Altered Retinal Perfusion in Patients with Inactive Graves Ophthalmopathy Using Optical Coherence Tomography Angiography

Objective: The aim of this study was to evaluate retinal and optic nerve head (ONH) perfusion in patients with inactive Graves ophthalmopathy (GO) and compare it to healthy controls using optical coherence tomography angiography (OCTA).Methods: Twenty-nine eyes of 29 patients with inactive GO (study group) and 29 eyes of 29 healthy subjects (control group) were included in this study. The vessel density (VD) data in the superficial and deep retinal OCT angiogram of the macula and the radial peripapillary capillary network (RPC) were extracted and analyzed. OCTA was performed using RTVue XR Avanti with AngioVue (Optovue Inc, Fremont, CA). Clinical activity was evaluated using the clinical activity score, the severity assessment using the NOSPECS classification.Results: The VD in the superficial OCT angiogram and in the OCT angiogram of the ONH was significantly lower in the GO group when compared to the control group (whole en face, P = .016; parafovea, P = .026; RPC peripapillary, P = .027). There was no significant correlation between VD and functional parameters or the NOSPECS classification.Conclusion: Macular VD and ONH capillary density measured using OCTA were significantly lower in the study group compared to healthy controls. Noninvasive quantitative analysis of retinal perfusion using OCTA could be useful in monitoring patients with GO.Abbreviations: CAS = clinical activity score; GO = Graves ophthalmopathy; OCTA = optical coherence tomography angiography; ONH = optic nerve head; RPC = radial peripapillary capillary; rSp = Spearman's correlation coefficient; VD = vessel density     

Retrospective Analysis of Patients With Graves Orbitopathy Treated By Pulses Of Methylprednisolone,With a Focus on Adverse Events

Objective: Graves orbitopathy (GO) is an extrathyroidal manifestation of autoimmune thyroid disease. Early treatment with glucocorticoids in appropriately selected patients is recommended for active, moderate to severe, and sight-threatening disease. The recently published European Group on Graves Orbitopathy guidelines re-evaluated the recommended doses of intravenous methylprednisolone (ivMP) in response to the potential for adverse effects. We retrospectively reviewed our patient cohort treated with our ivMP protocol and analyzed the side effects of this treatment when given during hospitalization in our tertiary referral center.Methods: Between May 2007 and May 2017, a total of 171 consecutive patients with active, moderate to severe, or sight-threatening GO were treated with ivMP in a cumulative dose of 7.5 grams, given monthly in three hospital sessions. Adverse events were reported using Version 4 of Common Terminology Criteria for Adverse Events.Results: Ninety-two percent of patients who started the treatment were able to finish it; 5% did not finish the study due to adverse events, and 3% did not finish the treatment protocol because of noncompliance. The most common adverse events were asymptomatic changes in laboratory values (liver enzymes), psychiatric disorders, and infectious complications. None of the patients in the study died during the ivMP treatment, including those patients who experienced adverse effects or discontinued the protocol because of noncompliance.Conclusion: High-dose ivMP for active, moderate to severe, and sight-threatening GO, when applied cautiously in carefully selected and monitored patients, is generally safe during the treatment period.Abbreviations: AE = adverse effect; CAS = clinical activity score; CTCAE = Common Terminology Criteria for Adverse Events; DM = diabetes mellitus; EUGOGO = European Group on Graves Orbitopathy; GC = glucocorticoid; GO = Graves orbitopathy; ivMP = intravenous methylprednisolone     

Gender Influences the Clinical Presentation and Long-Term Outcome of Graves Disease

Objective: The outcome of antithyroid drug (ATD) treatment for Graves disease (GD) is difficult to predict. In this study, we investigated whether male gender, besides other factors usually associated with a poor outcome of ATD treatment, may affect disease presentation and predict the response to medical treatment in subjects with GD.Methods: We studied 294 patients with a first diagnosis of GD. In all patients, ATD treatment was started. Clinical features, thyroid volume, and eye involvement were recorded at baseline. Serum levels of free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and TSH-receptor antibodies (TRAb) were measured at baseline and during the follow-up. Treatment outcome (FT4, FT3, and TSH serum levels and further treatments for GD after ATD withdrawal) was evaluated.Results: When compared to women, men showed a significantly larger thyroid volume and a higher family positivity for autoimmune diseases. During ATD, the mean serum levels of TSH, FT4, FT3, and TRAb did not differ between groups. Within 1 year after ATD discontinuation, relapse of hyperthyroidism was significantly more frequent in men than in women. Within the 5-year follow-up period, the prevalence of men suffering a late relapse was higher compared with that of women. The outcome at the end of the 5-year follow-up period was significantly associated with gender and TRAb levels at disease onset.Conclusion: Male patients with GD have a poorer prognosis when submitted to medical treatment with ATDs. A larger goiter at presentation and a stronger genetic autoimmune background might explain this gender difference in patients with GD.Abbreviations:ATD = antithyroid drugFT3 = free triiodothyronineFT4 = free thyroxineGD = Graves diseaseGO = Graves orbitopathyRAI = radioiodineTRAb = thyroid-stimulating hormone-receptor antibodyTSH = thyroid-stimulating hormone     

