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The role of TSH receptor antibodies in the management of Graves’ disease
Abstract
The central role of thyrotropin receptor antibodies (TRAbs) in the pathogenesis of Graves' disease has been recognised for several decades. However, the practical application of testing for TRAbs in clinical decision making remains the subject of controversy. The diagnosis of Graves' disease can be made in most cases simply based on a patient's clinical presentation. The TRAb test is therefore of most value in ambiguous clinical scenarios such as in the differential diagnosis of unilateral exophthalmos, euthyroid Graves' ophthalmopathy, subclinical hyperthyroidism, thyrotoxicosis associated with hyperemesis gravidarum, amiodarone-induced thyrotoxicosis and painless thyroiditis. It may also have a role in predicting the risk of a recurrence of Graves' disease following a course of antithyroid drug treatment. One further clinical utility of the TRAb test is in pregnancy where antibody titre measured during the third trimester is used to predict the risk of neonatal thyroid dysfunction. The TRAb titre not only aids in clinching a difficult diagnosis but can also help guide treatment in some patients. Although the TRAb assay has become more affordable in recent years, cost remains an important factor when considering its use routinely. Nonetheless, this is an underutilised blood test that could augment standard endocrine investigations in the differential diagnosis of hyperthyroidism.
... TSAbs dominate in GD hyperthyroidism. 7 TRAbs can be measured using two different molecular techniques: thyrotropin binding inhibiting immunoglobulin (TBII) assays and bioassays. In clinical practice, TRAb is measured using third generation TBII assays which detect TRAb inhibition of TSH binding to its receptor, and are non-invasive, inexpensive and commercially available. ...
... 8 They are unable to distinguish between stimulatory or inhibitory TRAb; however, this information can usually be deduced from clinical and biochemical tests. 7,9 Furthermore, the first immunoassay method declared to measure serum TSAb concentration has recently been successfully developed in an automated commercial platform with a sensitivity of 100% and specificity of 99%. 10 UK guidelines, which are over 10 years old, recommend the use of the TRAb test to determine the aetiology of clinically ambiguous cases of hyperthyroidism. 6 More recent American Thyroid Association (ATA) guidelines place greater emphasis on the use of TRAb, particularly in monitoring the course of Graves' disease, but similarly recommend that its place is in the diagnosis of GD in those patients whose aetiology of hyperthyroidism is unclear from their presentation and biochemistry. ...
... In the past, there has been controversy surrounding the value of a TRAb measurement in the initial clinical assessment of hyperthyroid patients. One reason for this apprehension was a lack of confidence in the early TBII assays 7,13 . The sensitivity and specificity of modern 3 rd generation TRAb assays has significantly improved. ...
Background: TSH receptor antibody (TRAb) is considered the gold standard diagnostic test for the autoimmunity of Graves' disease (GD), which is commonly diagnosed clinically.
Aim: To evaluate the true positive (sensitivity) and true negative (specificity) rates of clinical diagnosis of GD or non-GD hyperthyroidism compared to the TRAb test.
Setting: University teaching hospital in North West England Participants: Patients in the Endocrinology service who had a TRAb measurement between December 2009 and October 2015 Methods: Electronic patient records were studied retrospectively for a pre-TRAb clinical diagnosis of GD or non-GD hyperthyroidism. We examined descriptive statistics and binary classification tests; Fisher exact test was used to analyse contingency tables.
Results: We identified 316 patients with a mean age of 45 (range, 17 to 89) years; 247 (78%) were women. Compared to the TRAb result, clinical diagnosis had a sensitivity of 88%, specificity 66%, positive predictive value 72%, negative predictive value 84%, false negative rate 12%, false positive rate 34%, positive likelihood ratio 2.6 and negative likelihood ratio 0.2 (P < 0.0001).
Conclusions: Clinicians were liable to both over- and under-diagnose GD. The TRAb test can help reduce the number of incorrect or unknown diagnoses in the initial clinical assessment of patients presenting with hyperthyroidism.
... Thyroid hypervascularity in GD arises from increased inflammation and angiogenesis, driven by autoantibodies that stimulate the thyroid stimulating hormone (TSH) receptor (TRAb) [4,5]. Although TRAb concentration is clinically important and is indicative of GD severity [6], its association with operation outcomes remains unclear. ...
... As TRAb plays a major role in the pathophysiology of GD, it is strongly associated with disease severity and prognosis [6]. No study, however, has analyzed the association of TRAb with operative outcomes, except one study which reported that TRAb did not affect intraoperative blood loss in GD patients who underwent OT [1]. ...
Thyroidectomy in Graves’ disease can be challenging due to greater thyroid size and vascularity. While thyroid stimulating hormone receptor antibody (TRAb) level is associated with disease severity and thyroid vascularity, its impact on operative outcomes remains unclear. This study aimed to compare challenging factors for robotic thyroidectomy (RT) and open thyroidectomy (OT) in Graves’ disease patients, including TRAb as a predictive factor for difficult thyroidectomy. This retrospective study included Graves’ disease patients who underwent total thyroidectomy between September 2013 and January 2023. The clinical characteristics and operative outcomes were compared between patients who received OT and bilateral axillo-breast approach RT. Factors affecting operation time and estimated blood loss (EBL) were evaluated in both groups using regression analyses. A total of 85 patients received either OT (n = 48) or RT (n = 37). Median thyroid volumes in the OT and RT groups were 72.4 g and 57.6 g, respectively. Operation time was affected by thyroid volume in both groups. Additionally, higher thyroid hormone levels and bilateral central neck node dissection prolonged operation time in the RT group. EBL was marginally associated with thyroid volume in the OT group. However, in the RT group, TRAb level was independently associated with greater EBL (p = 0.04), while no significant association was found with thyroid volume. Predictive factors for difficult thyroidectomy differed by operation approaches. TRAb significantly predicted intraoperative bleeding in RT, while this association was absent in OT. Caution is warranted when performing RT on Graves’ disease patients with high TRAb levels.
... 2 Other common conditions causing hyperthyroidism include the passive release of thyroid hormones from damaged thyroid follicles; inflammation of the thyroid gland (thyroiditis), which may be autoimmune, post-viral, or drug-induced; and extrathyroidal sources of thyroid Methods hormone, most often iatrogenic or selfadministered. 2 Measurement of thyrotropin receptor antibodies (TRAb) plays a crucial role in the differential diagnosis of hyperthyroidism, which has important therapeutic and prognostic implications. 3,4 The autoimmune production of TRAb) is central to the pathogenesis of Graves' disease. 5 European clinicians and investigators advocate using TRAb as the primary test in the initial workup of hyperthyroidism. 1 The American Thyroid Association (ATA) and the American Association of Clinical Endocrinologists, in their joint guidelines, indicate a thyroid scan as the primary differential diagnostic test. ...
... However, TRAb measurements using modern 2nd-3rd generation receptor assays are increasingly more freely available, quickly done, and cheap (certainly in high volume laboratories). 3 They offer a greater advantage over TPOAb and thyroid scintigraphy in terms of higher sensitivity and specificity, logistical considerations, and cost savings. 18 Furthermore, newer automated 3rd-generation assays provide excellent sensitivity and specificity with high PPV and NPV in subjects with biochemical hyperthyroidism. ...
Background and objective: Sensitivity and specificity of clinical diagnosis of different hyperthyroid conditions were studied and compared with serum thyrotropin receptor antibodies test, as a standard test for diagnosing Graves' disease. This study aimed to assess the degree of sensitivity and specificity of clinical diagnosis of hyperthyroid conditions compared to the thyrotropin receptor antibodies test, which was selected as a standard test for diagnosis of Graves’ disease in the study. Methods: We studied patients presenting to endocrine outpatient clinics and other outpatient settings in Erbil city, presenting with clinical features of thyrotoxicosis. Serum or plasma thyroid-stimulating hormone, free T4, and thyrotropin receptor antibodies measurements were done for all the patients. Thyroid peroxidase antibodies and thyroid ultrasonography were done for most patients. Radioactive thyroid uptake was available for a limited number of patients. Sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, and accuracy index of clinical diagnosis of the thyrotoxicosis cases were calculated. Results: A total of 150 patients were included in our study, female 102, males 48, mean age 38 (range 16-78) years, pretest diagnosis of (Graves’ disease N=58, and non-Graves’ disease N=92 and posttest diagnosis of (Graves’ disease n= 59 vs. non-Graves’ disease=91). Sensitivity of 74.6%, specificity (84.60%), positive predictive value (75.9%), negative predictive value (83.7%), positive likelihood ratio (4.847), negative likelihood ratio (0.30), and accuracy index (80.7%) of the clinical diagnosis were estimated. Conclusion: The study showed that clinical diagnosis of Graves' disease and non-Graves’ disease disorders, using thorough clinical examination and primary essential investigations, has high sensitivity and specificity index. However, the serum thyrotropin receptor antibodies test remains the standard method in the differential diagnosis of Graves' disease. Other studies are needed to study ultrasound and scintigraphy compared to the thyrotropin receptor antibodies test.
... The modern TRAb assay has a sensitivity of over 97% and specificity of over 98% and indisputable superiority over clinical diagnosis [8]. It is effective for differentiating GD from other causes of thyrotoxicosis [9]. TRAbs are functionally heterogeneous; stimulating antibodies activate downstream effects resulting in thyrotoxicosis, blocking antibodies cause hypothyroidism, while neutral antibodies neither stimulate nor inhibit TSH receptor action [10]. ...
... All types of TRAbs can coexist in the same individual. The clinical and/or biochemical thyroid function status can usually indicate whether the predominant antibodies in question are of stimulating or inhibiting variety [9]. Intriguingly, alemtuzumab-induced GD exhibits spontaneous switching between hyperthyroidism and hypothyroidism, which can be bidirectional, more commonly than in GD presenting in the general population [11]. ...
Alemtuzumab, a humanized monoclonal antibody used as a disease-modifying treatment in relapsing-remitting multiple sclerosis (RRMS), frequently causes autoimmunity as its principal adverse effect. We describe a typical case of a young man treated with two courses of alemtuzumab presenting 18 months later with initial hyperthyroidism due to Graves' disease (GD) followed by persistent hypothyroidism. We discuss the pathophysiological role of stimulating and blocking thyrotropin receptor antibodies in the development of alemtuzumab-induced autoimmune thyroid dysfunction and clinical challenges posed by spontaneous, bidirectional switching between hyperthyroidism and hypothyroidism. Guidelines recommend monitoring thyroid function pre-treatment and every three months for four years following alemtuzumab treatment. Patient education is crucial for maintaining adherence to monitoring programs.
... When presentation is atypical (e.g. euthyroid ophthalmopathy) measurement of TRAb may be helpful [24]. Over 90% of Graves' disease has positive TRAbs. ...
... Using this assay TRAbs were detected in 97% of Graves' disease. It is helpful in the evaluation of possible Graves' disease without extra thyroidal features, unilateral exophthalmos or amiodarone thyrotoxicosis [24]. It has also been used to predict relapse after anti-thyroid therapy [49]. ...
... Thyrotrophin receptor antibody (TRAb) which stimulates and activates the TSH receptor (TSHR) plays an extremely important role in the occurrence and development of GD. The TRAb assay not only aids in diagnosis but also helps guide treatment in some patients (12). TRAb detection in GD became more sensitive with assay improvement in the last decades (13). ...
... Thyrotropin receptor antibodies (TRAbs) play an important role in Graves' disease. TRAb testing can be used to aid in the clinical diagnosis and to predict a recurrence of thyroid disease (12). Less is known about whether TRAb may be responsible for the hypothyroidism. ...
Context:
To analyze the dynamic changes of serum thyrotrophin receptor antibody (TRAb) and thyroid peroxidase antibody (TPOAb) in Graves' disease (GD) patients before and after radioactive iodine (RAI) treatment and to investigate if TRAb and TPOAb play a role in the occurrence of early hypothyroidism after 131I therapy for Graves' hyperthyroidism.
Subjects and methods:
A total of 240 patients newly diagnosed with GD were selected to study. A clinical and laboratory assessment was performed before and at 3, 6, and 12 months after 131I therapy. Chemiluminescent immunoassays were used to detect serum free triiodothyronine (FT3), free thyroxine (FT4), sensitive thyroid-stimulating hormone (TSH) and TPOAb concentration. Radio-receptor assay was used to measure serum TRAb concentration. According to the early onset of hypothyroidism in a year after RAI therapy, patients were divided into early hypothyroidism group (group A) and non-early hypothyroidism group (group B).
Results:
In both groups, serum TRAb and TPOAb increased at 3 months, reached the highest level at 6 months and returned to the baseline at 12 months after RAI therapy. TRAb showed a significant difference between the two groups at 6 months (P<0.01). Serum TPOAb in group A was higher than that in group B before and at 3, 6, 12 months after RAI therapy (P<0.05).
Conclusions:
Serum TRAb and TPOAb are closely related to the occurrence of the early hypothyroidism, and play an important role in judging prognosis after 131I treatment in Graves' disease.
