Onset Of Graves Research Articles

Can stress induce dysimmune dysthyroidism?

Hyperthyroidism due to Graves’ disease is autoimmune in origin. The initiation of dysimmunity responsible for the disease is still poorly understood. Numerous population studies show that genetic factors have a major role, but the environment and any kind of stress also contribute to the onset of the disease. There remains the recurring question for medical experts of the accountability of stress in the onset of Graves’ disease. To date, it is impossible to establish a direct link between this disease and a specific stress. The relationship can only be hypothetical, indirect and partial.

Graves' Immune Reconstitution Inflammatory Syndrome in Childhood

The use of hematopoietic stem cell transplantations (HSCTs) as a curative therapy for life-threatening immunodeficiencies has had a profound impact on clinical outcomes. A subset of patients may experience immune reconstitution inflammatory syndrome (IRIS) post-transplant affecting the thyroid gland, but this has received little attention in the pediatric literature. We present the clinical, biochemical, and cytological course of patients with Graves' disease after HSCT in the pediatric population. Four children (median age 1.5 years, range 2 months-9 years) underwent HSCT. The conditioning regimen included chemotherapy but not radiotherapy. None of the children or their donors had evidence of thyroid disease pre-HSCT or during the follow-up period. Engraftment was uneventful in all, with stable donor T-cell chimerism, and none had evidence of graft-versus-host disease. Patients developed Graves' disease soon after undergoing HSCT, with a median time interval between HSCT and Graves' disease of 22 months (range 16-28 months). Graves' disease was diagnosed on the basis of clinical and biochemical parameters, including a suppressed thyrotropin, raised free thyroxine, and raised thyrotropin receptor antibodies. Three patients were hypothyroid initially (suggestive of a Th1 profile) before Graves' disease (suggestive of a Th2 profile). In three patients, the clinical picture changed rapidly with hypothyroidism abruptly followed by profound thyroid hormone excess. The onset of Graves' IRIS coincided with a rapid expansion in naïve and total CD4. Immunological dysregulation during T-cell engraftment is the most likely mechanism for developing Graves' IRIS after allogenic HSTC. Clinicians need to be aware that HSCT-engendered immune recovery may result in a particularly aggressive form of autoimmune thyroid disease in children with implications for the developing central nervous system. Careful surveillance of thyroid function post-HSCT is essential.

The ATA guidelines of thyrotoxicosis

The authors of guidelines provide 100 recommendations describing many intensively discussed issues. Among them is hepatotoxicity of PTU and limitation of PTU treatment mainly to the first trimester of pregnancy. Methimazole becomes first line ATD for patients with new onset of Graves’ disease. Graves’ orbitopathy (GO) is classified according to its clinical activity and severity. Deterioration of GO after radioactive iodine (RAI) treatment and beneficial effects of steroids to prevent RAI induced exacerbation of GO are described. All patients with subclinical thyrotoxicosis who are older than 65 years and those who are below age 65 and have risk factors or hyperthyroid symptoms should be treated. It is proposed to measure TSH receptor autoantibodies in pregnant women with a previous history of autoimmune thyroid disease. The information about thyroid ultrasonography with the colour-flow Doppler for the rapid differentiation between the two main types of amiodarone-induced thyrotoxicosis, and its help for accurate treatment of these conditions is provided.

Graves' Disease Following Subacute Thyroiditis

Subacute thyroiditis is a painful, inflammatory disease frequently accompanied with fever. It is suspected to be a viral infectious disease, while Graves' disease is an autoimmune disease. Thus, there appears to be no etiological relationship between the two diseases. A total of 25,267 thyroid disease patients made their first visits to our thyroid clinic during a period of 24 years between 1985 and 2008. Among them, subacute thyroiditis and Graves' disease accounted for 918 patients (3.6%) and 4,617 patients (18.2%), respectively. We have encountered 7 patients (one male and six female) with subacute thyroiditis followed by Graves' disease in this period (0.15% of the 4,617 patients with Graves' disease and 0.76% of the 918 patients with subacute thyroiditis). The age ranges were 40~66 years (mean 48.7 years) at the onset of subacute thyroiditis. The intervals between the onsets of subacute thyroiditis and Graves' disease were 1~8 months (mean 4.7 months). Because Graves' disease was preceded by subacute thyroiditis, the signs and symptoms of both diseases were evident together in the intervening period. The diagnosis of Graves' disease in those patients is always difficult because of atypical signs and symptoms and an unclear onset time. The causes of the Graves'disease that followed subacute thyroiditis are still unknown. However, the inflammatory nature of subacute thyroiditis may lead to the activation of the autoimmune response in susceptible subjects, resulting in the onset of Graves' disease. Graves' disease should be suspected when a high blood level of thyroid hormone persists after subacute thyroiditis.