Prognosis of Differentiated Thyroid Carcinoma in Patients with Graves Disease: A Systematic Review and Meta-Analysis

Objective: It is still controversial whether differentiated thyroid carcinoma (DTC) in patients with Graves disease (GD) can be more aggressive than non-Graves DTC. We conducted a systematic review and meta-analysis to examine the association between GD and prognosis in patients with DTC.Methods: We comprehensively searched the databases of MEDLINE and EMBASE from inception to March 2019. We included published studies that compared the risk of mortality and prognosis between DTC patients with GD and those with non-GD. Data from each study were combined using the random-effects model.Results: Twenty-five studies from February 1988 to May 2018 were included (987 DTC patients with GD and 2,064 non-Graves DTC patients). The DTC patients with GD had a significantly higher risk of associated multifocality/multicentricity (odds ratio, 1.45; 95% confidence interval, 1.04 to 2.02; I², 6.5%; P =.381) and distant metastasis at the time of cancer diagnosis (odds ratio, 2.19; 95% confidence interval, 1.08 to 4.47; I², 0.0%; P =.497), but this was not associated with DTC-related mortality and recurrence/persistence during follow-up.Conclusion: Our meta-analysis demonstrates a statistically significant increased risk of multifocality/multicentricity and distant metastasis at the time of cancer diagnosis in DTC patients with GD than those without GD.Abbreviations: CI = confidence interval; DTC = differentiated thyroid carcinoma; GD = Graves disease; LN = lymph node; OR = odds ratio; PTC = papillary thyroid carcinoma; TC = thyroid carcinoma; TSAb = thyroid-stimulating antibody; TSH = thyroid-stimulating hormone     

Long-Term Outcomes of Radioiodine Therapy for Juvenile Graves Disease with Emphasis on Subsequently Detected Thyroid Nodules: A Single Institution Experience from Japan

Objective: To investigate the long-term outcomes of radioiodine therapy (RIT) for juvenile Graves disease (GD) and the ultrasonographic changes of the thyroid gland.Methods: All of 117 juvenile patients (25 males and 92 females, aged 10 to 18 [median 16] years) who had undergone RIT for GD at our clinic between 1999 and 2018 were retrospectively reviewed. Each RIT session was delivered on an outpatient basis. The maximum ¹³¹I dose per treatment was 13.0 mCi, and the total ¹³¹I dose per patient was 3.6 to 29.8 mCi (median, 13.0 mCi). ¹³¹I administration was performed once in 89 patients, twice in 26, and three times in 2 patients. Ultrasonography of the thyroid gland was regularly performed after RIT. The duration of follow-up after the initial RIT ranged from 4 to 226 (median 95) months.Results: At the latest follow-up more than 12 months after RIT (n = 111), the patients' thyroid functions were overt hypothyroidism (91%), subclinical hypothyroidism (2%), normal (5%), or subclinical hyperthyroidism (2%). New thyroid nodules were detected in 9 patients, 4 to 17 years after initial RIT. Patients with newly detected thyroid nodules underwent RIT with lower doses of ¹³¹I and had larger residual thyroid volumes than those without nodules. None of the patients were diagnosed with thyroid cancer or other malignancies during the follow-up period.Conclusion: Over a median follow-up period of 95 months (range, 4 to 226 months), RIT was found to be effective and safe in juvenile GD. However, cumulative evidence from further studies is required to confirm the long-term safety of RIT for juvenile GD.Abbreviations: ATD = antithyroid drug; GD = Graves disease; KI = potassium iodide; LT4 = levothyroxine; MMI = methimazole; PTU = propylthiouracil; RAIU = radio-active iodine uptake; RIT = radioiodine therapy; ^99mTc = technetium-99m; TSH = thyrotropin     

Long-Term Follow-up of Graves Orbitopathy After Treatment With Short- or Long-Term Methimazole or Radioactive Iodine