... No statistically significant differences were found in the prevalence of IgM RF, ACPA or ANA between RA patients with positive thyroid antibodies (anti-TPO, anti-TG) and patients in whom no such antibodies were detected. The literature available focuses on the discussion of the recommendations for testing autoantibodies, such as RF, in patients with AITD, emphasizing the well-established increased prevalence of AITD, anti-TPO and anti-TG in patients with RA [29]. ANA antibodies, on the other hand, are specific to SLE, which is why it would be purposeful to study the potential correlations between ANA and anti-TPO or anti-TG in patients with SLE, the more so that some reports indicate the probable existence of higher comorbidity between SLE and AITD than between RA and AITD [29]. ...
... The literature available focuses on the discussion of the recommendations for testing autoantibodies, such as RF, in patients with AITD, emphasizing the well-established increased prevalence of AITD, anti-TPO and anti-TG in patients with RA [29]. ANA antibodies, on the other hand, are specific to SLE, which is why it would be purposeful to study the potential correlations between ANA and anti-TPO or anti-TG in patients with SLE, the more so that some reports indicate the probable existence of higher comorbidity between SLE and AITD than between RA and AITD [29]. A comparison of the presence of non-organ-specific antibodies in patients with RA and pSS shows that a fairly high percentage of pSS patients have IgM RF (43.3%). ...
Objectives
The aim of the study was to investigate the prevalence of selected organ-specific autoantibodies in rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS) patients, and discuss their clinical significance.
Material and methods
The study included 121 RA and 30 pSS patients. Sera were tested for the presence of autoantibodies to thyroid peroxidase (anti-TPO), thyroglobulin (anti-TG), TSH receptor (TRAbs), mitochondrial antigen M2 (AMA-M2-3E) and gliadin-analogous fusion peptides (anti-GAF(3X)) using the ELISA method. Non-organ-specific antibodies were determined: rheumatoid factor in IgM class, anti-citrullinated peptide antibodies and antinuclear antibodies. The occurrence of antibodies was also examined with regards to RA activity.
Results
The following autoantibodies were detected in RA patients: anti-TPO – 13 (10.7%), anti-TG – 6 (5%), AMA-M2-3E – 3 (2.5%), anti-GAF(3X) – 5 (4.1%). The respective levels of these autoantibodies in pSS patients were 3 (10%), 2 (6.7%), 4 (13.3%) and 2 (6.7%). Polyautoimmunity was confirmed in 34 RA patients (including 20 cases of autoimmune thyroid disease [AITD]) and in 6 pSS patients (6 cases of AITD). When RA patients were divided into anti-TPO positive and anti-TPO negative groups, we found a statistically significant relationship between groups regarding age and hemoglobin concentration. In pSS patients the anti-TPO positive group was less likely to use immunosuppressive drugs as compared with the anti-TPO negative group. Anti-TPO was significantly more frequently detected in RA + AITD vs. RA, RA + SS + AITD vs. RA and in pSS + AITD vs. pSS patients.
Conclusions
Organ-specific autoantibodies are relatively frequently observed in patients with RA and pSS. Their presence is connected with the clinical picture of the diseases.
... The TRAb titer is a cost-effective test in making the distinction between GD and subacute thyroiditis when the clinical presentation is ambiguous [15]. ...
Background: Differentiating Graves hyperthyroidism from the other causes of hyperthyroidism, using serum TRAb testing is essential step for diagnosis. Objectives: To study importance of TRAb in the diagnosis of Graves' disease, distinguishing it from thyroiditis, and comparing it with clinical features and other tests such as TPOAb, US thyroid and thyroid scintiscan. Methods: A cross-sectional study was conducted on 120 patients attending endocrine cli-nicErbil city. Patients were studied on clinical feature basis and investigated with serum TRAb, TPOAb, TSH, Free T4, and Ultrasound examination of thyroid gland. Fisher exact test and Chi Square test of independence, Correlation coefficient and t-test of independence were used. Results: Fifty-two patients were found to have Graves' disease; There was significant correlation between TRAb positivity and diagnosis of Graves' disease p < 0.05. There was also strong relation between presence of goiter, Orbitopathy and Ultrasound findings and TRAb positivity, p < 0.05. There was statistically significant difference between mean levels of TRAb and fT4 between Graves patients and Thyroiditis groups, while there was no statistically significant difference in TPOAb and TSH means between the two groups, p > 0.05. Conclusion: A positive correlation was found between TRAb titer and positivity and no significant relation between TPOAb levels between Graves' disease patients compared with thyroiditis patients, respectively.
... Pathogenesis also varies among diseases, including tissue inflammation caused by complex reactions of immune cells, such as self-reactive T cells and granulocytes, and/or diverse autoantibodies (auto-Abs). At the other end of the auto-Ab spectrum, organ dysfunction is caused by organspecific auto-Abs, such as in myasthenia gravis (Conti-Fine et al, 2006) and Graves' disease (Matthews & Syed, 2011). Thus, the mechanisms of development and progression of autoimmune diseases are better understood than ever, but the exact mechanisms triggering disease onset, namely, how self-reactive T cells or B cells producing auto-Abs are generated, remain unclear. ...
IgA nephropathy (IgAN) is caused by deposition of IgA in the glomerular mesangium. The mechanism of selective deposition and production of IgA is unclear; however, we recently identified the involvement of IgA autoantibodies. Here, we show that CBX3 is another self-antigen for IgA in gddY mice, a spontaneous IgAN model, and in IgAN patients. A recombinant antibody derived from gddY mice bound to CBX3 expressed on the mesangial cell surface in vitro and to glomeruli in vivo. An elemental diet and antibiotic treatment decreased the levels of autoantibodies and IgAN symptoms in gddY mice. Serum IgA and the recombinant antibody from gddY mice also bound to oral bacteria of the mice and binding was competed with CBX3. One species of oral bacteria was markedly decreased in elemental diet-fed gddY mice and induced anti-CBX3 antibody in normal mice upon immunization. These data suggest that particular oral bacteria generate immune responses to produce IgA that cross-reacts with mesangial cells to initiate IgAN.
... Такие реакции могут потенцировать действие некоторых лекарственных средств, оказывающих стимулирующее воздействие на рецепторный аппарат клеток, например молекулы NMDA, опосредуя непереносимость терапии. По этому механизму развиваются такие аутоиммунные осложнения, как тиреотоксикоз (болезнь Грейвса) [61] и синдром Кушинга [5]. В биоптатах обнаруживается гипертрофия паренхимы органов без клеточной инфильтрации и отложение депозитов из антител, но не компонентов комплемента. ...
The publication covers the world-known Gell and Coombs classification of immunopathological reactions, last revised, in the context of immunodeficiencies theory. A great attention is paid to the description of protective immune reactions, allergic and autoimmune complications, being developed according to one or another mechanism, defined in the classification. The strong and weak points of the classification were marked and the promising trends to carry out further scientific enquiry were emphasized. Primary immunodeficiencies were considered in detail as natural models of immunopathological complications. The problems of immunodiagnosis and immunotherapy were discussed.
... TR-Ab is heterogeneous and may either stimulate the TSH receptor (TS-Ab, TSH receptor stimulating antibody) or inhibit it (TB-Ab, TSH receptor blocking antibody), or it may have no impact at all. The predominant type in Graves' Disease hyperthyroidism is TS-Ab [10,11]. Abnormal serum thyrotropin (TSH) levels but normal serum-free thyroxine (fT4) and triiodothyronine (fT3) levels are indicative of subclinical thyroid disease [12,13]. ...
Abstract
Background
Thyroid dysfunction is the leading endocrine disorder worldwide. Iodine deficiency disorders, which were once the major etiology of thyroid dysfunctions, now have been succeeded by autoimmune thyroid diseases with the rise in aberrant salt ionization protocols. This study endeavors to access the level of thyroid autoantibodies viz. anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (TGA), and anti-thyroid stimulating hormone receptor (TRAb) in individuals with subnormal thyroid profiles.
Methods
This hospital-based cross-sectional study was conducted at the Department of Clinical Biochemistry, Tribhuvan University for a period of six months. Using non-probability (purposive) sampling method, a total of 60 patients were enrolled with subnormal thyroid profiles to include the population who have not yet started medication. Thyroid hormones (free T3, free T4, TSH) and thyroid antibodies (anti-TPO, TGA, and TRAb) were measured. For non-parametric data, Chi-square test and Kruskal-Wallis test were used. Spearman’s correlation was done to determine the association between variables.
Results
Out of 60 participants, the majority of the population between 25 and 44 years were diagnosed with thyroid dysfunction with female preponderance. Among all, 40% (n = 24) had subclinical hyperthyroid states while, 60% (n = 36) had subclinical hypothyroid states, and 75% (n = 45) of the total exhibited positive thyroid antibodies. In subclinical hypothyroid patients with TSH above 10 µIU/ml, anti TPO (58.5%) and TGA (66.7%) positivity were highly prevalent. On the other hand, TRAb was exclusively positive in hyperthyroid condition (50% among the group) which is by far the first of its kind reported in Nepal.
Conclusion
The rise in autoimmune thyroid disease among the Nepalese population infers that addressing iodine deficiency simply through salt iodinization may not be adequate to deal with the rising burden of thyroid disorders, especially in iodine-depleted areas. Also, the increasing prevalence of thyroid autoantibodies positivity in subclinical hypothyroidism in the Nepalese population accounts for the arduous screening and monitoring of autoimmune thyroid disorders in Nepal.
... Graves' disease (GD) pathogenesis is related to autoimmune production for antibodies of TSH receptor (TRAbs). However, TRAbs are diverse and might have either an inhibitory effect (TSH-receptors blocking antibody-TBAb) or a stimulating effect (TSH receptor stimulating antibody-TSAb) which is the most frequent case in GD and finally a neutral effect on the TSH-receptors and that's one is rare (Matthews and Syed 2011). ...
Thyroid autoimmune disease is one of the most common disorders which are generally associated with existence of anti-thyroid peroxidase (TPO) in addition to ant thyroid stimulating hormone receptor (TSHR) antibodies, and anti-thyroglobulin (Tg). The present study was a cross-sectional one, conducted on (200) patients selected randomly from cases already diagnosed with thyroid disorder diseases by a specialized endocrinology center in AL-Basra city / Iraq. Where TPO test was performed for 127 of them, and TRAB test was conducted for the remaining 73 patients. The study showed that 74% of the cases that had a TPO test were positive, and 49% of the cases that had a TRAB test were also positive. The study also showed that the percentage of people with hypothyroidism was higher in those who had positive TPO results, in contrast to those who had positive TRAB results, where hyperthyroidism was the dominant disease.
... Такие реакции могут потенцировать действие некоторых лекарственных средств, оказывающих стимулирующее воздействие на рецепторный аппарат клеток, например молекулы NMDA, опосредуя непереносимость терапии. По этому механизму развиваются такие аутоиммунные осложнения, как тиреотоксикоз (болезнь Грейвса) [61] и синдром Кушинга [5]. В биоптатах обнаруживается гипертрофия паренхимы органов без клеточной инфильтрации и отложение депозитов из антител, но не компонентов комплемента. ...
THE PREPARATION OF PEDIATRICS IN DIFFERENT COUNTRIES OF THE WORLD V. G. Maidannyk, V. V. Zagorodnii (Kiev) Department of Pedіatrіcs N 4 A. Bohomolets National Medical University The authors carried out the analysis of training system of doctors-pediatrists in the different countries of Europe and USA. It is shown, that exists three models of the organization of rendering of medical care of children: pediatric model (the doctor-pediatrist as a primary part of rendering of medical care of children), system of the general practice (the doctor-pediatrist carries out functions of the adviser) and the combined system which is based on the listed above models. Pointed that the system of the general practice is inherent in the countries with a high level of incomes on one inhabitant of the country.
... Patients may have a small diffuse goiter with painless thyroiditis, like those with GD. However, it is very unlikely that thyrotoxicosis due to painless thyroiditis will last longer than two months [70]. ...
Graves’ disease is an autoimmune disorder in which hyperthyroidism (over active thyroid) is caused by the autoantibodies against the TSH receptor. It is mainly characterized by the appearance of goiter. The symptoms are wide ranging as thyroid hormone affects many body systems. It is common in women and in people with age below than 40. Graves’ disease is caused by a combination of genetic and environmental factors while genetics being the main cause. Graves’ disease is not a single gene defect but has a complex pattern of inheritance. Today it is clear that genetic predisposition to Graves’ disease is caused by multiple genes. HLA gene is one the most studied gene predisposing to Graves’ disease. Lot of polymorphisms in this gene has been to be associated with the disease. Lymphoid tyrosine phosphatase encoded by the gene PTPN22 has been found to increase the risk of many autoimmune diseases including Graves’ disease. The best documented association of PTPN22 variants to autoimmune disorders including GD is rs2476601 (C1858T). Other genes associated with the risk of GD are thyrotropin receptor (TSHR), thyroglobulin gene, FCRL3, SCGB3A2, and CTLA4. This chapter will discuss in detail the genetics, pathophysiology, diagnosis and treatment of Graves’ hyperthyroidism.
