Management of Thyrotoxicosis: Preconception,Pregnancy, and the Postpartum Period

Objective: To review the diagnosis and management of thyrotoxicosis in women who are preconception, pregnant, and in the postpartum period.Methods: Literature review of English-language papers published between 1980 and 2018.Results: Overt thyrotoxicosis occurs in 0.2% of pregnancies and subclinical thyrotoxicosis in 2.5%. Hyperthyroidism in women of childbearing age most frequently is caused by Graves disease (GD). Gestational thyrotoxicosis, transient human chorionic gonadotropin (hCG)-mediated hyperthyroidism, may develop in the first trimester. In the first year following delivery, postpartum thyroiditis, which frequently includes a thyrotoxic phase, occurs in 5% of women. Hyperthyroidism from nodular autonomy is uncommon in women of childbearing age. It is essential to understand the underlying etiology for thyrotoxicosis in order to recommend appropriate treatment. Gestational thyrotoxicosis requires supportive care, without antithyroid drug therapy. GD may be treated with antithyroid drugs, radioactive iodine, or thyroidectomy. Pregnancy, plans for pregnancy, and lactation have important implications for the choice of GD treatment. When thyrotoxicosis presents following delivery, postpartum thyroiditis must be differentiated from GD.Conclusion: The diagnosis and management of thyrotoxicosis in the peripregnancy period present specific challenges. In making management decisions, it is essential to weigh the risks and benefits of treatments not just for the mother but also for the fetus and for breastfed infants. A team approach to management is critical, with close collaboration among endocrinologists, maternal-fetal medicine specialists, and neonatologists.Abbreviations: GD = Graves disease; hCG = human chorionic gonadotropin; MMI = methimazole; PPT = postpartum thyroiditis; PTU = propylthiouracil; T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globulin; TRAb = TSH receptor antibody; TSH = thyroid-stimulating hormone     

Positive Thyrotropin Receptor Antibodies in Patients with Transient Thyrotoxicosis

Objective: Thyrotropin (TSH) receptor antibody (TRAb) testing is considered accurate for the diagnosis of Graves disease (GD) and has been identified rarely in thyrotoxic patients without GD. We describe 4 patients with transient thyrotoxicosis and positive TRAb to highlight this clinical possibility.Methods: Patient demographics, symptoms, laboratory findings, and time to resolution of thyrotoxicosis are summarized. TRAb testing was performed by either a third-generation thyrotropin-binding inhibitory immunoglobulin (TBII) competitive-binding assay or a thyroid-stimulating immunoglobulin (TSI) bioassay from either Mayo Clinic Laboratory or Quest Diagnostics.Results: Four patients with transient thyrotoxicosis and positive TRAb testing were identified. Of these, three were female, and the median age was 44 years (range, 25 to 49 years). Median symptom duration at evaluation was 6.5 weeks (range, 3 to 12 weeks). No patient had any clinical manifestations unique to GD or exposure to biotin, thyroid hormone, supplements, iodine, or relevant medications. The TSH was <0.1 mIU/L in all patients. Three patients had a positive TSI, which was elevated less than twice the upper limit of the reference range in all cases, and 1 patient had a strongly positive TBII. None of the patients were treated with thionamides or radioactive iodine. Spontaneous resolution occurred in all patients at a median of 5.5 weeks (range, 2 to 14.4 weeks).Conclusion: These cases demonstrate that TSI or TBII may be present in thyrotoxic patients with transient thyrotoxicosis. For clinically stable patients presenting without pathognomonic evidence of GD, mildly elevated TRAb results may require cautious interpretation, and alterative diagnostic testing or close monitoring should be considered.Abbreviations: cAMP = cyclic adenosine monophosphate; FT4 = free thyroxine; GD = Graves disease; TBII = thyrotropin-binding inhibitory immunoglobulin (also known as TBI); TRAb = thyrotropin receptor antibody; TSH = thyrotropin; TSHR = thyrotropin receptor; TSI = thyroid-stimulating immunoglobulin; TT3 = total triiodothyronine; TT4 = total thyroxine     

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     

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     

Low Vitamin D Status is Associated with Increased Thyrotropin-Receptor Antibody Titer in Graves Disease