Graves' Disease Associated with Infectious Mononucleosis due to Primary Epstein-Barr Virus Infection: Report of 3 Cases

Although the etiology of Graves' disease is still not clear, it is generally suggested that environmental factors such as infections contribute to the development of Graves' disease. We report here three cases of Graves' disease which presented simultaneously with infectious mononucleosis due to primary EBV infection. Acute EBV infection might play an important role in the onset of Graves' disease. These three women complained of a sore throat or neck pain, resembling subacute thyroiditis. In the case of thyrotoxicosis accompanied by sore throat or neck pain, Graves' disease must be distinguished from subacute thyroiditis.

Graves' Disease Accompanied by Pheochromocytoma: Report of a Case

We present here a rare case of Graves' disease accompanied by pheochromocytoma, and the patient showed normal urine and serum levels of catecholamines and their metabolites. A 45-year-old woman was referred to our hospital for the evaluation of a right adrenal incidentaloma that was detected by chest computed tomography. She had been diagnosed with Graves' disease 1 month previously. She had no symptoms of pheochromocytoma such as hypertension or a history of hypertension attack. Two consecutive 24-hour urine samples were sent to the lab for measurement of the catecholamines, and both samples showed normal levels of metanephrine and vanillylmandelic acid (VMA). After right adrenalectomy was performed, the final pathological diagnosis was adrenal pheochromocytoma. This case suggests that the onset of Graves' disease may be associated with excess catecholamine secreted by a pheochromocytoma. In addition, although the conventional method for detecting pheochromocytoma is to identify an increase of the urine catecholamines, physicians should be aware of the possibility of false negativity on this test. (J Korean Endocr Soc

The post partum period and the onset of Graves' disease: an overestimated risk factor

Aggravation of autoimmune diseases due to a rebound reaction to the pregnancy-associated immune changes is common during the post partum (PP) period. Previous studies demonstrated that up to 45% of women developing Graves' disease (GD) in the childbearing age had a PP onset of disease. Thus, the PP period was identified as a major risk factor for GD onset. The aim of this study was to evaluate the role of the PP period as a risk factor for GD occurrence. The reproductive histories of 291 consecutive GD patients (165 patients in the childbearing age and 126 in the non-childbearing age) were retrospectively collected. The rate of PP onset of GD in all patients with at least one successful pregnancy was 9.8 and 20.0% when only patients in the childbearing age were considered. In the entire cohort of GD women, independent of their age and parity status (i.e., the number of successful pregnancies), the rate of PP onset of GD was 7.2%. The relative frequencies of the rate of PP onset of GD were similar in relation with increasing parity. The rates of false negative (nulliparous) and false positive (parous non-childbearing+childbearing with a non-PP onset of GD) were estimated. The positive predictive value of the PP period for the onset of GD was less than 10%. The results of the current study would not support a role for the PP period as a major risk factor for de novo occurrence of GD.

What is the role of the allergic sensitization in Graves’ disease?

Recent data supported the presence of T helper 2 dominance in the immune processes of Graves' disease and allergic diseases. A common role of regulatory T cells in the antigen- (or allergen-) specific immune responses was also demonstrated. To study whether allergic events may play a role in the initiation or progression of autoimmune Graves' disease. The occurrence of seasonal allergy may explain the fluctuation in the onset of Graves' disease. The presence of specific IgE levels against inhalative allergens was investigated in 327 patients with thyroid disease (Graves' disease, Hashimoto's thyroiditis, euthyroid goitre). Western blot method was used for the measurement of allergen-specific IgE levels with densitometric evaluation. Allergic sensitization was found in 88 cases (58%) for Graves' disease, 51 cases (46%) for Hashimoto's thyroiditis and 31 cases (55%) for euthyroid goitre. According to allergens, significant difference was demonstrated by Penicillium notatum, Dermatophagoides farinae, alder - rye (pollens) between Graves' disease (depending ophthalmopathy) and euthyroid goitre. In the four groups based on allergen seasonality, the month of the onset in Graves' disease was associated with the season of early tree and mugwort allergy (P < 0.019 between Graves' disease and Hashimoto's thyroiditis). The number of cases, in whom the onset of Graves' disease in a given month was similar to the month of allergic season, was 17 cases vs 7 cases with Hashimoto's thyroiditis (P < 0.028). The allergic sensitization was more frequent in Graves' disease, and the allergic seasonality may explain the fluctuation in the onset of Graves' disease.