ObjectiveThe aim of this study was to compare long-term outcomes in terms of new onset or worsening of Graves orbitopathy (GO) in patients with Graves disease treated with different therapeutic modalities for hyperthyroidism.MethodsA total of 1163 patients with Graves disease were enrolled in this study; 263 patients were treated with radioiodine and 808 patients received methimazole (MMI) therapy for a median of 18 months, of whom 178 patients continued MMI for a total of 96 months (long-term methimazole [LT-MMI]). The thyroid hormonal status and GO were evaluated regularly for a median of 159 months since enrollment.ResultsThe rates of relapse, euthyroidism, and hypothyroidism at the end of follow-up were as follows: radioiodine treatment group: 16%, 22%, and 62%, respectively; short-term MMI group: 59%, 36%, and 5%, respectively; and LT-MMI group: 18%, 80%, and 2%, respectively. During the first 18 months of therapy, worsening of GO (11.5% vs 5.7%) and de novo development of GO (12.5% vs 9.8%) were significantly more frequent after radioiodine treatment (P <.004). Overall worsening and de novo development of GO from >18 to 234 months occurred in 26 (9.9%) patients in the radioiodine group and 8 (4.5%) patients in the LT-MMI group (P <.037). No case of worsening or new onset of GO was observed in patients treated with LT-MMI from >60 to 234 months of follow-up.ConclusionProgression and development of GO were associated more with radioiodine treatment than with MMI treatment; GO may appear de novo or worsen years after radioiodine treatment but not after LT-MMI therapy.     

Evaluación de la efectividad del tratamiento con glucocorticoides intravenosos en la oftalmopatía de Graves

ObjectiveTo assess the efficacy of intermittent, high-dose treatment with intravenous glucocorticoids (IV GCs) in moderate to severe Graves’ ophthalmopathy (GO).Materials and methodsPatients with GO treated with IV GCs from August 2007 to August 2011 at the Endocrinology Department of Reina Sofía Hospital were enrolled into the study. IV pulse prednisolone (7.5 mg/kg/day) was administered twice weekly every two weeks for 6 weeks, and at half the dose for 6 additional weeks.ResultsEighteen patients (mean age, 43+/-11 years) with moderate to severe GO were analyzed (83.3% females). Four were active smokers, five former smokers, and the rest had never smoked. Hyperthyroidism due to Graves’ disease was found in 66.7% of patients, 41.6% of whom had received radioiodine therapy. Response to treatment was satisfactory in 72.2%, partial in 11.1%, and poor in 16.7%. Mild side effects were reported by 5 patients. Before treatment, 83.3% had diplopia, 33.3% eyelid retraction, 72.2% eye pain, and 44.4% exophthalmos. After treatment, only 33.3% had diplopia (P = .004), 5.6% eyelid retraction (P = .063), 16.7% eye pain (P = .002), and 11.1% exophthalmos (P = .031). Response to treatment was not related to the underlying disease (P = .866), prior radioiodine treatment (P = .447), or smoking status (P = .368).ConclusionsIntravenous glucocorticoid therapy decreased activity in patients with moderate to severe active GO, with major improvement occurring in diplopia, eye pain, and exophthalmos. Side effects were mild and uncommon. Treatment response was independent from the underlying disease, prior radioiodine treatment, or smoking status.     

A 2017 Survey of the Clinical Practice Patterns in the Management of Relapsing Graves Disease

Objective: Previous surveys from different world regions have demonstrated variations in the clinical management of Graves disease (GD). We aimed to investigate the clinical approach to GD relapse among endocrinologists.Methods: Electronic questionnaires were e-mailed to all members of the Israeli Endocrine Society. Questionnaires included demographic data and different scenarios regarding treatment and follow-up of patients with GD relapse.Results: The response rate was 49.4% (98/198). For a young male with GD relapse, 68% would restart antithyroid drug (ATD) (98% methimazole), while 32% would refer to radioactive iodine (RAI) treatment. Endocrinologists who treat >10 thyroid patients a week tended to choose ATDs over RAI (P = .04). In the case of GD relapse with ophthalmopathy, 50% would continue ATDs, whereas 22.4% would recommend RAI treatment and 27.6% surgery. Most endocrinologists (56%) would continue ATDs for 12 to 24 months. Seventy-five percent would monitor complete blood count and liver function (39% for the first month and 36% for 6 months), and 44% would recommend a routine neck ultrasound. In a case of thyrotoxicosis due to a 3-cm hot nodule, most endocrinologists (70%) would refer to RAI ablation, 46.4% without and 23.7% with a previous fine-needle aspiration. No significant differences were found regarding gender, year of board certification, or work environment.Conclusion: Our survey demonstrates diverging patterns in the diagnosis and management of GD relapse that correlate well with previous surveys from other countries on GD-naïve patients and a less than optimal adherence to recently published clinical guidelines.Abbreviations: ATA = American Thyroid Association; ATD = antithyroid drug; CBC = complete blood count; GD = Graves disease; GO = Graves ophthalmopathy; LFT = liver function test; MMI = methimazole; PTU = propylthiouracil; RAI = radioactive iodine; TSI = thyroid-stimulating immunoglobulin     