ObjectiveVitamin D deficiency is reportedly linked to a variety of autoimmune diseases. However, the relationship between thyroid autoimmunity in Graves disease (GD) and vitamin D deficiency is unclear. The goal of this study was to determine whether increased thyroid hormone autoantibody titer is associated with vitamin D deficiency in GD patients.MethodsA total of 70 patients with GD and 70 matched control subjects were recruited to our study. The levels of 25-hydroxyvitamin D (25[OH]D), calcium, parathyroid hormone (PTH), free triiodothyronine (FT₃), free thyroxine (FT₄), thyroid-stimulating hormone (TSH), thyrotropin-receptor antibody (TRAb), thyroid-peroxidase antibody (TPOAb), and thyroglobulin antibody (TGAb) in serum collected from these patients and controls were examined.ResultsThe level of 25(OH)D in serum from TRAb-positive GD patients was significantly lower than that in serum of healthy controls or TRAb-negative patients. However, compared with control subjects, the level of PTH in serum was increased in TRAb-positive GD patients. The rate of vitamin D deficiency (defined as serum 25[OH]D < 50 nmol/L) in TRAb-positive GD patients was significantly higher than in healthy controls or TRAb-negative GD patients. The level of 25(OH)D in serum was inversely correlated with TRAb titer in serum of TRAb-positive GD patients. However, our results did not show a correlation between 25(OH)D level and the levels of TPOAb, TGAb, FT₃, FT₄, or TSH.ConclusionLow vitamin D status is associated with increased TRAb titer in GD, suggesting a possible link between vitamin D status and increased thyroid autoim-munity in GD patients. (Endocr Pract. 2015;21:258-263)     

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.     

Serum Thyrotropin in Graves’ Disease: A More Reliable Index of Circulating Thyroid-Stimulating Immunoglobulin Level than Thyroid Function?

ObjectiveTo assess the relationship between serum thyrotropin (thyroid-stimulating hormone or TSH) on one hand and thyroid-stimulating immunoglobulin (TSI), free thyroxine (T₄), and triiodothyronine (T₃) levels on the other in Graves’ disease, inasmuch as TSH may be suppressed in the presence of TSI because TSI may bind to the TSH receptor on the thyroid gland membrane and thus eliminate the need for circulating TSH for stimulating the thyroid gland.MethodsWe determined serum TSI levels in 37 women and 13 men with Graves’ disease, stratified into 4 groups on the basis of serum TSH levels irrespective of serum free T₄ and T₃ levels. Our reference ranges were 0.72 to 1.74 ng/dL for free T₄, 80 to 200 ng/dL for T₃, and to 4.0 μU/mL for TSH.ResultsMean serum TSI concentrations were highest (215% ± 28%) in patients with undetectable TSH levels (< 0.03 μU/mL) and lowest (103% ± 9%) in those with supernormal TSH concentrations (> 4.0 μU/mL). TSI levels were intermediate in the other study groups: 157% ± 16% in patients with subnormal though detectable TSH levels (0.03 to 0.39 μU/mL) and 125% ± 12% in those with normal TSH levels (0.4 to 4.0 μU/mL). Moreover, a progressive decline in TSI levels with increasing serum TSH concentrations was noted, along with a significant negative correlation (r = -0.45; P < 0.01) between serum TSI and TSH concentrations. Finally, relationships between free T₄ and T₃ levels on one hand and TSI or TSH levels on the other were not significant, with a considerable variability in free T₄ and T₃ levels being noted in individual study groups.ConclusionSerum TSH is frequently suppressed after treatment with antithyroid drugs or radioiodine (¹³¹I), irrespective of clinical thyroid function as expressed by increased, normal, or decreased free T₄ and T₃ concentrations. In an individual patient with Graves’ disease, the serum TSH level may be more reflective of the circulating TSI concentration than is thyroid gland function as expressed by free T₄ and T₃ concentrations and therefore may be as reliable a predictor of remission as TSI. (Endocr Pract. 2007;13:615-619)     

Baseline TSH Level is Associated with Risk of Anti–PD-1–Induced Thyroid Dysfunction

