepted Preprint first posted on 30 July 2008 as Manuscript EJE-08-0553

The prevalence and natural history of Graves' orbitopathy (GO) are poorly documented.A large series of 346 patients with newly diagnosed and recent onset Graves' hyperthyroidism seen at a single (nontertiary referral) center over an 8-year period were enrolled in an observational prospective study and evaluated for GO activity and severity according to the EUGOGO (European Group on Graves' Orbitopathy) criteria. After excluding patients immediately treated for moderate-to-severe GO, patients undergoing total thyroidectomy or radioactive iodine treatment, and patients lost to follow-up, 237 patients were submitted to antithyroid drug (ATD) treatment, with ocular evaluation at 6, 12, and 18 months.Among the whole cohort, at presentation 255 (73.7%) had no ocular involvement, 70 (20.2%) had mild and inactive GO, 20 (5.8%) had moderate-to-severe and active GO, and 1 (0.3%) had sight-threatening GO with dysthyroid optic neuropathy. Of the 237 patients who completed the 18-month follow-up during or after ATD treatment, 194 (81.9%) had no GO at baseline. Progression to moderate-to-severe GO occurred in 5 (2.6%) of these patients. Of the 43 (18.1%) patients with mild and inactive GO at baseline, 1 (2.4%) progressed to moderate-to-severe GO, and 25 (58.1%) experienced complete remission.Most patients with newly diagnosed Graves' disease have no ocular involvement. Moderate-to-severe and active GO or sight-threatening GO are rare at presentation and rarely develop during ATD treatment. Most patients (80%) with no GO at baseline do not develop GO after an 18-month follow-up period. Remission of mild GO occurs in the majority of cases.

Medical management of overt and active Graves’ orbi-topathy is frequently unsatisfactory, both for the patientand the physician [1]. Systemic glucocorticoids, moreefficaciously given intravenously [2], represent the first-line treatment [3, 4], but many patients require a secondcourse of steroids, associated with orbital radiotherapy orcyclosporine, to inactivate the disease [5]. And, eventually,some kind of rehabilitative surgery (orbital decompression,squint surgery, eyelid surgery) is needed in many patientswhen GO is inactive to correct residual invalidating man-ifestations, such as exophthalmos, strabismus/diplopia,eyelid retraction [3].Reasons why glucocorticoids are not always effectiveare not fully understood. They include selection of patientswith long-lasting GO, prevalence of proptosis with limitedinflammatory changes, long-standing eye muscle dysfunc-tion associated with fibrotic changes, smoking habits,mutations in the glucocorticoid receptor causing adecreased sensitivity to the drug. Most importantly, glu-cocorticoids, despite immunosuppressive actions, aremainly anti-inflammatory drugs and cannot be really con-sidered pathogenic drugs. Autoimmune pathogenesis ofGO is extremely complex, involving autoreactive T lym-phocytes, B-lymphocytes, the TSH receptor, the IGF-1receptor, secretion of a number of cytokines automain-taining the reactions occurring in the orbit. Studies areongoing to completely unveil the multiple steps of thecascade of events eventually causing remodeling of theorbital tissue, with an increase in the fibroadipose tissueand swelling of the extraocular muscles [6]. These studiesare essential to define the target of novel (‘‘pathogenic’’)treatments (T-cells? B-cells? Cytokines?). Among clinicalstudies based on better understanding of orbital patho-physiological processes, promising, although preliminary,results come from the evaluation of the CD20? depletingagent, rituximab [7] or some anti-TNFa agents [8]. Inpatients with mild GO, selenium administration for6 months prevented the progression to more severe formsof eye disease [9]. Expansion of the orbital adipose tissue isundoubtedly a key feature of GO under most circum-stances. In this issue of Endocrine, Zhang et al. [10]evaluated the effects of thalidomide on preadipocytes(3T3-L1 preadipocytes) and orbital fibroblasts from fewpatients with GO. This agent was initially used as an oralsedative hypnotic, but it is now used in the management ofseveral autoimmune disorders in view of its anti-inflam-matory and anti-angiogenic features. In Zhang et al.’sstudy, thalidomide dose-dependently inhibited adipogene-sis of 3T3-L1 preadipocytes; this was associated with adecreased expression of PPARc and the TSH receptor [10].These inhibitory effects were also observed on the differ-entiation of preadipocyte fibroblasts from GO orbital tissueinto adipocytes, in which the expression of TNFa and IL-6was also reduced by thalidomide [10]. The main limitationof this ex vivo study is the small size, because tissue fromonly three patients with GO was utilized. However, itseems reasonable to try and reproduce these preliminaryresults in larger studies before envisioning or advocating itspossible use in clinical practice in patients with GO.Pathogenesis of GO is so complex and implies the partic-ipation of so many actors that it is presently hard to believethat a single drug can cure or control the disease. It ishowever worth keep on trying.