A novel compound heterozygous variant Of SLC12A3 Gene in A Pedigree with Gitelman Syndrome Co-Existent with Thyroid Dysfunction

Objective: Gitelman syndrome (GS) is an autosomal recessive disorder characterized by salt wasting and hypokalemia resulting from mutations in the SLC12A3 (solute carrier family 12 member 3) gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. To date, more than 488 mutations of the SLC12A3 gene have been discovered in patients with GS. In this study, we reported a GS pedigree complicated by thyroid diseases or thyroid dysfunction.Methods: Sanger sequencing and next-generation sequencing analysis were performed to determine the SLC12A3 gene mutations in a GS pedigree including the 16-year old male patient with GS and his family members within 3 generations. Chemiluminescence immunoassays were used to detect thyroid hormone and antibody concentrations.Results: Genetic analysis of the SLC12A3 gene identified 2 mutations in the 16-year old male patient with GS concomitant with Graves disease (GD) and his younger sister accompanied by abnormal thyroid function. Additionally, one mutation site (c.1456G>A) in SLC12A3 gene was found in his father, paternal uncle and elder female cousin, who were complicated by subclinical hypothyroidism or autoantibody against thyroid. The other mutation site (c.2102_2107 delACAAGA) in SLC12A3 gene, a novel mutated variant of SLC12A3 gene, was carried by his mother and maternal grandfather.Conclusion: Two mutation sites were documented in the pedigree with GS, and one has not been reported before. Moreover, we found a mutation at nucleotide c.1456 G>A in the SLC12A3 gene that may affect thyroid function. However, further studies are needed to explore the underlying molecular mechanisms.Abbreviations: FT3 = free triiodothyronine; FT4 = free tetraiodothyronine; GD = Graves disease; GS = Gitelman syndrome; SLC12A3 = solute carrier family 12 member 3; TGAb = thyroglobulin antibody; TPOAb = thyroid peroxidase antibody; TSH = thyroid-stimulating hormone; TT3 = total triiodothyronine; TT4 = total tetraiodothyronine     

TSH Receptor Antibodies: Relevance & Utility

Objective: Antibodies (Abs) to the thyrotropin (TSH) receptor (TSH-R) play an important role in the pathogenesis of autoimmune thyroid disease (AITD). We define the complex terminology that has arisen to describe TSH-R-Abs, review the mechanisms of action of the various types of TSH-R-Abs, and discuss significant advances that have been made in the development of clinically useful TSH-RAb assays.Methods: Literature review and discussion.Results: TSH-R-Abs may mimic or block the action of TSH or be functionally neutral. Stimulating TSH-R-Abs are specific biomarkers for Graves disease (GD) and responsible for many of its clinical manifestations. TSH-R-Abs may also be found in patients with Hashimoto thyroiditis in whom they may contribute to the hypothyroidism of the disease. Measurement of TSH-R-Abs in general, and functional Abs in particular, is recommended for the rapid diagnosis of GD, differential diagnosis and management of patients with AITD, especially during pregnancy, and in AITD patients with extrathyroidal manifestations such as orbitopathy. Measurement of TSH-R-Abs can be done with either immunoassays that detect specific binding of Abs to the TSH-R or cell-based bioassays that also provide information on their functional activity and potency. Application of molecular cloning techniques has led to significant advances in methodology that have enabled the development of clinically useful bioassays. When ordering TSH-R-Ab, clinicians should be aware of the different tests available and how to interpret results based on which assay is performed. The availability of an international standard and continued improvement in bioassays will help promote their routine performance by clinical laboratories and provide the most clinically useful TSH-R-Ab results.Conclusion: Measurement of TSH-R-Abs in general, and functional (especially stimulating) Abs in particular, is recommended for the rapid diagnosis, differential diagnosis, and management of patients with Graves hyperthyroidism, related thyroid eye disease, during pregnancy, as well as in Hashimoto thyroiditis patients with extra-thyroidal manifestations and/or thyroid-binding inhibiting immunoglobulin positivity.Abbreviations: Ab = antibody; AITD = autoimmune thyroid disease; ATD = antithyroid drug; cAMP = cyclic adenosine 3′,5′-monophosphate; ELISA = enzyme-linked immunosorbent assay; GD = Graves disease; GO = Graves orbitopathy; HT = Hashimoto thyroiditis; MAb = monoclonal antibody; TBAb = thyrotropin receptor blocking antibody; TBII = thyroid-binding inhibiting immunoglobulin; TSAb = thyrotropin receptor–stimulating antibody; TSB-Ab or TRBAb = thyrotropin receptor–stimulating blocking antibody; TSH = thyrotropin; TSH-R = thyrotropin receptor     