Objective: To characterize anti–programmed cell death 1 (PD-1)–induced thyroid immune-related adverse events (irAEs) in metastatic melanoma patients treated at our institution and to identify risk factors associated with their development.Methods: We reviewed the files of 154 patients with metastatic melanoma treated with PD-1 inhibitors at a single institution from November 1, 2011, to February 28, 2017. The association of thyroid irAEs within 120 days posttreatment initiation with age, gender, melanoma characteristics, treatment protocol, and baseline thyroid-stimulating hormone (TSH) was examined.Results: Overall, 42.4% developed thyroid dysfunction following treatment, including 20.2% (20/99) subclinical thyroid dysfunction, 13.1% (13/99) overt hypothyroidism, and 9.1% (9/99) overt hyperthyroidism. Of those that developed overt hyperthyroidism, 8 progressed to overt hypothyroidism, consistent with thyroiditis. Age, gender, melanoma characteristics, or treatment protocol did not modify the risk of developing thyroid irAEs. Higher baseline TSH was observed in patients who developed overt hypothyroidism versus hyperthyroidism versus those who remained euthyroid (P = .05). A pretreatment TSH >2.19 mIU/mL was associated with an increased risk of overt thyroid dysfunction (odds ratio, 3.46; 95% confidence interval, 1.2 to 9.8).Conclusion: Thyroid dysfunction following treatment with PD-1 inhibitors is common, and patients with a higher baseline TSH appear to be at increased risk. Such patients may benefit from closer monitoring of their thyroid function following initiation of anti PD-1 agents.Abbreviations: CTLA-4 = cytotoxic T-lymphocyte antigen 4; FT3 = free triiodothyronine; FT4 = free thyroxine; irAE = immune-related adverse event; PD-1 = programmed cell death 1; TFT = thyroid function test; TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone     

The Association of Thyroid Hormones and Tsh with the Metabolic Syndrome in Euthyroid Taiwanese Individuals

Objective: There are conflicting studies in euthyroid males and females regarding associations between thyroidrelated hormones and parameters of the metabolic syndrome (MetS). We investigated the association between serum thyroid hormones and thyroid-stimulating hormone (TSH) concentrations and MetS in euthyroid men and women.Methods: Taiwanese subjects aged 20 to 65 years who had undergone a voluntary health examination at a preventive examination agency in Taipei were enrolled in this cross-sectional study. The definition of MetS was suggested by the Bureau of Health Promotion, Department of Health, Taiwan. Euthyroidism was defined as TSH and free thyroxine (FT4) levels within the normal reference ranges while not taking any thyroid medication. We conducted multiple logistic regression to identify the ability of serum triiodothyronine (T3), FT4, and TSH concentrations to identify the relative risk for the presence of MetS and components of the MetS in euthyroid Taiwanese individuals.Results: A total of 8,207 Taiwanese subjects (mean age: men, 45.3 ± 9.9 years; women, 43.5 ± 9.3 years) were enrolled in this study. A total of 1,672 subjects (20.4%) were defined as having MetS; these subjects had significantly higher (P<.0001) mean age (48.4 ± 9.1 years vs. 43.6 ± 10.7 years), prevalence of men (78.7% vs. 53.4%), and smoking (16.8% vs. 11.6%) than those without MetS. The median TSH, FT4, and T3 levels in all subjects were 1.70 mIU/L, 1.41 ng/dL, and 1.20 ng/mL, respectively. Higher T3 and lower FT4 values rather than TSH increased the odds ratio for MetS in men and women after adjusting for smoking and age, particularly for the association of T3 and MetS in women (uppermost quartile versus lowermost quartile: odds ratio, 2.4; 95% confidence interval, 1.6 to 3.5; P for trend <.0001).Conclusion: In euthyroid Taiwanese men and women, relatively high serum T3 concentrations was most strongly associated with the presence of the MetS; relatively low serum T4 was less strongly related, and serum TSH levels were not associated with the MetS. It is not known if the relationship of serum T3 and T4 to the MetS is causal.Abbreviations:BMI = body mass indexFT4 = free thyroxineMetS = metabolic syndromeOR = odds ratioT3 = triiodothyronineTSH = thyroid-stimulating hormoneWC = waist circumference     

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     

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.     

Thyroid And Aging

Objective: Review physiologic thyroid function changes with aging and emphasize careful interpretation of tests in the aging population.Methods: Literature review.Results: Using age-specific thyroid-stimulating hormone (TSH) reference ranges should minimize or avoid the unnecessary diagnosis of thyroid disease in elderly patients. Subclinical thyroid dysfunction and abnormal TSH with normal thyroid levels may improve with time, so careful monitoring of thyroid function is recommended. Overt thyroid disease should always be treated.Conclusion: Clinical judgement is always warranted to decide how and when to treat subclinical thyroid disease in the elderly.Abbreviations: FT4 = free thyroxine; rT3 = reverse triiodothyronine; T3 = triiodothyronine; T4 = thyroxine; TFT = thyroid function test; TSH = thyroid-stimulating hormone     

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     

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     

The Diagnostic Utility of Color Doppler Ultrasonography,TC -99 Pertechnetate Uptake,and TSH-Receptor Antibody for Differential Diagnosis of Graves’ Disease and Silent Thyroiditis:A Comparative Study