... Approximately 10% of the general population suffers from autoimmune thyroid diseases (AITDs), and at least 2-3% of pregnant women are affected by thyroid dysfunction worldwide. 1 When women become pregnant, they undergo many physiological changes and may face diseases, influencing the health of both the mother and foetus. The associations among antithyroid antibodies, thyroid diseases, and pregnancy have garnered increasing attention. ...
Background:
Immunosuppression occurs during pregnancy, and the antithyroid antibody titre drops, rebounding after delivery. We aimed to determine variations in antithyroid antibody titres during pregnancy and after delivery.
Methods:
This retrospective study was conducted in a single centre. Antibody titres of 142 patients were measured to assess variations in the levels of thyroid-stimulating hormone receptor antibodies (TRAbs), thyroid peroxidase antibodies (TPOAbs), and thyroid globulin antibodies (TgAbs). We compared the titres of each antibody between adjacent time periods (eg, first trimester (T1) vs second trimester (T2), T2 vs third trimester (T3), T3 vs the postpartum period (PP)) by paired t-test or the Wilcoxon test. Then, we analysed data from patients with complete laboratory examination results in all four periods with the Friedman test, performing comparisons among groups.
Results:
In the TgAb group, significant differences existed between T1 and T2 and between T2 and T3 in the LT4 subgroup and between T1 and T2 in the no-medication subgroup. In the TRAb group, significant differences existed between T1 and T2 in the LT4 subgroup. In the TPOAb group, significant differences existed among each group in the LT4 subgroup, and there were significant differences between T1 and T2 and between T2 and T3 in the no-medication subgroup. The Friedman test showed that the P-values were 0.013 and 0.004 in the LT4 and no-medication subgroups of the TgAb group, respectively; 0.122 in the LT4 subgroup of the TRAb group; and <0.001 and 0.272 in the LT4 and no-medication subgroups of the TPOAb group, respectively. In the LT4 subgroup of the TgAb group, the P-values for comparisons of time periods were 0.602 between T1 and T2, 0.602 between T2 and T3, 0.006 between T1 and T3, and 0.602 between T3 and PP. In the no-medication subgroup of the TgAb group, the P-values were 0.078 between T1 and T2, 1.000 between T2 and T3, 0.011 between T1 and T3, and 0.078 between T3 and PP. In the LT4 subgroup of the TPOAb group, the P-values were 0.09 between T1 and T2, 0.014 between T2 and T3, <0.001 between T1 and T3, and 0.772 between T3 and PP.
Conclusion:
We can conclude that the TgAb and TPOAb titres dropped during pregnancy.
... Our practice preference in Cyprus is also to perform both thyroid sonography and TRAb, in that sequence, invariably in all patients presenting with hyperthyroidism. It is worth mentioning the better diagnostic performance of TRAb vs. the clinical assessment of hyperthyroidism, as well as the fact that a negative TRAb does not distinguish among other aetiologies and may, on occasion, be seen in very mild GD (1,10,31). ...
In this mini-review, we examine the utilization of thyroid sonography as a ‘point-of-care’ tool for assessing and managing patients with (suspected) hyperthyroidism who present to the endocrine outpatients. Thyroid USS may aid the distinction between hyperthyroidism and destructive thyroiditis. Presence of intense vascularity (‘thyroid inferno’) on power Doppler has a very high positive predictive in identifying hyperthyroidism. It may also allow the sub-classification of hyperthyroidism into autoimmune and nodular hyperthyroidism. The presence of thyroid nodules is important to acknowledge at an early stage as this may affect management. Not only toxic nodules are managed with definitive treatment, but the presence of nodules is important to be clarified in Graves’ disease because of the evidence of an increased risk of malignancy and, possibly, more aggressive behaviour if malignant disease is confirmed. Current guidelines on hyperthyroidism do not clearly state thyroid sonography as a first line investigation although recent authoritative reviews point in that direction. Given the aforementioned benefits of thyroid sonography, alongside the reduced costs and widespread availability of high-resolution (including portable) ultrasound devices, there is an argument for thyroid sonography to be applied as a first line investigation for all patients with hyperthyroidism. More precisely, formally trained endocrinologists could perform thyroid sonography as an extension of their clinical examination when patients first present with hyperthyroidism in the endocrine clinic.
... Therefore, they thought pregnancy might depress TSAbs; but once the effect was not sufficient, the influence of the abnormal elevation of TSAbs on the neonate's thyroid could not be avoided [110]. Researchers have proposed measuring TRAb levels during the third trimester of pregnancy to predict the risk of neonatal thyroid dysfunction [111]. ...
Antithyroid antibodies, which include thyroid-stimulating hormone receptor antibodies (TRAbs), thyroid peroxidase antibodies (TPOAbs), and thyroid globulin antibodies (TgAbs), are widely known for their tight association with thyroid autoimmune diseases. The variation in all three kinds of antibodies also showed different trends during and after pregnancy (Weetman, 2010). This article reviewed the the physiological changes, while focusing on the variation of thyroid antibodies concentration in women during and after pregnancy, and adverse consequences related to their elevation. Since abnormal elevations of these antithyroid antibodies may lead to adverse outcomes in both mothers and fetuses, special attention must be paid to the titer of the antibodies during pregnancy. The molecular mechanisms of the variations in those antibodies have yet to be explained. The frequency and timing of thyroid antibody measurement, as well as different reference levels, also remain to be elucidated.
... The TRAb titer is a cost-effective test in making the distinction between GD and subacute thyroiditis when the clinical presentation is ambiguous [15]. ...
... Approximately 10% of the general population suffers from the autoimmune thyroid diseases (ATD) and at least 2-3% of pregnant women are affected by thyroid dysfunction across the world [1]. It is widely known that adverse pregnancy outcomes are associated with thyroid function disturbances in pregnancy [2]. ...
Background: Thyroid autoantibody has been associated with adverse pregnancy outcomes. However, thyroid-receptor antibody (TRAb) has not been considered as a potential risk assessment indicator for adverse pregnancy outcomes. Therefore, we assessed the role of TRAb in evaluation of the risk of adverse pregnancy outcomes. Methods: Pregnant women residing in Chongqing were enrolled in the study from 2012 to 2014. The TRAb, thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) of all patients were analyzed via electrochemiluminescence assays. All data were recorded and analyzed statistically using SPSS. Results: A total of 468 pregnant women were included in the analysis. TRAb levels were higher in women with adverse pregnancy outcomes than those in women without adverse pregnancy outcomes. The incidence rate of pregnancy loss was significantly higher in the TRAb-positive group than that in the negative group, but this difference was not found in preterm delivery and early preterm delivery. In the logistic regression model, TRAb was an independent risk factor for pregnancy loss, but not for preterm delivery and early preterm delivery. The optimal cutoff point for TRAb was 3.53 IU/L, and the sensitivity and specificity of TRAb to assess the risk of pregnancy loss are 83.5% and 85.3%, respectively. Receiver-operating characteristic (ROC) curves revealed that TRAb was superior to the combination of TSH, FT4 and FT3 as an indicator for assessment. Conclusions: TRAb as a more sensitive indicator providing valuable detection to assess the potential risk of pregnancy loss, and it can be used as an effective tool to improve the clinical management of thyroid disease in pregnant women.
... The detection of thyroid-stimulating hormone-receptor (TSH-Receptor) antibodies (TSH-R-Abs) may confirm the autoimmunity and the diagnosis of TAO. But these antibodies are not present in all cases [19,22,23]. ...
Background
Thyroid-associated orbitopathy (TAO) is the most common autoimmune disease of the orbit. It occurs more often in patients presenting with hyperthyroidism, characteristic of Graves' disease, but may be associated with hypothyroidism or euthyroidism. The diagnosis of TAO is based on clinical orbital features, radiological criteria, and the potential association with thyroid disease. To date, there is no specific marker of the orbital disease, making the early diagnosis difficult, especially if the orbital involvement precedes the thyroid dysfunction.
Summary
The goal of this review is to present the disease and combine the available data in the literature concerning investigation of TAO biomarkers.
Conclusions
Despite the progress done in the understanding of TAO disease, some important pieces are still missing. Typically, for the future, major efforts have to be done in the discovery of new biomarkers, validation of the suspected candidates on multicenter cohorts with standardized methodologies, and establishment of their clinical performances on the specific clinical application fields in order to improve not only the management of the TAO patients but also the therapeutic options and follow-up.
... It is thought that HG appears to occur as a complex interaction between biological, psychological, and sociocultural factors and severe form of HG may carry allot of maternal and fetal complication including weight loss, dehydration, metabolic ketoacidosis, anemia and peripheral neuropathies, Wernicke's encephalopathy, intrauterine growth retardation and fetal death. (6), (7), (8) A cholecystokinin (CCK) is a hormone released from endocrine cells that line the mucosa of the upper small intestine in response to the amino acid and fatty acid in the chyme. It's a major hormone of the gastrointestinal tract that is responsible for gallbladder contraction and pancreatic enzyme secretion. ...
Background: Cholecystokinin is a gastrointestinal tract hormone synthesized and released from the upper part of small intestine and central
nervous system.
Objective: To assess the cholecystokinin level in pregnancy with and without hyperemesis gravidarum and correlate it with the severity of
condition.
Patients and methods: A case-control study conducted at AL-Yarmouk Hospital from March-November 2015. Sixty pregnant women were
included, thirty with hyperemesis gravidarum and thirty pregnant women with normal pregnancy. For both groups, cholecystokinin level was
measured with other hematological, biochemical, and hormonal parameters. The patient's group was classified according to the severity into
mild, moderate, and severe according to classification posted by HER foundation.
Results: The mean level of cholecystokinin for the hyperemesis gravidarum group was significantly lower than control group (p< 0.001).
Blood urea nitrogen and free thyroxin were significantly higher, while sodium, potassium, and thyroid stimulating hormone levels were
significantly lower in comparison to control group. Twenty women with moderate hyperemesis gravidarum and ten with severe condition. The
cholecystokinin was significantly lower in the severe cases vs. moderate cases (28.7 ± 11vs. 39.8 ± 13.9; P=0.036). The β-HCG is significantly
higher in patients with severe cases than moderate cases.
Conclusion: serum cholecystokinin level was significantly reduced in hyperemesis gravidarum in comparison to the healthy pregnant women.
This reduction is inversely correlated with the severity of the condition. This relationship with the severity triggers studies to evaluate the role
of cholecystokinin as a marker of severity of hyperemesis gravidarum rather than a causal relationship.
... The etiology of HG is most likely to be multifactorial. Women with HG are more likely to be younger, primiparous and with Female infant sex while Body mass index, smoking, socioeconomic status and Paternal genes didn't not affect the occurrence of HG [5]. ...
... The etiology of HG is most likely to be multifactorial. Women with HG are more likely to be younger, primiparous and with female infant sex while body mass index, smoking, socioeconomic status and paternal genes didn't not affect the occurrence of HG [5]. ...
Background: One of the serious problems affecting pregnant females is Hyperemesis gravidarum. Different theories were suggested. But the main etiology is still unknown. Objectives: To determine the incidence of Helicobacter pylori infection in cases of Hyperemesis gravidarum. Patients and methods: Case control study of 80 cases (40 cases of Hyperemesis gravidarum (HEG) and 40 cases of normal pregnant females). Determination of Helicobacter pylori antibodies was done in serum and stool for the two studied groups. Results: 75% of cases of HEG were positive of Helicobacter pylori in stool samples and 37.50% of normal pregnant females. These results were statistically significant (P = 0.001). The prevalence of HpIgG AB and HpSAB was 77.5% in the patients group with HEG, and 55.0% in control studied group (P = 0.05). There was a significant difference between HEG cases and normal pregnancy as regards serum sodium (0.042). Conclusions: Infection by Helicobacter pylori may be one of the risk factors for HEG. Helicobacter pylori AB in both serum and stool is higher in HEG cases than in normal pregnant females.
... B12 (Cobalamin) deficiency d. Metabolic imbalances such as metabolic ketoacidosis [10] or thyrotoxicosis [11] e. Physical and emotional stress of pregnancy on the body f. Difficulty with activities of daily living g. ...
... In women with hyperemesis gravidarum and clinical features of hyperthyroidism, TFTs and TRAbs should be measured. TRAbs have high sensitivity and specificity for the diagnosis of Graves' disease [72,92]. ...
... In women with hyperemesis gravidarum and clinical features of hyperthyroidism, TFTs and TRAbs should be measured. TRAbs have high sensitivity and specificity for the diagnosis of Graves' disease [72,92]. ...
Thyroid dysfunction is the commonest endocrine disorder in pregnancy apart from diabetes. Thyroid hormones are essential for fetal brain development in the embryonic phase. Maternal thyroid dysfunction during pregnancy may have significant adverse maternal and fetal outcomes such as preterm delivery, preeclampsia, miscarriage and low birth weight. In this review we discuss the effect of thyroid disease on pregnancy and the current evidence on the management of different thyroid conditions in pregnancy and postpartum to improve fetal and neonatal outcomes, with special reference to existing guidelines on the topic which we dissect, critique and compare with each other.