Serum Selenium Levels in Patients With Graves Disease With or Without Thyroid Ophthalmopathy

BackgroundGraves disease is one of the most common autoimmune thyroid diseases. Thyroid has the highest concentration of selenium (Se) in the body. Se plays a crucial role in the functioning of some thyroid enzymes; however, there are controversial results regarding the administration of serum Se levels in patients with Graves disease.MethodsIn this study, patients with Graves disease with orbitopathy (GO group) or without orbitopathy (GD group) were recruited. Healthy individuals without a history of any disease were enrolled as the control group. Serum Se and thyroid hormone levels, including T3, T4, and thyroid-stimulating hormone (TSH), were measured using atomic absorption and radioimmunoassay techniques, respectively.ResultsIn this cross-sectional study, 60 and 56 patients and 58 healthy subjects were included in the GO, GD, and control groups. Serum Se levels in the GO, GD, and control groups were 94.53 ± 25.36 μg/dL, 96.82 ± 30.3 μg/dL, and 102.55 ± 16.53 μg/dL, respectively (P = .193). There was a reverse association between the serum Se level and thyroid hormones, including T3, T4, and TSH, in the GO group. However, serum Se levels exhibited a significant reverse association with T4 and TSH hormones but not with T3 in the GD group.ConclusionOur results showed no significant differences in the serum Se levels in the GO and GD groups compared with that in the control group. In addition, we did not detect any significant difference in the serum Se levels between the GO and GD groups.     

Thyroid Peroxidase Antibody Positivity is Associated With Relapse-Free Survival Following Antithyroid Drug Treatment for Graves Disease

Objective: Graves’ disease is an autoimmune disease characterized by production of autoantibodies directed against the thyroid gland. Thyrotropin-receptor antibodies (TRAbs) are clearly pathogenic, but the role of thyroidperoxidase antibodies (TPOAbs) in Graves disease is unknown.Methods: We retrospectively studied whether TPOAb positivity reduced risk of relapse following antithyroid drug (ATD) treatment in newly diagnosed Graves disease.Results: During follow-up of 204 patients with TRAb-positive Graves disease, 107 (52%) relapsed following withdrawal of ATD. Mean age was 40.0 years, and 82% were female. The average duration of ATD treatment was 23.5 months and was not different between patients who relapsed and those with sustained remission. Absence of TPOAbs significantly increased risk of Graves relapse (odds ratio, 2.21). Male sex and younger age were other factors significantly associated with increased risk of relapse.Conclusion: TPOAb positivity significantly improves the odds of remission following ATD treatment in newly diagnosed Graves’ disease.     

Increased Risk of Radioiodine Treatment Failure Associated with Graves Disease Refractory to Methimazole

Objective: Iodine 131 (I-131) radioactive iodine (RAI) therapy has been the preferred treatment for Graves disease in the United States; however, trends show a shift toward antithyroid drug (ATD) therapy as first-line therapy. Consequently, this would favor RAI as second-line therapy, presumably for ATD refractory disease. Outcomes of RAI treatment after first-line ATD therapy are unclear. The purpose of this study was to investigate treatment failure rates and potential risk factors for treatment failure, including ATD use prior to RAI treatment.Methods: A retrospective case control study of Graves disease patients (n = 200) after I-131 RAI therapy was conducted. Treatment failure was defined as recurrence or persistence of hyperthyroidism in the follow-up time after therapy (mean 2.3 years). Multivariable regression models were used to evaluate potential risk factors associated with treatment failure.Results: RAI treatment failure rate was 16.5%. A majority of patients (70.5%) used ATD prior to RAI therapy, predominantly methimazole (MMI) (91.9%), and approximately two-thirds of patients used MMI for >3 months prior to RAI therapy. Use of ATD prior to RAI therapy (P = .003) and higher 6-hour I-123 thyroid uptake prior to I-131 RAI therapy (P<.001) were associated with treatment failure. MMI use >3 months was also associated with treatment failure (P = .002).Conclusion: More patients may be presenting for RAI therapy after failing first-line ATD therapy. MMI use >3 months was associated with RAI treatment failure. Further studies are needed to investigate the association between long-term first-line ATD use and RAI treatment failure.     