Intercellular adhesion molecule 1 gene polymorphisms do not contribute to Graves’ disease in Chinese patients

In order to study the association of G241R polymorphism of ICAM-1 gene with an earlier onset of Graves' disease (GD) and the susceptibility of K469E polymorphism to Graves' ophthalmopathy (GO) in Chinese population. A case-control and replication study was performed in 212 GD patients and 204 healthy subjects to analyze the genotypes. Furthermore the distribution of ICAM-1 genotypes was investigated in subgroups of patients with GD according to the onset age and the ophthalmopathy. No G241R polymorphism of ICAM-1 gene was detected in Chinese. No significant differences of allele and genotype frequencies regarding K469E polymorphism were found between GD patients and healthy controls (chi2 = 0.092, P = 0.762; chi2 = 1.089, P = 0.580). In addition, the genotype-phenotype correlation was not identified either. We found no association of G241R and K469E polymorphisms of the ICAM-1gene with the development of GD in a Chinese population. However, we could not rule out possible contributions of other polymorphisms of the ICAM-1gene to the pathogenesis of GD. Therefore, further studies are needed to elucidate the role of ICAM-1gene in Graves' disease in different population.

The onset of Graves’ disease during the clinical course of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis

A 47-year old man presented with atrial fibrillation, weight loss, hand tremor, and hyperperspiration concurrent with the reactivation of the disease activity of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis. Laboratory findings indicated that the hyperthyroidism had already existed when glomerulonephritis was detected, and Graves' disease became evident while decreasing the dose of prednisolone. Although the levels of thyroid-stimulating hormone receptor antibody, antithyroid peroxidase antibody, and myeloperoxidase antibody increased, both disease activities were suppressed by increasing the dose of prednisolone. This case indicates that MPO-ANCA-associated glomerulonephritis and Graves' disease may share a common pathogenesis.

A C/T Polymorphism in the 5' Untranslated Region of the CD40 Gene Is Associated with Later Onset of Graves' Disease in Japanese

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. CD40, which stimulates lymphocyte proliferation and differentiation, is an important immunomodulator and is expressed in the thyroid follicular cells as well as antigen-presenting cells. A single nucleotide polymorphism (SNP) at position -1 of the Kozak sequence of the CD40 gene has been reported to be associated with the development of GD. The aim of the present study was to investigate whether CD40 gene polymorphism confers susceptibility to GD in Japanese. CD40 gene polymorphisms were studied in Japanese GD patients (n = 324) and healthy control subjects without anti-thyroid autoantibodies or a family history of autoimmune disorders (n = 229). A C/T polymorphism at position -1 of the CD40 gene was measured using the polymerase chain reaction restriction fragment length polymorphism. There was no significant difference in allele or genotype frequency of the CD40 SNP between GD and control subjects. There was a significant decrease in the TT genotype frequency in the GD patients, who developed GD after 40 years old, than those under 40 year of age. These data suggest that the SNP of CD40 gene is associated with susceptibility to later onset of GD in Japanese.

Stress and Thyroid Autoimmunity

While many studies have shown a connection between stress and autoimmune disease, most of the evidence for stress contributing to the onset and course of autoimmune disease is circumstantial and the mechanisms by which stress affects autoimmune disease are not fully understood. The best circumstantial evidence for an effect of stress on autoimmune thyroid disease is the well-known relationship between the onset of Graves' hyperthyroidism and major stress but even this is debated. However, most of the recent case-control studies have supported stress as a factor that affects the onset and clinical course of Graves' disease. On the other hand, there have been few reports concerning the possible relationship between stress and Hashimoto's thyroiditis. Because the onset and course of Hashimoto's thyroiditis is generally insidious, the effect of stress on Hashimoto's thyroiditis might be overlooked. Numerous human and animal studies have demonstrated that psychological and physiologic stressors induce various immunologic changes. Stress affects the immune system either directly or indirectly through the nervous and endocrine systems. These immune modulations may contribute to the development of autoimmunity as well as the susceptibility to autoimmune disease in genetically predisposed individuals. Stress can be one of the environmental factors for thyroid autoimmunity.