Overt hypothyroidism and hyperthyroidism should be treated appropriately in pregnancy, aiming to maintain euthyroidism. Subclinical hypothyroidism is often pragmatically treated with levothyroxine, although it has not been definitively proven whether this alters maternal or fetal outcomes. Subclinical hyperthyroidism does not usually require treatment and the possibility of non-thyroidal illness or gestational thyrotoxicosis should be considered.
Autoimmune thyroid diseases tend to improve during pregnancy but commonly flare-up or emerge in the post-partum period. Accordingly, thyroid auto-antibodies tend to decrease with pregnancy progression.
Postpartum thyroiditis should be managed based on the clinical symptoms rather than abnormal biochemical results.
... 4 When hyperemesis gravidarum is severe or inadequately treated, it may result in the following: loss of 5% or more of pre-pregnancy body weight. 2 Dehydration, causing ketosis, metabolic imbalances such as metabolic ketoacidosis or thyrotoxicosis. 2, 4,5 Helicobacter pylori, previously Campylobacter pylori, is a Gram-negative, microaerophilic bacterium found in the stomach, and may be present in other parts of the body, such as the eye. 6,7 Nashaat et al suggested that chronic infection with Helicobacter pylori may a role in hyperemesis gravidarum. ...
... Persistently high levels of maternal serum TRAb have been associated with fetal hyperthyroidism [52]. Therefore, it is recommended that the TRAb test be performed by 24 to 28 weeks of gestation to predict the risk of fetal thyroid dysfunction [53]. Fetal thyroid assessment by ultrasound is recommended in women with uncontrolled hyperthyroidism or high TRAb titers. ...
Thyroid dysfunction during pregnancy can result in serious complications for both the mother and infant; however, these complications can be prevented by optimal treatment of maternal overt thyroid dysfunction. Although several studies have demonstrated that maternal subclinical hypothyroidism is associated with obstetric complications and neurocognitive impairments in offspring, there is limited evidence that levothyroxine treatment can improve these complications. Therefore, most professional societies do not recommend universal screening for thyroid dysfunction during pregnancy, and instead recommend a case-finding approach in which only high-risk women are tested. However, recent studies have estimated that targeted thyroid function testing misses approximately 30% to 55% of hypothyroidism cases in pregnant women, and some associations and researchers have recommended universal screening of pregnant women to facilitate the early detection and treatment of overt hypothyroidism. This review summarizes recent data on thyroid function test changes, thyroid functional disorder management, and thyroid screening during pregnancy.
... When untreated, hyperthyroidism in Graves disease might be a life-threatening condition. 2,3 Stimulating thyrotropin (TSH) receptor antibodies (TRAb) clearly, but not 100% accurately, differentiate between hyperthyroid postpartum thyroiditis and Graves disease [3][4][5] and are therefore highly recommended to be used for this purpose. 6 Other possibilities for differentiation between the conditions are thyroid scintigraphy, which shows reduced uptake of radiopharmaceuticals in hyperthyroid postpartum thyroiditis and increased uptake in Graves disease, 3 the time of disease occurrence after delivery, which was reported to be shorter in postpartum thyroiditis than in Graves disease, and the ratio between free triiodothyronine (T 3 ) and free thyroxine (T 4 ), which was found to be lower in hyperthyroid postpartum thyroiditis than in Graves disease. ...
Objectives:
To evaluate the diagnostic value of spectral Doppler sonography in women with thyroid dysfunction during the first postpartum year.
Methods:
This prospective observational clinical study included 83 consecutive untreated women: 32 with hyperthyroid postpartum thyroiditis, 32 with hypothyroid postpartum thyroiditis, and 19 with Graves disease, which first appeared within 12 months after delivery. Thyrotropin, free thyroid hormones, thyroid peroxidase antibodies, thyroglobulin antibodies, and thyrotropin receptor antibodies were measured. With a 7.5-MHz linear transducer, we measured the thyroid volume and peak systolic velocity (PSV) at the level of intrathyroid arteries.
Results:
Hyperthyroid postpartum thyroiditis appeared significantly earlier (mean ± SD, 4.4 ± 1.9 months after delivery) than hypothyroid postpartum thyroiditis (6.5 ± 2.1 months) and Graves disease (7.2 ± 2.7 months; P< .001). The thyroid volume in hyperthyroid postpartum thyroiditis (9.7 ± 6.3 mL) was significantly lower than in hypothyroid postpartum thyroiditis (14.7 ± 10.2 mL; P = .030) and Graves disease (19.4 ± 10.2 mL; P< .001). The PSV in hyperthyroid postpartum thyroiditis (9.4 ± 3.4 cm/s) was significantly lower than in hypothyroid postpartum thyroiditis (14.4 ± 3.9 cm/s; P < .001) and Graves disease (19.8 ± 7.0 cm/s; P < .001). With a cutoff level of 15 cm/s, the sensitivity and specificity of the PSV as a predictor of the correct diagnosis in hyperthyroid postpartum women were 94.7% and 96.8%, respectively. A multinomial logistic regression revealed PSV and the time after delivery at which the disorders presented as independent predictors of the differentiation between hyperthyroid postpartum thyroiditis and Graves disease (P = .003; P = .022).
Conclusions:
Spectral Doppler sonography was shown to be a useful and accurate method for thyroid dysfunction evaluation during the postpartum period.
... The measurement of TRAb in patients with hyperthyroidism is a helpful test in establishing the diagnosis, which often helps predict the clinical course and response to treatment. This study plays a special role in ambiguous clinical cases, such as: painless thyroiditis, unilateral exophthalmos, Graves' opthalmopathy in the condition of euthyreosis, subclinical hyperthyroidism, hyperthyroidism induced by amiodarone, hyperemesis gravidarum, with a hyperthyroidism and anticipating the risk of neonatal hyperthyroidism in mothers with Graves' disease [27]. Due to the much higher sensitivity, and low cost to measure the concentrations of antibodies against the TSH receptor, this test should be performed in every patient suspected of having Graves' disease, especially in the absence of symptoms beyond thyroid including Graves' ophthalmopathy [8]. ...
Graves’ disease is an autoimmune disease. It accounts for 50–80% of cases of hyperthyroidism. Antibodies against the TSH receptor (TRAb) are responsible for hyperthyroidism (TRAB). The key role in monitoring and diagnosis of Graves’ disease plays the level of hormones of free thyroxine and triiodothyronine. Helpful is an ultrasound of the thyroid scintigraphy which due to its functional character is both a valuable addition to morphological studies as well as plays an important role in the diagnosis and therapy in patients with Graves’ disease. There is no perfect treatment for Graves’ disease. The reason for this is the lack of therapy directed against primary pathogenic mechanisms. Currently available treatments need to be thoroughly discussed during the first visit as the patient’s understanding of the choice of a treatment constitutes a vital role in the success of therapy. Graves’ disease treatment is based on three types of therapies that have been carried out for decades including: pharmacological treatment anti-thyroid drugs, I131 therapy and radical treatment — thyroidectomy. The purpose of the treatment is to control symptoms and patient to return to euthyreosis. Treatment of Graves’ disease is of great importance because if left untreated, it can lead to long-term harmful effects on the heart, bone and mental well-being of patients.
... Thyroiditis is diagnosed by the presence of thyrotoxicosis and absence of TSH receptor antibodies, reduced tracer uptake on a radioiodine scan and (often) diffusely reduced echogenicity and vascularity on thyroid ultrasonography; it usually occurs early postinterferon therapy, its duration varies from weeks to months, can have subclinical course and can ultimately lead to transient, or (occasionally) permanent, hypothyroidism [65]. Graves' disease is less common than thyroiditis and can be diagnosed in the presence of TSH receptor antibody positivity [71,72], with supporting evidence from radioiodine scan (normal or increased uptake) and thyroid ultrasound (may have increased vascularity); it can occasionally emerge after thyroiditis or hypothyroidism [65]. Female gender, interferon dose and treatment duration were identified as predisposing factors for thyroid toxicity. ...
Thyroid disorders commonly impact on the gastrointestinal system and may even present with gastrointestinal symptoms in isolation; for example, metastatic medullary thyroid carcinoma typically presents with diarrhoea. Delays in identifying and treating the underlying thyroid dysfunction may lead to unnecessary investigations and treatment, with ongoing morbidity, and can potentially be life-threatening. Similarly, gastrointestinal diseases can impact on thyroid function tests, and an awareness of the concept and management of non-thyroidal illness is necessary to avoid giving unnecessary thyroid therapies that could potentially exacerbate the underlying gastrointestinal disease. Dual thyroid and gastrointestinal pathologies are also common, with presentations occurring concurrently or sequentially, the latter after a variable time lag that can even extend over decades. Such an association aetiologically relates to the autoimmune background of many thyroid disorders (e.g. Graves' disease and Hashimoto's thyroiditis) and gastrointestinal disorders (e.g. coeliac disease and inflammatory bowel disease); such autoimmune conditions can sometimes occur in the context of autoimmune polyglandular syndrome. Emphasis should also be given to the gastrointestinal side effects of some of the medications used for thyroid disease (e.g. anti-thyroid drugs causing hepatotoxicity) and vice versa (e.g. interferon therapy causing autoimmune thyroid dysfunction). In this review, we discuss disorders of the thyroid-gut axis and identify the evidence base behind the management of such disorders.
Copyright © 2015. Published by Elsevier B.V.
... Current, solid-phase assays to detect TSHR autoantibodies use competitive binding technology in which serum from autoantibody positive patients prevents the binding of either TSH (second-generation bioassays) or a TSHR-stimulatory monoclonal antibody, M22, (third-generation bioassays) to immobilized TSHR [61][62][63]. The sensitivity and specificity of the second-and third-generation of TSAb assays has prompted proposals for the wider use of these tests in clinical practice [64,65]. Binding assays, however, do not distinguish between TSAbs and TBAbs. ...
Cell-based bioassays are used to determine the biological activity of complex biotherapeutic products, to assign potency and to assure the quality and consistency of the manufacturing process. Clinically, these assays are used to assess bioactivity in patient samples, particularly for the detection of antidrug neutralizing antibodies. Owing to their versatility, cellular assays that measure endogenous gene expression by quantitative reverse transcription PCR offer a rapid and automatable alternative to assays measuring functional, late-stage responses. Notably, detection of immediate early gene expression represents a direct response of the cell to receptor ligation by the biotherapeutic. We review current developments in the use of this approach and demonstrate its application to the detection of receptor-binding autoantibodies using, as a case study, the detection of autoantibodies to the thyroid-stimulating hormone receptor.
Aims
To investigate the impact of various clinical factors associated with Graves' disease on the success rate of radioiodine (RAI) therapy for Graves' disease within 3 years, and to determine the optimal range of iodine dosage per unit volume that yields the highest cure rate for Graves' disease within 1 year.
Materials and Methods
This retrospective study included patients diagnosed with Graves' disease who underwent RAI therapy at the Second Affiliated Hospital of Anhui Medical University between October 2012 and October 2022. The cumulative success rate was analysed using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards regression models were employed to evaluate factors associated with successful treatment of Graves' disease. Outcomes were categorized as either success or failure for all patients.
Results
Overall, 1994 patients were enrolled in this study, including 594 (29.8%) male and 1399 (70.2%) female patients. The success and failure groups comprised 1645 (82.4%) and 349 patients (17.6%), respectively, after a 3‐year follow‐up period. Multivariate regression analysis demonstrated that sex, antithyroid drug (ATD) use before RAI therapy, age, thyroid receptor antibody (TRAb) levels, iodine dose, thyroid mass, and early ATD use before RAI therapy were independent influencing factors for Graves' disease cure.
Conclusions
We found that female patients and those with TRAbs ≥31.83 IU/L and thyroid mass ≥ 73.42 g had a lower cure rate. Therefore, thyroid size, disease severity, and duration of disease should be comprehensively considered when making treatment decisions and iodine dose selection in clinical practice.
Background
Thyrotoxicosis is a clinical status due to hypersecretion of thyroid hormones by diffuse goiter (Grave’s disease [GD]), multinodular goiter, single toxic adenoma, and pituitary adenoma secreting thyroid-stimulating hormone (TSH) rarely. GD: It is diffuse toxic goiter (GD) or (Basedow disease) it is a triad of: Diffuse toxic goiter, hyperthyroidism, and exophthalmos (proptosis).
Aims
1. Positivity of TRAb and TPO in thyrotoxic subjects. 2. Correlation of the titer of these antibodies with the clinical status of the patients. 3. Correlation between TRAb and TPO titer. 4. To find out if TPO titer on enrollment has any correlation with the clinical status of the patients.
Methods
A cross-sectional study conducted in the National Diabetes Center–Mustansiriyah University in the period from November 2021 to April 2022 where 93 patients with GD are enrolled to check their thyroid status and check some biochemical variables in their sera as thyrotropin receptor antibody (TRAB), thyroid peroxidase (TPO) antibody, TSH, and free thyroxine (FT4). 44.6% are women and 35.7% are men, at the time of recreuitment 49.4% are toxic while the remaining 58.6% are euthyroid being on anti thyroid drugs. 87 persons are recruited as normal euthyroid, they are sex and age-matched, the control TRAb were negative.