Use of Methotrexate to Treat Isolated Graves Ophthalmopathy Developing Years After Thyroidectomy and Iodine 131 Treatment of Papillary Thyroid Cancer

ObjectiveTo describe a case of Graves ophthalmopathy developing years after subtotal thyroidectomy and radioactive iodine treatment of papillary thyroid cancer.MethodsWe present a case report including clinical and laboratory data. Current relevant literature is reviewed and summarized with regard to Graves ophthalmopathy.ResultsIn 2001, a 51-year-old woman presented with an asymptomatic thyroid nodule. Fine-needle aspiration biopsy results showed Hürthle cells, and the patient had a subtotal thyroidectomy in 2002. Stage 2 follicular variant of papillary thyroid carcinoma was diagnosed. She received radioactive iodine (I 131) therapy (94.8 mCi and 147.2 mCi) in 2003. Thyrotropin was suppressed with levothyroxine. The patient remained asymptomatic and had undetectable thyroglobulin antibodies. In 2007, her eyes became irritated (ie, erythematous, pruritic, watery). Thyroperoxidase and thyroglobulin antibodies were undetectable, but thyrotropin receptor antibody was elevated to 44% (reference range, < 16%). On physical examination, moderate periorbital edema and conjunctival injection were present; orbital magnetic resonance imaging was normal. Computed tomography of her orbits showed symmetric bilateral exophthalmos and prominence of orbital fat. Other ophthalmologic etiologies were ruled out by 2 independent ophthalmologists. She had minimal improvement with oral and intravenous steroids. Subsequent treatment with methotrexate resulted in marked symptomatic improvement and lowered the thyrotropin receptor antibody level to 24%.ConclusionsIsolated Graves ophthalmopathy in a patient after treatment of thyroid cancer and radioactive iodine ablation has not been previously reported. Methotrexate therapy may be a useful therapeutic approach in this setting. (Endocr Pract. 2008;14:422-425)     

HLA DQ2 Haplotype,Early Onset of Graves Disease,and Positive Family History of Autoimmune Disorders are Risk Factors for Developing Celiac Disease in Patients with Graves Disease

Objective: The diagnosis of celiac disease (CD) in patients with different autoimmune diseases including Graves disease (GD) remains a challenge. The aims of our study were to: (1) assess the prevalence of CD in Polish patients with GD and (2) evaluate the prevalence of CD in the subgroups of patients with GD divided on the basis of clinical and human leukocyte antigen (HLA) typing criteria.Methods: The prospective study was conducted at an academic referral center. The study groups consisted of consecutive, euthyroid patients with GD (n = 232) and healthy volunteers without autoimmune thyroid diseases (n = 122). The diagnosis of CD was based on elevated immunoglobulin A autoantibodies to the enzyme tissue transglutaminase (IgA-TTG) and small intestine biopsy findings.Results: CD was diagnosed in 8 patients with GD (3.4%) and 1 healthy volunteer (0.8%). The development of CD in patients with GD was strongly associated with HLA-DQ2 haplotype (as predicted from linkage disequilibria, 14.6% vs. 1.5%, P = .009; odds ratio [OR] = 11.3; 95% confidence interval [CI] 1.3–252.7): 6 patients with CD carried HLA-DRB1*03, 1 carried an HLA-DRB1*04 allele, and 1 had an HLA-DRB1*07/*11 genotype. Multivariate analysis showed independent associations between CD and early GD onset (P = .014, OR = 9.6), autoimmunity in family (P = .029, OR = 6.3) and gastroenterologic symptoms (P = .031, OR = 8.1).Conclusions: The results of our study suggest that serologic screening for CD may be considered in GD patients (1) with the HLA alleles typical for CD, (2) with an early onset of GD, or (3) a family history of autoimmunity. Moreover, the diagnosis of CD should be explored in euthyroid GD patients with nonspecific gastrointestinal symptoms.Abbreviations: AITD = autoimmune thyroid disease APS = autoimmune polyglandular syndromes CD = celiac disease CI = confidence interval GD = Graves disease GFD = gluten-free diet HLA = human leukocyte antigen IgA-TTG = immunoglobulin A autoantibodies to the enzyme tissue transglutaminase OR = odds ratio T1D = type 1 diabetes mellitus TBII = TSH-binding inhibitory immunoglobulins TSH = thyroid-stimulating hormone     

Rationale of treatment in Graves ophthalmopathy.