Seasonal Variation in Relapse Rate of Graves' Disease after Thionamide Drug Treatment

Controversy abounds on the issue of seasonal variation in new onset of Graves' disease, partly due to the difficulty of precisely dating the exact start of symptoms. To address the possible relationship between climatic changes and disease activity from a different perspective, we reviewed time of relapse during regular follow-up after successful drug treatment with thionamides. Retrospective analysis of a case series in a university clinic. We consecutively registered patients who experienced re-emergence of hyperthyroidism between 1992 and 2001 after successful antithyroid drug therapy. Excluded were subjects with superimposing painless thyroiditis, in postpartum, on immunomodulatory drugs, or off thionamides prematurely on their own volition. Fifty-two patients recurred 2 to 36 months after drug cessation. The frequency was higher in spring and summer (March to August) than in autumn and winter (September to February). With a new coated-tube radioreceptor assay, TSH binding inhibitor immunoglobulin activity was detected in sera from 87.5% of the reworsened patients. Graves' disease tends to relapse more frequently in spring and summer. Further clinical studies are warranted to clarify underlying mechanism (s) for this seasonal variation.

Stress e Doença de Graves. Relações entre o número e o impacto dos acontecimentos geradores de Stress e o início da Doença de Graves.

In recent years, there have been many reports about a possible association between Stressful Life Events (SLE) and the onset of Graves' Disease (GD). Nevertheless, most papers have been criticised and no such association has yet been proven. To assess the possible associations between SLE and the onset of GD. Retrospective study of 62 subjects, divided into 2 groups of 31 each, GD (Gp1) and controls (Gp2). The patients in Gp1 had thyroid disease diagnosed within the last 12 months, with clinical and biochemical confirmation. In Gp2, psychopathological and endocrine disturbances had been ruled out. Each 2 group consisted of 9 males (29%) and 22 females (71%). The mean age was 38.48 + 10.9 in Gp1 and 41.1 + 11.8 in Gp2. SLE evaluation (number and impact) was reported for the 12 months preceding the onset of symptoms of thyroid disease. To assess SLE, we used the Life Experiences Survey-LES from Saranson, Johnson and Siegel (1978; 1985). Statistical analysis was done using Mann-Whitney and Kruskal-Wallis tests. Patients with GD had a significantly greater number of SLEs compared to Controls (p < .001). The number and impact of negative SLEs was significantly higher in Gp1 compared to Gp2 (p < .001). There were no significant differences between the groups in terms of the number and impact of both positive and neutral SLEs. The findings of this study support that SLEs may contribute to the precipitation of GD. We observed that patients with GD had significantly more negative events and experienced a greater negative impact from them prior to the onset of GD. The association of SLEs with GD is probably related to the association of stress with changes in the immune system, which can play an important role in the aetiology of thyrotoxicosis.

Does Graves’ Disease during Puberty Influence Adult Bone Mineral Density?

Aim: To evaluate the bone mineral density at lumbar spine and at femoral neck in a group of young adults in whom Graves’ disease developed during childhood and adolescence. Patients and Methods: We examined 28 patients (5 male, 23 female, age 20.9 ± 3.3 years) who were 11.8 ± 2.9 years old at the onset of Graves’ disease. They were treated either with methimazole (14 patients) or with methimazole plus l-thyroxine (14 patients). At the time of the investigation, 13 patients were considered cured following antithyroid treatment, 2 were still on antithyroid drugs, 3 were on replacement therapy with l-thyroxine because of hypothyroidism, and 10, treated either surgically or with ¹³¹I, were on replacement therapy. The bone mineral density was measured at the lumbar spine (L2–L4) and at the femoral neck, using dual-energy X-ray absorptiometry. Results: The spinal bone mineral density SD score was –0.28 ± 1.02, the femoral neck bone mineral density SD score was 0.36 ± 1.02, and both were not different from zero (NS). We did not find any correlation between the bone mineral density of the femoral neck and that of the lumbar spine and the clinical parameters. Conclusion: Graves’ disease, beginning in childhood and adolescence, when appropriately treated, does not affect attainment of peak bone mass.

Relationship between the number and impact of stressful life events and the onset of Graves' disease and toxic nodular goitre.