Results
GD patients are as follows: 54 (58.06%) euthyroid and 39 (41.94%) toxic at the time of recruitment. Eighty-two percent of toxic patients have goiter and 74.07% of euthyroid GD patients have goiter. Ophthalmopathy is found in (64.1% of toxic GD patients and 42.59% of euthyroid GD patients. TPO median in the control, toxic, and euthyroid GD patients is (22.76%), (75%) and (63.5%) (highest among toxic GD patients) ( P < 0.001). TSH in the control group has a mean of (2.18 ± 1.72) and a median of (1.89). The TRAb is the highest in toxic GD patients, followed by euthyroid GD patients and the least in the control, its mean is (9.98 ± 8.42), (7.24 ± 7.8) and (0.93 ± 0.15), respectively. It is recommended to conduct a longitudinal study in which patients with GD are checked at variables times in the course of illness (remission and relapse) studying these biochemical and immunological markers in these variable states of thyroid function.
Conclusion
Ninety-three thyrotoxic patients, 39 are toxic and 54 are euthyroid on arrival. Eye sings are more in toxic patients, goiter and eye signs are predictor of GD, TRAb is the highest among toxic patients, TPO are higher among GD patients versus the control.
Although the majority of pregnancies are uneventful, sometimes complications do happen. Pregnancy complications are the conditions or pathological processes associated with pregnancy. They can occur during or after pregnancy and range from minor discomforts to serious diseases that require medical interventions. They can involve the mother's health, the baby's health, or both. Complication of pregnancy can cause maternal morbidity and mortality. The most common causes of maternal mortality are maternal bleeding, maternal sepsis, hypertensive disease, obstructed labour, and pregnancy with the consequence of abortion, which includes miscarriage, ectopic pregnancy, and medical abortion. The primary means of preventing maternal deaths is to provide rapid access to emergency obstetric care, including treatment of haemorrhage, infection, hypertension, and obstructed labour. Proper antenatal care can reduce the maternal mortality rate by reducing the number of pregnancies among women of reproductive age. Thus, adequate monitoring and appropriate intervention strategies should be provided for better maternal and fetal outcome.
Thyrotoxicosis is a term for excess thyroid hormone action. Hyperthyroidism is when thyroid is producing and releasing excess hormones. The most common cause is Graves’ hyperthyroidism, the next being toxic nodular goiter (Plummer’s disease). There are also several rare causes of overproduction of thyroid hormones. In conditions when destructive process in the thyroid results in release of stored hormones, the process is usually transient, and only symptomatic therapy is needed. For hyperthyroid overproduction category, either an 18-month course of antithyroid medication or ablative therapies such as surgery and radioactive iodine are needed. Long-term antithyroid therapy as an option for some patients with Graves’ disease has been recently recommended by ATA guidelines. Periodic TRAB (thyrotropin receptor antibodies) measurement during antithyroid therapy can be used as a guide for prediction of remission.Management of hyperthyroid and thyrotoxicosis syndromes should be tailored to the cause, associated with autoimmune manifestations, age of the patient, and other clinical considerations and patient preferences.KeywordsHyperthyroidismThyrotoxicosisGraves’ diseaseThyroiditisRadioactive iodine therapyAntithyroid therapyThyrotropin receptor antibody (TRAB)Thyroidectomy
Objective
To survey the status of iodine nutrition and the prevalence of thyroid diseases in Guangxi, China, and to explore the risk factors for positive thyroid antibody.
Methods
We used the multistage stratified cluster random sampling method to select a total of 2488 subjects from an urban and a rural location. All the subjects completed a questionnaire survey, blood and urine samples were also collected, and B-mode thyroid ultrasound was used to determine thyroid function and detect thyroid antibodies.
Results
1) The median level of urinary iodine was 148.53 µg/L in school-age children in Guangxi, China. 2) The prevalence rates for thyroid diseases were as follows: hyperthyroidism, 0.89%; subclinical hyperthyroidism, 1.05%; hypothyroidism, 0.69%; and subclinical hypothyroidism, 8.87%. The rates of thyroid antibody positivity were as follows: thyroid peroxidase antibody (TPOAb), 13.60%; thyroglobulin antibody (TGAb), 13.60%; thyroid antibodies, 18.2%; and thyroid nodules, 16.94%. 3) The rate of TPOAb positivity was significantly higher in women aged 18-29, 30-39, 40-49, or 60-69 years than in men in the same age groups (P < 0.05), and the TGAb positivity rate was significantly higher in women than in men of the same age group (P < 0.05). 4) The rate of thyroid antibody positivity was significantly higher in individuals with iodine deficiency than in individuals with adequate iodine (21.6% vs 18.4%) or excess iodine (21.6% vs 15.5%) (both P < 0.05). 5) The female sex and a family history of thyroid diseases were the major risk factors for thyroid antibody positivity (odds ratio [OR] 3.010, P <0.05; OR 2.486, P <0.05).
Conclusion
The overall level of iodine is adequate in Guangxi, China; this level should be maintained to prevent the thyroid diseases related with iodine deficiency or excess of iodine. Female sex and a family history of thyroid diseases are independent risk factors for thyroid antibody positivity.
The pathogenesis of autoimmune thyroid diseases (AITD) is poorly understood. We previously observed systemic depletion of IgG core fucosylation and antennary α1,2 fucosylation of peripheral blood mononuclear cells in AITD, correlated with thyroid peroxidase antibody (TPOAb) levels. We hypothesized that deficiency in IgG core fucose enhances antibody-dependent cell-mediated cytotoxicity of thyrocytes by TPOAb, contributing to thyroid autoimmunity. Multi-omic evaluations in 622 individuals (172 with AITD) from the TwinsUK cohort showed decreased IgG core fucosylation levels associated with a subpopulation of natural killer (NK) cells featuring CD335, CD314, and CD158b immunoreceptors, and increased levels of apoptosis-associated Caspase-2 and Interleukin-1α, positively associated with AITD. AITD-associated genetic variants rs1521 and rs3094228 alter expression of thyrocyte ligands of the CD314 and CD158b immunoreceptors on NK cells. The combination of low-core fucose IgG associated with an NK cell subpopulation and genetic variant-promoted ligand activation in thyrocytes may promote antibody-dependent NK cell-mediated cytotoxicity of thyrocytes in AITD.
Thyroid and parathyroid diseases are among the most frequent conditions we have to deal with in otolaryngology. The overall incidence and prevalence of these glands disorders have increased remarkably over the past decades. The widespread use of neck ultrasonography has led to a dramatic increase in diagnosis of thyroid nodules and cancers in the population. This increase is evident primarily in low-risk differentiated thyroid carcinomas, which confronts the clinician with the dilemma of performing overtreatment vs. jeopardizing the patient life while choosing a conservative approach. This chapter will discuss the updated approaches to the thyroid and parathyroid diseases, based on the researches that have been made over the last two decades.
Oral and oropharyngeal cancers (OPC) are a major global health concern traditionally caused by tobacco and alcohol abuse. The last decade has revealed the emerging role of Human Papilloma Virus (HPV) as a major etiological factor for oropharyngeal cancer predominantly in the developed world. Cancers affecting both these subsites are distinct entities. Changes have been incorporated in the recent staging system with recognition of the prognostic importance of depth of invasion (DOI) and extranodal extension (ENE) for oral cancers as well as the favourable biology of HPV-related cancers necessitating a separate staging system and attempts at deintensification of treatment. Oral cancers are predominantly treated by primary surgery and oropharyngeal cancers with non-surgical approaches. The advent of transoral robotic surgery (TORS) has resulted in its exploration of its role for select oropharyngeal cancers. There has been an emergence of recent new data which has resulted in changes in traditional management protocols of these cancers.
Background:
Antithyroid drugs (ATDs) are known to cause various adverse drug reactions (ADRs) that can lead to treatment complexity and unpredictable risks. With the aim of ensuring safer drug use, we assessed whether thyrotropin receptor antibody (TRAb) titers are associated with ATD-induced cutaneous reactions and/or hepatotoxicity, and examined potential genetic predisposition factors.
Methods:
We compared TRAb titers of 37 Graves' disease (GD) patients who had experienced carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity with those of 40 normal individuals, or 78 GD patients without the aforementioned ATD-induced ADRs. We performed a genome-wide association study and/or human leukocyte antigen genotyping on GD patients [first stage (chart reviews): 24 cases with ADRs and 423 controls; second stage (actively recruited): 45 cases with ADRs and 137 controls].
Results:
For patients with Graves' hyperthyroidism, individuals with higher TRAb titers showed a predisposition to carbimazole/methimazole-induced cutaneous reactions and/or hepatotoxicity, with an estimated odds ratio of 5.19 (cut-off value: 64%). Potential associations with the rs144542704 and rs61893841 on chromosomes 17 and 11, respectively, warrant further genetic association analysis.
Conclusion:
Our findings support the use of carbimazole/methimazole in patients with low TRAb titers to ensure safer drug use. The identified genetic associations warrant further research.
Thyroid dysfunction during pregnancy can result in serious complications for both the mother and infant. However, these complications can be prevented by the optimal treatment of overt maternal thyroid dysfunction. The serum thyroid-stimulating hormone (TSH) concentration is the most reliable measure of thyroid function during pregnancy. Due to the physiologic changes in TSH levels during pregnancy, the correct interpretation of thyroid function requires knowledge of the gestational week and the appropriate population-based reference interval. In addition to a TSH test, the measurement of thyroid peroxidase antibody helps determine whether to treat subclinical hypothyroidism during pregnancy. Since the use of antithyroid drugs during pregnancy is associated with birth defects, it is recommended to discontinue the medication and to perform repeated thyroid function testing during the first trimester. If therapy is needed during the first trimester, propylthiouracil is preferred over methimazole.
Background: The antithyroid drugs, Carbimazole, Methimazole, and Propylthiouracil remain the mainstay of Graves’ disease management in pregnancy. A series of Clinical Practice Guidelines aimed at optimising fetal and maternal outcomes in women with Graves’ disease have been published in recent years.
Areas covered: This review examines existing guideline recommendations on antithyroid drug management of Graves’ disease in pregnancy.
Expert Commentary: Recent guidelines have been shaped by expanding knowledge of the adverse effect profiles of antithyroid drugs on the developing fetus. A core management strategy is to limit fetal exposure to excess thyroid hormones and to curtail adverse drug effects through effective preconception and peri-conception management. Propylthiouracil is the recommended treatment in the first trimester of pregnancy but there is uncertainty regarding antithyroid drug choices in women who continue to require treatment in later pregnancy. Further studies are needed to fully evaluate the risks of congenital anomalies following intrauterine thionamide exposure.
Objective:
To compile an inventory of the clinical practices regarding the management of GD during pregnancy in the Poitou-Charentes region of France. This was a retrospective, multicentre study covering the period 2005 to 2012. Ninety-five pregnancies were reviewed: 14 GD diagnosed during pregnancy, 24 GD already treated with synthetic antithyroid drugs (SAT) prior to pregnancy, 25 GD in remission before pregnancy and 32 GD who had undergone thyroidectomy prior to pregnancy. In patients under SAT and/or with TSH receptor antibody levels (TRAb)>3N at the 2nd (T2) and/or 3rd trimester (T3) of pregnancy, a foetal thyroid ultrasound (FTU) was performed in 18/32 cases and neonatal thyroid screening (NTS) in 14/20 cases. One case of foetal hyperthyroidism, two of neonatal hyperthyroidism and three of foetal hypothyroidism (including one neonatal hypothyroidism) were observed. Propylthiouracil was the preferred treatment prescribed, whatever the trimester. A congenital malformation was observed in 4/19 foetuses exposed to carbimazole during the 1st trimester (T1). In operated patients, TSH levels were>2.5mIU/L during T1 in 23/32 cases, while TRAb were not assayed during pregnancy in 12/32 cases. The management of GD during pregnancy could be improved by adjusting SAT therapy during its course, titrating levothyroxine prior to conception and in early pregnancy in thyroidectomised patients, and a more targeted use of FTU during T2 and T3 and of neonatal thyroid screening.
The term thyrotoxicosis applies to a clinical condition resulting from increased thyroid hormone concentration and action. When the clinical condition is diagnosed by appropriate laboratory tests, the etiology should be determined. A high radioiodine uptake of thyroid will indicate either a very common condition called Graves' hyperthyroidism or a very uncommon TSH-secreting pituitary adenoma. A very low uptake or no uptake will indicate destructive thyroiditis, iodine-induced hyperthyroidism, or very rare cases of extra-thyroidal thyroid hormone production or exogenous thyroid hormone intake. Normal radioactive thyroid uptake can occur in mild Graves' hyperthyroidism or in multinodular toxic goiter and toxic adenoma. Management should be problem oriented and should depend on the etiology. Antithyroid medications, surgery, or radioactive iodine therapy can be used for high uptake causes and symptomatic therapy can be used for destructive thyroiditis. Iodine-induced hyperthyroidism will respond to antithyroid medications and elimination of exogenous iodine. © 2014 Springer Science+Business Media New York. All rights are reserved.