ObjectiveThe differential diagnosis of Graves disease (GD) and silent thyroiditis (ST) is important for the selection of appropriate treatment. To date, no study has compared the diagnostic utility of color Doppler ultrasonography (CDUSG), Tc-99m (technetium-99m) pertechnetate uptake, and thyroid-stimulating hormone (TSH)-receptor antibody (TRAb) for the differential diagnosis of these two conditions. In the present study, we compared the diagnostic utility of inferior thyroid artery (ITA) peak systolic and end diastolic velocities (PSV and EDV) measured by CDUSG, Tc-99m pertechnetate uptake, and TRAb for differential diagnosis of GD and ST.MethodsA total of 150 subjects with GD, 79 with ST, and 71 healthy euthyroid controls were included in the study. Diagnoses of GD and ST were made according to patient signs and symptoms, physical examination findings, the results of TRAb and Tc-99m pertechnetate uptake, and follow-up findings. All subjects underwent CDUSG for the quantitative measurement of ITA blood-flow velocities.ResultsThe mean ITA-PSV and EDV in patients with GD were significantly higher than in ST patients. In receiver operating characteristic analysis, the sensitivity/ specificity of the 30 and 13.2 cm/s cutoff values of the mean ITA-PSV and EDV for discrimination of GD from ST were 95.3/94.9% and 89.3/88.6%, respectively. The sensitivity/specificity of the 1.0 international unit (IU)/L and 3% cutoff values of the TRAb and Tc-99m pertechnetate uptake analyses were 93.0/91.0% and 90.7/89.9%, respectively.ConclusionThe measurement of ITA-PSV by CDUSG is a useful diagnostic tool and is a complementary method to the TRAb and Tc-99m pertechnetate uptake methods for differential diagnosis of GD and ST. (Endocr Pract. 2014;20:310-319)     

Radioactive Iodine Therapy Without Recent Antithyroid Drug Pretreatment For Hyperthyroidism Complicated By Severe Hyperbilirubinemia Due To Hepatic Dysfunction: Experience Of A Chinese Medical Center

Objective: The objective of this work is to report our experience with ¹³¹I therapy without recent antithyroid drug (ATD) pretreatment for refractory severe hyperthyroidism complicated by hyperbilirubinemia due to hepatic dysfunction.Methods: Five patients with refractory severe hyperthyroidism were treated with ¹³¹I at 90 to 120 μCi/g-thyroid (total activity, 6.2 to 10.1 mCi). The patients previously had received ATD treatment from 2 months to 12 years and discontinued ATDs from 2 months to 4 years before ¹³¹I treatment due to treatment failure or severe jaundice. Prior to ¹³¹I therapy, the patients were asked to take a low-iodine diet and were treated with bisoprolol fumarate, digoxin, furosemide, S-adenosylmethionine, polyene phosphatidylcholine, and plasma exchange as supportive treatment for related clinical conditions. Four of the patients also received lithium carbonate in conjunction with their ¹³¹I treatment. The patients were followed for 4 to 9 years after ¹³¹I therapy.Results: After ¹³¹I treatment, jaundice disappeared completely within 3 to 4 months in all patients, and liver function tests returned to normal. Concurrent atrial fibrillation and heart failure, leukopenia and thrombocytopenia, or thrombocytopenia and left cardiac enlargement improved remarkably in 3 patients during the follow-up period. Three to 45 months after ¹³¹I treatment, hypothyroidism was noted in the patients and they were treated with L-thyroxine replacement therapy.Conclusion:¹³¹I therapy without recent ATD pretreatment for refractory severe hyperthyroidism complicated by serious jaundice appears to be safe and effective, with good long-term results. It may be the preferred therapy for such patients and should be used as early as possible.Abbreviations:ATD = antithyroid drugFT₄ = free thyroxinePTU = propylthiouracilRAIU = radioactive iodine uptakeTSH = thyroid-stimulating hormone     