Graves ophthalmopathy is a chronic and multisystem disorder caused by an autoimmune process, characterized by the presence of antibodies that stimulate a general fibroblastic reaction (thyroid gland and lower extremities), and involves orbital fat tissue and muscles. The clinical findings and therapy for the treatment of the exophthalmos, such as changes in extrinsic eye motility, diplopia, optic nerve involvement, and lid retraction, were analyzed, and the various types of surgical treatment currently available for Graves ophthalmopathy were evaluated. The aim was to choose the best option to treat each case.The surgical techniques were transpalpebral decompression by removal of intraorbital fat, three-wall osseous expansion, and zygomatic osteotomy. Adjunctive procedures were lengthening of the levator muscle of the upper eyelid, lengthening of the retractor of the lower eyelid (if necessary), and surgery of the extrinsic muscles to correct diplopia. All these techniques were useful in treating the disease, which is characterized by chronic evolution and, at times, a "malignant" outcome. A total of 39 orbits were treated using different techniques of decompression and secondary adjunctive procedures. Results were analyzed after a minimum 6-month follow-up. It was evident that surgery greatly reduced the degree of exophthalmos and improved eye motility, diplopia, and visual acuity.Close cooperation among a team of specialists, including an endocrinologist, ophthalmologist, neuroradiologist, surgeon, anesthesiologist, and radiotherapist, is essential to manage and to quantify the postoperative results of this complex disorder.The authors' experience and application of different surgical strategies, as based on clinical data and histopathological classification, are presented.     

Risk Factors for Central Lymph Node Metastases in Patients with Papillary Thyroid Microcarcinoma

Objectives: Papillary thyroid carcinoma with a maximum tumor diameter no more than 10 mm is defined as papillary thyroid microcarcinoma (PTMC). The proportion of newly diagnosed PTMCs has increased significantly in recent years. Different guidelines have different comments about optimal management of PTMC, especially on prophylactic central lymph node (CLN) dissection. The aim of the present study was to analyze the risk factors for CLN metastases in patients with PTMC.Methods: A total of 4,389 patients underwent thyroid surgery at our center from January 2017 to March 2018, and 2,129 patients with PTMC were selected and assessed retrospectively. The relationship between CLN metastases and clinicopathologic features of PTMC were analyzed by both univariate and multivariate analyses.Results: Of the 2,129 patients with PTMC, CLN metastases were confirmed by pathology in 923 patients. Univariate and multivariate analyses found several independent factors associated with CLN metastases. They were male gender (odds ratio [OR], 1.694; 95% confidence interval [CI], 1.386 to 2.071; P<.001), younger age (<45 years) (OR, 2.687; 95% CI, 2.196 to 3.288; P<.001), larger tumor size (>5 mm) (OR, 2.168; 95% CI, 1.782 to 2.636; P<.001), positive CLN metastases via ultrasound (OR, 4.939; 95% CI, 3.534 to 6.902; P<.001), and multifocality (OR, 1.424; 95% CI, 1.176 to 1.724; P<.001).Conclusion: CLN metastases are common in PTMC patients. Male gender, younger age (<45 years), larger tumor size (>5 mm), positive CLN metastases via ultrasound, and multifocality are independent risk factors for CLN metastases. Our data should be considered in the decision-making process related to performing CLN dissection.Abbreviations: CLN = central lymph node; PTC = papillary thyroid carcinoma; PTMC = papillary thyroid microcarcinoma     

Quality of Life in Patients with Low-Risk Papillary Thyroid Microcarcinoma: Active Surveillance Versus Immediate Surgery

Objective: This study aimed to compare the quality of life (QoL) and psychological issues of patients with papillary thyroid microcarcinoma (PMC) who were under active surveillance (AS) and those who underwent immediate surgery (OP).Methods: This was a cross-sectional study conducted on 347 patients with low-risk PMC who were under AS (n = 298) or who underwent OP (n = 49). They were asked to complete two questionnaires (thyroid cancer–specific health-related QoL [THYCA-QoL] and the Hospital Anxiety and Depression Scale [HADS]). The results between the AS and OP groups were compared.Results: The mean ages of patients in the AS and OP groups were 58.6 ± 12.5 and 58.4 ± 13.1 years (P =.94), respectively, and the male ratios were 34/298 (11%) and 2/49 (4.1%) (P =.14), respectively. The median follow-up periods from diagnosis in the AS and OP groups were 56.5 months (interquartile range [IQR], 32 to 88 months) and 84 months (IQR, 64 to 130 months) (P<.001), respectively. In the THYCA-QoL questionnaire, the OP group had more complaints about “voice” (P<.001), “psychological” (P =.025), “problems with scar” (P<.001), and “gained weight” (P =.047) than the AS group. Other scales of the THYCA-QoL were comparable in the two groups. In the HADS questionnaire, the AS group had significantly better anxiety (P =.020), depression (P =.027), and total scores (P =.014) than the OP group.Conclusion: PMC patients in the OP group had more complaints and were more anxious and depressed than the AS group. These findings suggest that AS is a reasonable alternative to surgery for patients with low-risk PMC from the point of view of QoL and psychology.Abbreviations: AS = active surveillance; CI = confidence interval; HADS = Hospital Anxiety and Depression Scale; LT4 = levothyroxine; OP = immediate surgery; PMC = papillary microcarcinoma; PTC = papillary thyroid carcinoma; QoL = quality of life; STAI = State-Trait Anxiety Inventory; THYCA-QoL = thyroid cancer–specific health-related quality of life; TSH = thyrotropin     