Although the thyroid-associated orbitopathy (TAO) aka Graves’ disease (GD) is a common form of orbital inflammation, capricious clinical features of this disease, primarily proptosis may be confused with orbital tumors. Therefore, a brief review of GD covering its pathogenesis, morphology, systemic and ophthalmic clinical features, imaging characteristics, and particularly its differential diagnosis is included in this book.
GD may present with great variability in its clinical signs and, for this reason, there are numerous nomenclatures and classifications in the literature.
The central role that antibodies against the TSH receptor play in the pathogenesis of GD has been recognized for several decades. In the active inflammatory stage, perivascular clusters of plasma cells and lymphocytes are found in loose edematous tissue. During the later stages, the volume of the orbit is increased by infiltration of fibroblasts, collagen, glycoproteins, and hygroscopic mucopolysaccharides leading to the edema of all orbital soft tissues, particularly muscles. In the chronic stages, the muscles become fibrotic and this can be best demonstrated with the absence of high signal intensity in T2-weighted MRI images.
Most cases present bilaterally and can be diagnosed with ease but the unilateral presentations are the most confusing patients to be differentiated from orbital mass lesions such as lymphoma, leukemia, metastatic tumors, orbital myositis, and varix.
Treatment choices vary according to the basis of hormonal imbalance and include observation and symptomatic management, surgery, and radiation.
Radioiodine therapy may cause the development or exacerbation of thyroid associated orbitopathy (TAO). Therefore the patients at risk have been treated with glucocorticosteroids during radioiodine treatment. The aim of this retrospective study was to determine the impact of corticosteroid therapy on the development of thyroid orbitopathy, specifically in smokers and non-smokers, and the dynamic of antibodies against the TSH receptor levels (TRAK) as markers of autoimmune process. Group 1 represented 98 patients (without symptoms of TAO) treated with radioiodine without steroids and in the second group there were 31 patients treated with corticosteroids. Prophylaxis failed to prevent the deterioration of TAO, progression was actually more common in group 2, which is certainly a selection bias. The TRAK levels did not predict TAO progression. Prednisone prevent TAO deterioration in smokers (relative risk of deterioration without steroids 7.6, with corticosteroids 1.2, respectively). TRAK level rise significanttly without steroids, that action can be prevented by Prednisone. Prophylactic treatment with corticosteroids cannot prevent worsening of endocrine orbitopathy in all cases and in patients with active TAO. Total thyroidectomy should be preferred management in these patients. Corticosteroids are also useful in smokers without clinical signs of TAO.
Objective: To investigate the therapeutic effect and safety of local intrathyroid injection of immunosuppressive agents dexamethasone(Dex), cyclophosphamide(CTX) and octreotide in the treatment of recurrent toxic diffuse goiter associated with hyperthyroidism(Graves' disease). Methods: Three hundred patients with recurrent Graves' disease were randomly divided into 2 groups by single blind method. Patients in both groups were treated with conventional oral therapy of thiamazole or propylthiouracil. Patients in the treatment group were treated with Dex(4 mg), CTX(50 mg) and octreotide(0.1 mg) by local intrathyroid injection, once a week for three months, then once every two weeks for two months, and once a month for 4 months. Changes in size and function of thyroid, including plasma concentrations of total triiodothyronine(TT 3), total thyroxine (TT 4), free triiodothyronine(FT 3), free thyroxine (FT 4), sensitive thyroid-stimulating hormone(sTSH), thyroid-stimulating hormone receptor antibody (TRAb), thyroid globulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb), liver and kidney functions, blood and urine routine were examined. Results: Thyroid sizes of the patients in the treatment group were significantly decreased than those of the control group: (21.3±6.9) vs (28.7±9.2) cm 3 (P<0.01) in the 3 rd month; (16.4±7.8) vs (25.6±8.2) cm 3 (P<0.01) in the 6 th month and (7.9±6.1) vs (20.9±8.5) cm 3 (P<0.001) at the end of 24 th month, respectively. The negative conversion rates of thyroid-related antibodies within 6 months were significantly higher in the treatment group than those in the control group: TRAb (31.3±12.5) vs (62.8±11.3)%(P<0.01), TGAb (20.7±9.5) vs (52.3±8.2)%(P<0.01), TPOAb (24.7±12.8) vs (55.8±10.9)%(P<0.01). Thyroid function of the patients in both the treatment and control groups returned to normal, following treatment for 6 and 12 months respectively. The relapse rate was only 21% in the treatment group after two years, while that of the control group was 70%. In the whole process of treatment, no significant changes could be noted in liver and kidney functions, blood and urine routines in the patients of both groups. Conclusion: Local intrathyroid injection of immunosuppression agents is safe and effective in the treatment of recurrent Graves' disease. The mechanism of which might be related with the alleviation of thyroid enlargement and the restricated level of thyroid-related antibodies.
The value and practice of thyroid radionuclide imaging in the diagnosis and management of hyperthyroidism is unsettled. Our objectives were to determine the influence of thyroid uptake and scintigraphy on the diagnosis of hyperthyroidism and the prediction of outcome following radioiodine therapy.
We reviewed records and scintigraphic studies on 881 hyperthyroid patients carried out between 2000 and 2007. The agreement between the clinical and scintigraphic diagnosis was evaluated by kappa statistics. We determined the relationship between 4-h (123)I uptake and the outcome of (131)I treatment in 626 patients. A multiple logistic regression model was used to determine variables influencing treatment outcome in 1 year.
The diagnostic categories were Graves' disease (GD, n = 383), toxic multinodular goitre (n = 253), solitary toxic nodule (n = 164) and Graves' disease coexisting with nodules (n = 81). The mean age of the patients was 58 +/- 17, (M:F 160:721). There was good agreement between clinical and scintigraph diagnosis (K = 0.60, 95% CI 0.57-0.64, P < 0.001); and they were correctly matched in 74%; mismatched in 6% and indeterminate in 20% of patients. Treatment outcome was not associated with scintigraph diagnosis (P = 0.98) or radioiodine uptake at 4 h (P = 0.2). The use of antithyroid medications before treatment predicted treatment failure (odds ratio 2.0, 95% CI 1.2-3.6, P = 0.01).
Thyroid scintigraphy and uptake studies did not influence diagnosis or treatment outcomes in most cases of hyperthyroidism. Our findings in this retrospective study do not justify their routine use. Selective scanning will reduce cost and exposure to radioisotopes without compromising diagnostic accuracy or treatment outcomes.
We investigated the interrelationship and the influence of thyroid-stimulating antibodies (TSAb), TSH-blocking antibodies (TSHBAb), and of radioiodine (131I)-induced thyroid damage in the early (within 1 yr) outcome of thyroid function in hyperthyroid patients with Graves' disease (GD) treated with 131I. TSAb, TSHBAb, and ultrasound thyroid volume (as an index of thyroid damage) were simultaneously measured before and at 1, 3, 6, and 12 months after 131I in 31 GD patients. One year after radioiodine, 9.7% of patients were hyperthyroid (Hyper-group), requiring methimazole; 12.9% were euthyroid (Eu-group); and 77.4% were hypothyroid (Hypo-group). Pretreatment thyroid volume in the Eu-group and Hyper-group was significantly greater (P = 0.009) than in the Hypo-group. Pre-131I TSAb levels were higher in the Hyper-group vs. the Hypo-group (P = 0.01) or the Eu-group (P = 0.03). A significant post-131I increase in TSAb levels occurred in 66% of patients developing hypothyroidism but not in those remaining hyperthyroid. After 131I, TSHBAb appeared in 7 patients, in all but one associated with high levels of TSAb. One year after radioiodine: 1) the mean percent reduction in thyroid volume was greater in the Hypo-group (80.7%) or the Eu-group (83.5%) than in the Hyper-group (35.7%) (P = 0.007 and 0.0033 respectively); 2) hypothyroid patients had smaller (P = 0.0058) post-131I thyroids than hyperthyroid patients; and 3) TSAb were still elevated in 75% hypothyroid patients, but all of them had a thyroid volume < or = 8 mL, indicating major postradioiodine gland damage. In conclusion: 1) the early outcome of thyroid function after 131I for GD is mainly related to pretreatment thyroid volume and to the degree of its reduction after therapy; 2) high TSAb levels before 131I are associated with a relative resistance to therapy; 3) a postradioiodine increase in TSAb levels is related to the development of hypothyroidism; and 4) the concomitant appearance of TSHBAb and disappearance of TSAb are not frequent after 131I and play a role in the development of early postradioiodine hypothyroidism only in a minority of patients.
Hyperthyroidism due to Graves' disease is induced by autoantibodies stimulating the thyroid-stimulating hor- mone (TSH) receptor. In most patients these antibodies can be measured in serum. Graves' disease is common in women of reproductive age, with a prevalence rate of past or present disease of 0.5-1% (1). Classically, three therapeutic approaches are used: (i) Antithyroid drugs given for a long period, which is commonly 1-2 years. During therapy most patients enter remission, but relapses are frequent (around 50%) after withdrawal of medication; (ii) Radioiodine therapy. This may initially aggravate the autoimmune reaction, but most patients become euthyroid or hypothyroid, due to the reduction in thyroid follicular cell mass; (iii) Subtotal or near total thyroidectomy. Pregnancy is commonly accompanied bya fall in thyroid autoimmune activity, and women with Graves' disease may spontaneously enter remission during pregnancy. However, disease activity persists in some pregnant patients, and occasionally onset of Graves' disease is seen. The recommended therapy for Graves' disease during pregnancy is monotherapy with antithyroid drugs (propylthiouracil, methimazol or carbimazol). While thyroid hormones produced by or given to the mother cross the placenta in only limited amounts, both TSH-receptor stimulating antibodies and antithyroid drugs readily cross the placenta and affect fetal thyroid function. Ideally, a balance between stimulating anti- bodies and drugs which keeps the mother euthyroid will also maintain euthyroidism in the fetus. Fortunately this is close to reality; during therapy with antithyroid drugs the thyroid state of the fetus parallels that of the mother, but with a tendency to be slightly lower (2). Hence, a pregnant woman with Graves' disease and an intact thyroid should receive the minimal dose of antithyroid drugs which keeps her thyroid function near the upper end of normality. After delivery, antithyroid drugs are cleared from the neonatal circulation within the first days, whereas TSH-receptor antibodies disappear much more slowly and may stimulate the thyroid during the first weeks or even months of life. Delayed neonatal hyperthyroidism may therefore develop, constituting a potentially life-threatening medical condition. The situation is different when a pregnant woman has previously been treated for Graves' hyperthyroidism with radioiodine or surgery, and especially when she is receiving thyroxine substitution therapy. In this situation, the thyroid function of the mother does not reflect thyroid function in the fetus. If the mother still produces large amounts of TSH-receptor stimulating antibodies, fetal hyperthyroidism may develop. Also, neonatal hyperthyroidism may be present at birth and last for months if left untreated. Occasionally antibodies against the TSH receptor will bind to the receptor without stimulation, but rather will block the normal effect of TSH. This may cause hypothyroidism in the mother and the fetus, and transiently in the newborn. This rare variant, which has been detected in 1 in 180 000 newborns in North America (3), is not discussed in detail.
Detection of autoantibodies to the TSH receptor (TSH-R) in Graves' disease has found widespread use in clinical routine and is performed mostly by commercial RRAs measuring TSH binding inhibitory activity. We report in this study on a second generation TSH binding inhibitory assay using the human recombinant TSH-R with two major improvements: 1) superior diagnostic sensitivity for Graves' disease, and 2) for the first time, nonradioactive and radioactive coated tube (CT) technology. Full-length human recombinant TSH-R was expressed in the K562 leukemia cell line and grown in suspension at a high density. A murine monoclonal antibody was selected for binding to the native TSH-R without interfering with autoantibodies or TSH and was coated to polystyrene tubes. After detergent extraction, TSH-R was affinity immobilized on antibody-coated tubes. The binding of TSH to the TSH-R could be demonstrated by the addition of 125I- or acridinium ester-labeled bovine TSH, and this binding could be inhibited by sera from patients with Graves' disease up to 95%. Subsequently, these novel assays, a CT RRA and a CT luminescence receptor assay, were compared to the conventional RRA based on porcine antigen in a blinded clinical multicenter trial. Sera from 328 patients with Graves' disease (86 untreated, 116 treated, and 126 in remission) and 520 controls (comprised of healthy blood donors and patients with autoimmune diseases or goiter) were tested in all 3 assays. Receiver-operating characteristic plot analysis resulted in a specificity of 99.6% with a sensitivity of 98.8% for both CT assays, compared to 99.6% specificity and 80.2% sensitivity for the conventional RRA (P < 0.001). In all 3 groups of patients with Graves' disease, the 2 CT assays were significantly more sensitive for the disease than the conventional assay, without loss of specificity in the control groups. This increase in sensitivity and the nonradioactive or radioactive CT format constitute a significant improvement over the currently available assays.