Radioiodine (RAI) therapy may cause progression of mild or absent Graves' orbitopathy (GO), preventable by oral prednisone. Optimal doses of prednisone are undefined.The aim of this study was to compare the effectiveness of reported doses [starting dose,0.3 mg/kg body weight (bw)], and lower (0.3 mg/kg bw)] doses of prednisone.We conducted a retrospective matched cohort study at a University Center.Of 111 RAI-treated Graves' patients with mild or no GO, 35 received no steroid prophylaxis (absence of GO and/or risk factors for RAI-associated GO progression); 28 received low-dose prednisone (starting dose, 0.16-0.27 mg/kg bw; mean +/- sd, 0.22 +/- 0.03 mg/kg bw; group 1); and 48 received higher doses (group 2). Among the latter, 28 (starting dose, 0.32-0.56 mg/kg bw; mean +/- sd, 0.36 +/- 0.05 mg/kg bw) were matched with group 1 according to several relevant variables. Prednisone was started 1 d after RAI and withdrawn after 6 wk.We assessed ocular changes (1, 3, and 6 months after RAI) and side effects of prednisone.Two of 35 patients not receiving steroid prophylaxis (6%) developed mild-to-moderate GO (clinical activity score, 2/7 and 3/7) after RAI. No patients in group 1 or group 2 had GO progression. Side effects were very mild and inconstant, although more frequent in group 2. Both groups showed an increase in bw, an increase that was significantly higher in group 2.Lower doses of oral prednisone (about 0.2 mg/kg bw) are as effective as previously reported doses (0.3-0.5 mg/kg bw). A shorter treatment period (6 wk) is probably sufficient. The increase in bw is less using lower doses of prednisone.

Radioactive iodine (RAI) is a common therapy for hyperthyroidism due to Graves' disease. A small but significant proportion of patients have recurrence of hyperthyroidism after RAI therapy. Lithium might increase RAI effectiveness by increasing RAI retention in the thyroid. However, whether lithium favorably affects the long-term outcome of RAI therapy is still a matter of argument.The objective of the study was to compare the efficacy of RAI given with or without concomitant lithium treatment.This was a retrospective cohort study.The study was conducted at a tertiary university center.Six hundred fifty-one patients with newly diagnosed Graves' disease participated in the study.Two hundred ninety-eight patients were treated with RAI plus lithium (900 mg/d for 12 d) and 353 with RAI alone.Proportion of cured patients and time to achieve cure of hyperthyroidism during 1 yr of follow-up was measured.PATIENTS treated with RAI plus lithium had a higher cure rate (91.0%) than those treated with RAI alone (85.0%, P = 0.030). In addition, patients treated with RAI plus lithium were cured more rapidly (median 60 d) than those treated with RAI alone (median 90 d, P = 0.000). Treatment with lithium prevented the serum free T(4) increase after methimazole withdrawal and RAI therapy. Side effects after RAI therapy occurred in a subset of patients and were mild, transient, and without differences in the two groups.RAI combined with lithium is safe and more effective than RAI alone in the cure of hyperthyroidism due to Graves' disease.