Disease Presentation and Remission Rate in Graves Disease Treated With Antithyroid Drugs: is Gender Really A Factor?

Objective: Male gender is considered an adverse prognostic factor for remission of Graves disease treatment with antithyroid drugs (ATDs), although published data are conflicting. This often results in early consideration of radioiodine treatment and surgery for men. Our objective was to compare disease presentation and outcome in men versus women treated with ATDs.Methods: Retrospective study of 235 patients (64 men, 171 women) with Graves disease who were evaluated for features at presentation and outcome at the end of follow-up between 2010 and 2015.Results: Disease presentation was similar in men and women for age at diagnosis (41.4 ± 14 years vs. 40 ± 15 years), duration of follow-up (6.6 ± 7 years vs. 7.7 ± 6 years), rates of comorbid autoimmune diseases, and rate of Graves ophthalmopathy. Smoking was more prevalent in males (31% vs. 15%; P = .009). Free thyroxine and triiodothyronine levels were comparable. ATDs were first-line treatment in all males and in 168 of 171 females, for a median duration of 24 and 20 months, respectively (P = .55). Remission rates were 47% in men and 58% in women (P = .14). Males had fewer adverse events (9% vs. 18%) and treatment discontinuation (5% vs. 16%). Disease recurrence was comparable (14% vs. 20%; P = .32), as was requirement for second-line treatment, either radioiodine therapy or thyroidectomy.Conclusion: Graves disease presentation is similar in men and women. Men treated with ATDs have high remission rates and similar recurrence rates compared to women, with fewer adverse events and less discontinuation of treatment. ATDs are an attractive first-line treatment for both genders.Abbreviations: ATA = American Thyroid Association; ATD = antithyroid drug; GO = Graves ophthalmopathy; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone     

Serum Metabolomic Patterns in Patients with Autoimmune Thyroid Disease

Objective: Autoimmune thyroid disease, including Graves disease (GD) and Hashimoto thyroiditis (HT), is one of the most common endocrine diseases. GD and HT are the main etiologies for hyperthyroidism and hypothyroidism, respectively. This study aimed to provide a metabolomic analysis of GD patients with hyperthyroidism and HT patients with hypothyroidism.Methods: This study investigated serum metabolomics in 43 GD patients with hyperthyroidism, 45 HT patients with hypothyroidism, and 52 age- and sex-matched healthy controls. The metabolomic data were analyzed by performing multivariate statistical analysis.Results: The 186 metabolites including amino acids, bile acids, free fatty acids, and lipids were identified in all participants. Multivariate models indicated systematic differences in the hyperthyroidism, hypothyroidism, and control groups. Compared to healthy controls, the 22 metabolites in the hyperthyroidism group and the 17 metabolites in the hypothyroidism group were significantly changed. Pathway analysis showed that hyperthyroidism had a significant impact on arginine and proline metabolism and aminoacyl-transfer ribonucleic acid biosynthesis, while hypothyroidism had a significant impact on alanine, aspartate, and glutamate metabolism.Conclusion: The serum metabolomic pattern changes in patients with autoimmune thyroid dysfunction.Abbreviations: BMI = body mass index; CA = cholic acid; CDCA = chenodeoxycholic acid; DCA = deoxycholic acid; FBG = fasting plasma glucose; FINS = fasting plasma insulin; FT3 = free triiodothyronine; FT4 = free thyroxine; GD = Graves disease; GDCA = glycodeoxycholic acid; HDL-C = high-density lipoprotein cholesterol; HOMA-IR = homeostasis model assessment of insulin resistance; HT = Hashimoto thyroiditis; LDL-C = low-density lipoprotein cholesterol; PC = phosphatidylcholine; PCA = principal component analysis; PLS-DA = partial least squares discriminant analysis; SM = sphingomyelin; TBA = total bile acid; TC = total cholesterol; TG = triglyceride; TSH = thyrotropin; VIP = variable influences on projection