The thyrotropin receptor, also known as the thyroid-stimulating hormone receptor (TSHR), is the primary antigen of Graves disease. Stimulating TSHR antibodies are the cause of thyroid overstimulation and were originally called long-acting thyroid stimulators due to their prolonged action. Here we report the successful cloning and characterization of a monoclonal antibody (MS-1) with TSHR-stimulating activity. The thyroid-stimulating activity of MS-1 was evident at IgG concentrations as low as 20 ng/ml. MS-1 also competed for radiolabeled TSH binding to the native TSHR and was able to compete for TSH-induced stimulation. MS-1 recognized a conformational epitope within the TSHR alpha (or A) subunit but excluding the receptor cleavage region. Using an assay measuring loss of antibody recognition after cleavage we demonstrated that MS-1, in contrast to TSH, was unable to enhance TSHR posttranslational cleavage. Since receptor cleavage is followed by alpha subunit shedding and receptor degradation, the functional half-life of the receptor may be extended. The isolation and characterization of MS-1 provides a novel explanation for the prolonged thyroid stimulation in this disease which may be secondary to the lack of receptor cleavage in addition to the prolonged half-life of IgG itself.
The aim of this study was to determine whether or not the titre of thyroid-stimulating hormone receptor antibody with stimulating (TRAb-S) activity changes in patients with Graves' disease (GD) or toxic multinodular goitres (TMNG) 3 months after treatment with sodium iodide ((131)I).
Serum specimens were obtained from 21 hyperthyroid patients (15 with GD and 6 with TMNG) at a median 0.5 months before and 3 months after (131)I treatment using a standard ablative dose of 555 MBq. TRAb-S activity was measured in a sensitive and specific luminescent bioassay employing the lulu cell line and expressed as a stimulation index (SI; normal </=1.5).
The mean TRAb-S in the GD patients was 2.72 SI (95% CI: 1.51-4.03) 0.5 months before administration of (131)I and 3.98 SI (95% CI: 1.20-6.76) 3 months after administration of (131)I. The difference was not statistically significant at p LT; 0.8. It was not elevated in the TMNG patients before (0.57 SI; 95% CI: 0.41- 0.73) and after (1.00 SI; 95% CI: 0.74-1.26) treatment either.
Radioiodine therapy for GD or TMNG did not induce a significant change in TRAb-S activity at 3 months after treatment with (131)I, probably due to effective antithyroid therapy or the timing of samples.
To investigate the analytical and diagnostic accuracy of thyrotrophin (TSH) receptor antibody assays using recombinant human TSH receptors.
Sera from 68 patients with Graves' disease, 23 patients with autoimmune thyroiditis, and 119 healthy controls were evaluated in four different laboratories using both radioactive and chemiluminescent tracers. Functional sensitivity, interlaboratory precision, optimal cutoff values for Graves' disease, and the correlation between the two methods were evaluated.
Functional sensitivity was 0.98 IU/litre for both assays. Interlaboratory precision, expressed as per cent coefficient of variation over a wide range of antibody concentrations, varied from 5.7% to 15.1% for the radioligand, and from 6.6% to 19.9% for the chemiluminescence assay. The two methods (radioactive and chemiluminescent) were closely correlated. All the sera from untreated or relapsing patients with Graves' disease gave TSH receptor antibody values above 2.1 IU/litre, whereas in none of the healthy controls did values exceed 2.5 IU/litre. Receiver operating curve analysis allowed an optimal cutoff point to be defined at 1.99 IU/litre, according to a sensitivity of 100% and specificity of 99.1%.
These data show the high analytical and diagnostic accuracy of the human TSH receptor assays, both with radioactive and chemiluminescent tracers, when both functional sensitivity and interlaboratory reproducibility are considered. These two methods could be proposed as first line diagnostic markers for Graves' disease.
Amiodarone is a benzofuranic-derivative iodine-rich drug widely used for the treatment of tachyarrhythmias and, to a lesser extent, of ischemic heart disease. It often causes changes in thyroid function tests (typically an increase in serum T(4) and rT(3), and a decrease in serum T(3), concentrations), mainly related to the inhibition of 5'-deiodinase activity, resulting in a decrease in the generation of T(3) from T(4) and a decrease in the clearance of rT(3). In 14-18% of amiodarone-treated patients, there is overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Preexisting Hashimoto's thyroiditis is a definite risk factor for the occurrence of AIH. The pathogenesis of iodine-induced AIH is related to a failure to escape from the acute Wolff-Chaikoff effect due to defects in thyroid hormonogenesis, and,
In agreement with previous authors we found patients with Graves' disease to have an increased incidence of the DR 3 antigen. We could find no association, however, between the presence of the antigen and relapse after carbimazole treatment. A concordant HLA status and thyrotrophin receptor antibody (TRAb) index, obtained at either 6 or 12 months after the start of treatment could only predict cases of relapse and remission in a minority of patients making this of very limited clinical use. The TRAb index obtained at 12 months after the start of medical therapy could accurately predict cases of relapse and remission for the next 3 years in 24/30 patients studied.
Antithyroid drugs are widely used in the therapy of hyperthyroidism. There are wide variations in the dose, regimen or duration of treatment used by health professionals.
To assess the effects of dose, regimen and duration of antithyroid drug therapy for Graves' hyperthyroidism.
We searched seven databases and reference lists.
Randomised and quasi-randomised trials of antithyroid medication for Graves' hyperthyroidism.
Two authors independently extracted data and assessed risk of bias. Pooling of data for primary outcomes, and select exploratory analyses were undertaken.
Twenty-six randomised trials involving 3388 participants were included. Overall the quality of trials, as reported, was poor. None of the studies investigated incidence of hypothyroidism, changes in weight, health-related quality of life, ophthalmopathy progression or economic outcomes. Four trials examined the effect of duration of therapy on relapse rates, and when using the titration regimen 12 months was superior to six months, but there was no benefit in extending treatment beyond 18 months. Twelve trials examined the effect of block-replace versus titration block-regimens. The relapse rates were similar in both groups at 51% in the block-replace group and 54% in the titration block-group (OR 0.86, 95% confidence interval (CI) 0.68 to1.08) though adverse effects (rashes (10% versus 6%) and withdrawing due to side effects (16% versus 9%)) were significantly higher in the block-replace group. Three studies considered the addition of thyroxine with continued low dose antithyroid therapy after initial therapy with antithyroid drugs. There was significant heterogeneity between the studies and the difference between the two groups was not significant (OR 0.58, 95% CI 0.05 to 6.21). Four studies considered the addition of thyroxine alone after initial therapy with antithyroid drugs. There was no significant difference in the relapse rates between the groups after 12 months follow-up (OR 1.15, 95% CI 0.79 to 1.67). Two studies considered the addition of immunosuppressive agents. The results which were in favour of the interventions would need to be validated in other populations.
The evidence suggests that the optimal duration of antithyroid drug therapy for the titration regimen is 12 to 18 months. The titration (low dose) regimen had fewer adverse effects than the block-replace (high dose) regimen and was no less effective. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism. Immunosuppressive therapies need further evaluation.
Most recently, a new rapid and fully automated electrochemiluminescence immunoassay for the determination of TSH receptor autoantibodies (TRAb) based on the ability of TRAb to inhibit the binding of a human thyroid-stimulating monoclonal antibody (M22) has been established.
To evaluate this assay system in clinical routine based on an international multicentre trial and to compare the results with other established TRAb assays.
Totally 508 Graves' disease (GD), 142 autoimmune thyroiditis, 107 subacute thyroiditis, 109 nonautoimmune nodular goitre, 23 thyroid cancer patients and 446 normal controls were retrospectively evaluated.
ROC plot analysis revealed an area under curve of 0.99 (95% CI: 0.99-1.0) indicating a high assay sensitivity and specificity. The highest sensitivity (99%) and specificity (99%) was seen at a cut-off level of 1.75 IU/l. Here, the calculated positive predictive value was 95%, whereas the negative predictive value was 100%. Applying the ROC plot-derived cut-off of 1.75 IU/l we found a sensitivity for TRAb positivity within the group of newly diagnosed GD patients of 97% which is in accordance to the sum of different nonautomated porcine TSH receptor-based assays with a sensitivity of 94% indicating an excellent analytical performance of the new assay format. Detailed comparison of the automated and the sum of manual assays revealed a near identical specificity.
Our results demonstrate that this new assay system has a high sensitivity for detecting GD and specificity for discriminating from other thyroid diseases. This assay may represent the future technology for rapid fully automated TRAb detection.
Graves' disease is a common autoimmune disorder in women in fertile ages. The hyperthyroidism is causedby generation of TSH-receptor activating antibodies. In pregnancy both the antibodies and the antithyroid medication given to the mother pass the placenta and affect the foetal thyroid gland. Thyroid function should be controlled not only in the mother with Graves' hyperthyroidism but also in her foetus.The review includes two cases illustrating some of the problems in managing Graves' disease in pregnancy.
Major threats to optimal foetal thyroid function are inadequate or over aggressive antithyroid drug therapy of the mother. It should be taken into account that antithyroid drugs tend to block the foetal thyroid function more effectively than the maternal thyroid function, and that levothyroxin ( l -T 4 ) given to the mother will have only a limited effect in the foetus.
Surgical thyroidectomy of patients with Graves' hyperthyroidism does not lead to immediate remission of the autoimmune abnormality, and the combination thyroidectomy+withdrawal of antithyroid medication+ l -T 4 replacement of the mother involves a high risk of foetal hyperthyroidism.
Conclusion
Antithyroid drug therapy of pregnant women with Graves' hyperthyroidism should be balanced to control both maternal and foetal thyroid function. Surgical thyroidectomy of a pregnant woman with active disease may lead to isolated foetal hyperthyroidism.
They're useful in diagnosing Graves' disease and, to a lesser extent, autoimmune thyroid disease; they can also help predict hypothyroidism. Thyrotropin receptor antibodies (TRAb) may be mildly elevated in a variety of thyroid disorders, but a TRAb level >10 U/L increases the probability of Graves' disease by a moderate to large degree (strength of recommendation [SOR]: cross-sectional study). A positive or negative thyroid peroxidase antibody (TPOAb) test increases or decreases the probability of autoimmune thyroid disease by only a small to moderate degree (SOR: 3 cross-sectional studies). Thyroid-stimulating hormone (TSH) levels >2 mU/L, although still in the normal range, can be followed up with TPOAb testing to determine whether the patient has an increased probability of developing hypothyroidism (SOR: cohort study with a vague hypothyroidism reference standard).
Thirty consecutive patients with hyperthyroid Graves' disease received a 6-month course of antithyroid drugs. Sixteen patients relapsed within 6 months of the withdrawal of antithyroid therapy. All patients with high levels of thyroid-stimulating antibodies (TSAb) at the time of drug withdrawal relapsed within 2 months of discontinuing the antithyroid treatment while all patients with low or undetectable TSAb activity at the time of drug withdrawal remained in remission. It was not possible to predict the disease course in patients who had intermediate levels of TSAb when antithyroid therapy was stopped.
A 54-year-old woman was treated with an oral dose of S55MBq of 131I radioiodine for thyrotoxicosis. She had no clinically detectable extrathyroidal manifestations of Graves' disease at the time, but within two months developed moderately severe ophthalmopathy and very extensive thyroid dermopathy affecting her face, arms, hands and feet, in addition to the classic pre-tlblal area. Although she developed mild post radioiodine hypothyroidism, this was detected at an early stage and its treatment had no effect on the extrathyroldal signs. Thyrotrophin receptor antibodies (TRAb) were positive before treatment (22% Inhibition of T S H binding in neat serum), rose to very high levels following radioiodine (97.6% Inhibition), and fell progressively over the following year during treatment with prednisolone. Thyroglobulln autoantibodies became detectable following radioiodine but thyroid peroxidase antibodies were undetectable throughout. Serum and purified IgG from blood samples obtained prior to steroid therapy and over the subsequent year were tested on a dermal fibroblast cell line in vitro for the stimulation of synthesis of glycosamlnoglycans, protein and DNA, but no increase in radiolabel incorporation was apparent for any sample when compared to controls. The temporal relation between the radioiodine and the acute onset of dermopathy and ophthalmopathy, together with the abrupt rise in TRAbs, indicates a probable causal association.
However, the absence of In-vitro fibroblast stimulation would suggest that the pathogenesis of Graves' dermopathy is not dependent solely on any simple humoral factor.