弥漫性毒性甲状腺肿患者血清高半胱氨酸蛋白61及Fractalkine水平的表达及其临床意义

摘要 目的：探讨弥漫性毒性甲状腺肿（GD）患者血清高半胱氨酸蛋白61（CYR61）、Fractalkine水平的表达及其临床意义。方法：选取2018年3月～2021年10月河北省邯郸市中心医院收治的57例GD患者作为研究组。另取同期健康体检者50例。采集所有受试者的静脉血,检测血清CYR61、Fractalkine水平,甲状腺功能及甲状腺自身抗体相关指标。采用Pearson检验分析GD患者血清CYR61、Fractalkine水平与甲状腺功能及甲状腺自身抗体相关指标的相关性。结果：研究组血清CYR61、Fractalkine水平均高于对照组,差异均有统计学意义（均P＜0.05）。研究组血清游离三碘甲腺原氨酸（FT3）、游离四碘甲腺原氨酸（FT4）均高于对照组,而促甲状腺激素（TSH）水平低于对照组,差异均有统计学意义（均P＜0.05）。研究组抗甲状腺球蛋白抗体（TGAb）、甲状腺过氧化物酶抗体（TPOAb）及促甲状腺激素受体抗体（TRAb）水平均高于对照组,差异均有统计学意义（均P＜0.05）。经Pearson相关性分析发现,GD患者血清CYR61、Fractalkine水平与FT3、FT4、TGAb、TPOAb、TRAb水平均呈正相关,而与血清TSH水平呈负相关（均P＜0.05）。结论：GD患者血清CYR61、Fractalkine水平异常高表达,且与患者甲状腺功能及甲状腺自身抗体有关。     

Effectiveness of Percutaneous Ethanol Injection in Nodular Diseases of the Thyroid Gland: 10-Year Follow-Up

Objective: Percutaneous ethanol injection (PEI) of thyroid cysts is not considered to be the standard of care in Kazakhstan, although thyroid nodules are highly prevalent. Patients with cystic nodules >3 cm typically undergo surgery with high rate of disability due to postsurgical hypothyroidism. Adoption of PEI as a standard of care will help reduce the number of unnecessary surgical interventions. The objective of this study was to assess effectiveness of PEI in patients with thyroid cysts and colloid nodules with 10 years of follow-up.Methods: A total of 257 patients were treated with PEI and have been followed for 10 ± 1.2 years. All patients had baseline labs (thyroid-stimulating hormone [TSH] and free thyroxine [FT4] levels) and ultrasonography prior to the procedure. The Short Form Health Survey (SF-36) assessing quality of life (QoL) was performed 12 months after the last PEI procedure.Results: At baseline, all patients had normal levels of FT4 and TSH that remained within normal limits throughout the follow-up period. Ultrasound evaluation performed over 3 months after PEI demonstrated significant volumetric reduction from 18.4 to 0.2 mL (P<.001) in cystic nodules and from 10.2 to 1.1 cm³ (P<.001) in colloid nodules. Patients who underwent the procedure had better SF-36 survey scores compared to their baseline QoL scores.Conclusion: PEI for cystic and colloid thyroid nodules could be considered as an effective and safe procedure. It enables up to a 100% reduction of nodule volume and has a low rate of adverse effects.Abbreviations: FT4 = free thyroxine; PEI = percutaneous ethanol injection; QoL = quality of life; SF-36 = Short Form Health Survey; TSH = thyroid-stimulating hormone; US = ultrasound; VRR = volume reduction rate     

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 &lsqb;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     

Maternal Thyroid-Stimulating Hormone Level in the First Trimester and Sex Ratio at Birth

Objective: Few studies have explored the influence of thyroid status on sex ratio at birth, and conclusions are inconsistent. The aim of this study was to determine if there is an association between serum thyroid-stimulating hormone (TSH) level in first trimester and sex ratio at birth.Methods: The study was a retrospective cohort study performed at a tertiary care center. From March 2014 to February 2017, a total of 4,822 women who had thyroid function testing during the first trimester were included. Study population was divided into five groups according to quintile of TSH level (≤0.60 mIU/L; 0.61 to 1.02 mIU/L; 1.03 to 1.44 mIU/L; 1.45 to 2.13 mIU/L; and ≥2.14 mIU/L). Logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of the percentage of male infants across the quintiles, with the lowest quintile as the reference category.Results: Median level of TSH was 1.27 mIU/L in women who delivered a boy, which was significantly higher than that in women who delivered a girl (1.15 mIU/L). After adjusting for age, gravidity, and parity, multivariate logistic analysis found that women in quintiles 3, 4, and 5 all showed significantly higher ORs for delivering a boy than those in quintile 1. In addition, after adjusting for age, gravidity, and parity, serum TSH was significantly associated with likelihood of having a boy (OR, 1.08; 95% CI, 1.03 to 1.13).Conclusion: Maternal TSH level in the first trimester is positively associated with the probability of delivering a male newborn.Abbreviations: CI = confidence interval; FT3 = free triiodothyronine; FT4 = free thyroxine; OR = odd ratio; SRB = sex ratio at birth; TBG = thyroxin-binding globulin; TSH = thyroid-stimulating hormone