Treatment of Graves' disease patients with radioactive iodide (RAI) can induce two therapeutically important alterations in immune response to thyroid antigens. These may be characterized as a first response and a second phase response. Initial treatment of patients with Graves' disease by RAI leads to killing of thyroid cells and releases antigen into the circulation. In association with this, there is a dramatic increase in levels of thyroid-stimulating immunoglobulins and in cell-mediated immunoreactivity to TSH receptor (TSH-R) and it peptide epitopes. During this phase, ophthalmopathy often is exacerbated. Although it is logical to believe that the release of antigens and stimulation of immunoreactivity is the cause of the worsened ophthalmopathy, a direct cause and effect only can be inferred. Ophthalmopathy often remains a significant problem or develops during the course of treatment of Graves' disease. My observations are that almost all patients who have progressive ophthalmopathy after many form of thyroid treatment usually have residual thyroid tissue stimulated by thyroid stimulating antibodies, even though they may be hypothyroid and on replacement therapy. In this situation, destruction of residual thyroid tissue is associated with amelioration in ophthalmopathy and is presumed to be effective because of diminution in antigenic stimulation, with a subsequent drop in antibody levels and cell-mediated immunoreactivity to TSH-R extracellular domain (ECD). This constitutes a second phase in the radioiodine response, with effects dramatically different from the initial phase, because this phase is associated with a loss in antigenic stimulation rather than an increase. In a series now comprising > 40 patients treated in an uncontrolled prospective manner, comparison to preablation and postablation ophthalmopathy demonstrates clear benefit in almost all patients over a period of 3-12 months. Radioiodine ablation of residual thyroid tissue is the logical first treatment in management of severe ophthalmopathy and should be used before or with the institution of steroids or radiotherapy.
Many physicians would pay dearly to obtain a marker for the disease that interests them most. Those of us interested in caring for patients with Graves' disease have such a marker. Knowing the titer of TSHR-Abs in patients is useful in the prediction of thyrotoxic recurrence after antithyroid drugs. A careful review of the literature shows strong evidence for the observation that their accurately measured presence predicts hyperthyroidism in more than 90% of cases in iodine-sufficient areas. The assay of TSHR-Abs, therefore, remains a most useful addition to the clinical armamentarium and a low-cost help in treatment planning. Assays to distinguish blocking from stimulating antibodies remain expensive but are only clinically important in patients with pregnancy (40). The major hurdle remains one of increasing the sensitivity of the available assays for TSHR-Ab so that their usefulness can be applied successfully to an even greater proportion of patients with Graves' disease.
Amiodarone is a benzofuranic-derivative iodine-rich drug widely used for the treatment of tachyarrhythmias and, to a lesser extent, of ischemic heart disease. It often causes changes in thyroid function tests (typically an increase in serum T(4) and rT(3), and a decrease in serum T(3), concentrations), mainly related to the inhibition of 5'-deiodinase activity, resulting in a decrease in the generation of T(3) from T(4) and a decrease in the clearance of rT(3). In 14-18% of amiodarone-treated patients, there is overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Preexisting Hashimoto's thyroiditis is a definite risk factor for the occurrence of AIH. The pathogenesis of iodine-induced AIH is related to a failure to escape from the acute Wolff-Chaikoff effect due to defects in thyroid hormonogenesis, and, in patients with positive thyroid autoantibody tests, to concomitant Hashimoto's thyroiditis. AIT is primarily related to excess iodine-induced thyroid hormone synthesis in an abnormal thyroid gland (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), but mixed forms frequently exist. Treatment of AIH consists of L-T(4) replacement while continuing amiodarone therapy; alternatively, if feasible, amiodarone can be discontinued, especially in the absence of thyroid abnormalities, and the natural course toward euthyroidism can be accelerated by a short course of potassium perchlorate treatment. In type I AIT the main medical treatment consists of the simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. Radioiodine therapy is usually not feasible due to the low thyroidal radioiodine uptake, while thyroidectomy can be performed in cases resistant to medical therapy, with a slightly increased surgical risk.
Graves' disease is characterized by stimulating autoantibodies to the TSH-receptor (TRAb). The aim of this study was to compare the performance of a new TRAb assay based on competitive binding to recombinant human TSH-receptors (H-TRAb) with an assay employing purified porcine TSH-receptors (P-TRAb). Furthermore, to evaluate the applicability of the H-TRAb assay to discriminate between patients with hyperthyroidism due to Graves' disease (GD) and multinodular toxic goitre (MNTG).
H-TRAb and P-TRAb were measured in patients with newly diagnosed hyperthyroidism due to GD (n = 106) and MNTG (n = 94). For comparison, TRAb was measured in patients with primary autoimmune hypothyroidism, euthyroid subjects with an enlarged thyroid gland by ultrasound, and healthy controls (n = 100 for each group). Patients were consecutively included from a population survey.
If the cut-off values recommended by the manufacturer for TSH-receptor antibody positivity were used for evaluation, the sensitivity of the H-TRAb assay vs. the P-TRAb assay in diagnosing GD was: 95.3/67.9% (P < 0.001). Specificity was (H/P-TRAb): 99/99%. The sensitivity of P-TRAb was increased if the upper 97.5% limit of measurements in controls was used as cut-off (H-TRAb vs. P-TRAb: 95.3/80.2%, P < 0.001). Specificity (H/P-TRAb): 98/98%. The difference between assay performance may partly be due to a better technical performance of the H-TRAb assay with more reliable results in the low range of measurements. However, even in GD patients with clearly measurable TRAb, 25% had a P-TRAb < 50% of the value expected from the H-TRAb measurement. This suggests that a subgroup of patients produce TRAb with a higher affinity for the human than the porcine TSH receptor. A relatively high proportion of patients with MNTG were TRAb positive (H-TRAb/P-TRAb: 17/9%). Characteristics of H-TRAb positive and negative MNTG patients were compared. There was no difference between size of thyroid gland and number of nodules by ultrasonography. H-TRAb positive patients had significantly higher serum T4 and T3 and a greater number were TPO-Ab positive.
H-TRAb diagnosed Graves' disease with a high sensitivity and specificity than P-TRAb. The high occurrence of TRAb in multinodular toxic goitre might in part reflect an overlap between Graves' disease and multinodular toxic goitre in some patients.
A new procedure for measuring patient serum thyrotropin receptor (TSHR) autoantibodies is described in which the autoantibodies inhibit binding of a human monoclonal thyroid stimulating antibody M22 (labeled with biotin) to TSHR-coated enzyme-linked immunosorbent assay (ELISA) plate wells. In the assay, M22-biotin binding is detected by addition of streptavidin peroxidase. The M22 based assay was more sensitive than a similar ELISA based on inhibition of TSH-biotin binding to TSHR coated wells with 1 U/L of NIBSC 90/672 giving approximately 35% inhibition in the M22-based system compared to approximately 15% inhibition in the TSH-based ELISA. This had an important impact on the precision of the 2 assays with the M22-based ELISA showing an interassay coefficient of variation (CV) of 10% at 1 U/L whereas the TSH-based ELISA had an interassay CV of 20% at 1 U/L. Analysis of sera from 307 control subjects without a diagnosis of Graves' disease indicated that only 2 (0.65%) gave inhibition of M22 binding values of greater than 10% (11% and 12% inhibition). In the case of sera from 108 patients with Graves' disease (treated and untreated) 103 (95%) gave inhibition of M22 binding values of 14% or greater. Receiver operating characteristic (ROC) plot analysis showed that 100% specificity for TSHR autoantibody detection in Graves' disease was obtained at 95% sensitivity for the M22-based ELISA and 89% sensitivity for the TSH-biotin-based ELISA. Inhibition of M22 binding to the TSHR was closely correlated to inhibition of TSH binding in the 108 Graves' sera (r = 0.99). However, inhibition of M22 binding was almost always greater resulting in improved sensitivity and precision.
Advanced technical methods are essential for accurate diagnosis of Graves' or Basedow's disease (GD). Inadequate methods may lead to a false diagnostic conclusion. We have analyzed the clinical features and methodology aspects of cases diagnosed as GD with negative findings for TSH receptor autoantibodies. The initial diagnosis was based on clinical findings (patient record, hypermetabolic state, goiter palpation) and laboratory testing (fT4 and TSH). From a total of 255 newly registered patients with GD, fifty-one (20%) were negative in a conventional porcine TBII assay. All fifty-one patients were retested with 131I or 99mTc uptake tests, thyroid scintigraphy, and a second-generation TBII assay. Results disclosed twenty-one cases (8.3%) with diagnosis other than GD: ten cases of autonomous hyperthyroidism (Plummer's disease), seven cases of painless thyroiditis and four cases of euthyroid endocrine ophthalmopathy. All twenty-one patients remained negative in the second-generation TBII assay. Measurement by second-generation TBII assay was performed on the remaining thirty patients initially found negative for TBII. As a result of this reevaluation, only 234 of the original 255 patients had GD. Of those, 231 (204 according to porcine plus 27 according to human TRAb assay) had detectable TBII (98.7%). This investigation stresses the problem of correct diagnosis and the methodological limitations in the assessment of laboratory parameter validity in GD. Based on this work, TSH receptor autoantibody-negative GD is extremely rare.
According to many guidelines, scintigraphy remains the first suggested diagnostic procedure in hyperthyroid patients in spite of the widespread availability of ultrasounds. The aim of this study was to evaluate the cost-effectiveness of sonography versus scintigraphy in the management of Graves's disease, and to assess ultrasound features suggesting cancer in detecting thyroid nodules. Among 1470 hyperthyroid patients evaluated in our department from 2002 to 2005, 426 (29%) had Graves’ disease: echographic and scintigraphic features were not suggestive of GD in 20/426 (4.8%) and 11/426 (2.6%) patients, respectively (p = 0.763), even if one of the two procedures was almost always diagnostic. Ultrasound identified 68/426 (16%) patients with a concomitant solid lesion, while scintigraphy detected only 9/426 (2.1%) “cold” nodules (p < 0.001). Thyroid cancer was diagnosed in 30/68 (47.7%) patients. Malignancy presented at ultrasound investigation blurred margins (26.7% versus 15.8%), microcalcifications (33.3% versus 28.9%) and an anteroposterior and transverse diameter ratio ≥1 (73.3% versus 71.1%); more frequently than benign nodules, but this was not statistically significant. The total cost to obtain a diagnosis by ultrasound was €14645.34 (€13312.5 for echography + €1332.84 for scintigraphy in the 29 patients “negative” at echographic evaluation for GD) versus €19922.71 by scintigraphy (€19578.96 for scan + €343.75 for ultrasounds in the 11 patients “negative” at scintigraphy).
It is claimed that second generation thyrotropin-binding inhibitory immunoglobulin (TBII) assays have a very high sensitivity for the diagnosis of Graves' hyperthyroidism (GH). However, studies evaluating the accuracy of TBII have been retrospective in nature and/or GH had not been diagnosed independently of TBII. The aim of the present study, therefore, was to prospectively evaluate the frequency and characteristics of TBII-seronegative patients in a population of untreated GH diagnosed independent of serum TBII.
Prospective multicentre observational study.
A total of 259 consecutive untreated patients with a first episode of GH, diagnosed independent of serum TBII. TBII levels were measured by second generation assay and correlated to thyroid function, clinical characteristics and exposure to environmental factors.
Serum TBII was positive in 245 (94.6%) patients and negative (< 2 IU/l) in 14 (5.4%) patients. TBII-seronegative patients had lower fT4 (median 42.5 vs. 53.9 pmol/l, P = 0.02), T3 (median 3.55 vs. 4.90 nmol/l, P < 0.01) and fT3-index (median 4.30 vs. 6.27, P < 0.01) compared to TBII-seropositive patients. None of the TBII-seronegative patients had TSH-receptor activating mutations, Graves' orbitopathy or pretibial myxedema. Serum TBII was positively correlated to free T3 (fT3)-index and free T4 (fT4)-index (P < 0.01), goitre size (P < 0.01) and the prevalence of Graves' orbitopathy (P < 0.01). There were no significant differences between TBII-seropositive and TBII-seronegative patients in environmental factors.
The prevalence of TBII-seronegativity in untreated patients with GH is 5.4% using a second generation assay. TBII-seronegative patients have biochemically less severe thyrotoxicosis and no Graves' orbitopathy. TBII-seronegative and TBII-seropositive patients apparently belong to the same population of GH, albeit the severity of the autoimmune attack is less in TBII-seronegative patients.
The presence of antibodies to TSH receptor (TSHR) is the hallmark of Graves disease (GD). These antibodies mimic the action of TSH, resulting in TSHR stimulation and hyperthyroidism, and have been associated with GD-associated extrathyroidal manifestations. TSH binding inhibition assays and bioassays for measurement of TSHR antibody levels have been used for clinical and research purposes. In the former, inhibition of TSH binding to purified or recombinant TSHR by a patient's immunoglobulins is measured by radioactive or chemiluminescent techniques. In the latter, cyclic AMP production is measured by use of radioimmunoassays or chemiluminescent methods in cells natively or artificially expressing TSHR. In this Review, the different techniques used for the detection of antibodies to TSHR are discussed, together with the clinical applications of antibody measurement, including diagnosis of GD and Graves ophthalmopathy. Prediction of relapse after medical treatment and the clinical course of Graves ophthalmopathy are also addressed.
Thyroid [8] Davies TF. Thyroid-stimulating antibodies predict hyperthyroidism
- Tf Davies
- E Roti
- Le Braverman
- Degroot
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- Tj Mckenna
- Graves 'disease
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