In the last few decades, several studies have suggested a possible association between Stressful Life Events (SLEs) and the onset of Graves' Disease (GD). However, others have criticised this association and it has not yet been possible to prove it unequivocally. At present, we are not aware of studies correlating SLE and non autoimmune thyrotoxicosis. To assess possible associations between SLEs, the onset of GD and the onset of non autoimmune thyrotoxicosis (toxic nodular goitre, TNG). A case-control retrospective study. This study included 93 subjects, divided into three groups of 31 each: GD, TNG and control (CG). The GD and TNG patients had thyroid disease diagnosed within the last 12 months, with clinical and biochemical confirmation. In the CG, psychopathological and endocrine disturbances had been ruled out. All three groups consisted of nine males (29%) and 22 females (71%). The mean age was 38.4 +/- 10.9 years in the GD group, 48.3 +/- 11.1 years in the TNG group and 41.1 +/- 11.8 years in the CG group. SLEs were evaluated (number and impact) for the 12 months preceding the onset of symptoms of thyroid disease. SLE occurrences and their impact on each group of cases were measured. To assess SLEs, we used the Life Experiences Survey (LES). Our statistical analysis included descriptive techniques and parametric and/or nonparametric comparative tests. P < 0.01 was considered statistically significant. Odds ratios were also calculated. Patients with GD had a significantly greater number of SLEs compared to the TNG group and the CG (P < 0.001). The number and impact of negative SLEs were significantly higher in GD compared to TNG and CG (P < 0.001). The difference between TNG and CG was not significant (P > 0.01). GD had a higher impact of positive SLEs than TNG (P = 0.004), and no significant differences were found between the GD group and CG. Neutral SLEs were similar in the three groups. These results suggest that SLEs are a precipitating factor of the onset of GD. We also demonstrated that SLEs do not seem to have any conclusive relationship with the onset of TNG.

Postpartum autoimmune thyroid syndrome.

Postpartum thyroid dysfunction is rather a common problem during postpartum period, found in approximately 5% of mothers in the general population. It occurs from subclinical autoimmune thyroiditis that is aggravated after parturition and causes various types of thyroid dysfunction. Immune activity is physiologically suppressed during pregnancy so that the fetus is not rejected, and rebounds above the normal level after parturition. Graves' disease and Hashimoto's thyroiditis spontaneously ameliorate during pregnancy, and are often aggravated after parturition. The high-risk mothers for postpartum thyroid dysfunction can be well screened by anti-thyroid microsomal antibody (MCAb) and 60% to 70% of MCAb-positive mothers develop postpartum thyroid dysfunction, which is transient in most cases. New onset of Graves' disease may be screened by thyroid stimulating antibody (TSAb) and 70% of TSAb-positive mothers develop either transient or persistent postpartum Graves' disease that usually occurs at 3-6 months postpartum. Immune rebound after parturition may not cause only autoimmune thyroid diseases but other autoimmune Table 4. Various types of postpartum autoimmune disease diseases, which may be investigated with the similar strategies to those in postpartum autoimmune thyroid disease. Thus, we found that postpartum onset of rheumatoid arthritis occured in 0.08% of women in the general population and could be partially predicted by measuring rheumatoid factors in early pregnancy. There are several case reports of other autoimmune diseases developed after delivery; postpartum renal failure or post-delivery hemolyticuremic syndrome, postpartum idiopathic polymyositls, postpartum syndrome with antiphospholipid antibodies, postpartum autoimmune myocarditis. Many other possible postpartum autoimmune diseases are still unexplored. Postpartum autoimmune thyroid syndrome is a good model for understanding the mechanism of onset and aggravation of other autoimmune diseases. Prediction and prevention of postpartum onset of many autoimmune diseases could be established in the near future.

HLA-DRB1*08, DRB1*03/DRB3*0101, and DRB3*0202 are susceptibility genes for Graves' disease in North American Caucasians, whereas DRB1*07 is protective.

Graves' disease is known to be HLA-D associated; however, the primary loci involved remain unclear. We examined HLA genotypes of DRB1 and DQB1 plus DRB3 subtypes using PCR-based sequence-specific priming in two groups of North American (Gainesville, FL; and Toronto, Canada) Caucasian patients with Graves' disease. We stratified patients into those with either early age at onset (<20 yr; 13.1 +/- 4.8 yr; n = 30) and later age at onset of disease (38.8 +/- 9.7 yr; n = 62) and compared the results to 192 normal controls. As expected, we found that DRB1*03 was associated with Graves' disease, but at a higher odds ratios for early-onset than later-onset patients (3.7 vs. 2.2). The frequency of DRB1*08 was also increased in both groups of patients, but significantly so only in patients with early-onset Graves' (P = 0.001; chi2 = 10.8). DRB3 was highly associated with Graves' in both groups of patients (P = 0.009; chi2 = 6.83 and P = 0.0015; chi2 = 10.1, respectively); however, the subtypes of DRB3 revealed differential susceptibilities. Whereas the frequencies of both DRB3*0101 and DRB3*0202 were increased over the entire cohort, that of DRB3*0301 was not. Significant P values were found for DRB3*0101 in patients with early-onset and for DRB3*0202 in patients with later onset of Graves' disease. When the haplotypes of DRB1*03-DRB3 of all subtypes were removed for analysis (all DRB1*03 positive also had DRB3*0101), the frequency of DRB3*0202 remained significantly higher in the patients with later onset of Graves' disease than in controls (P = 0.0043; chi2 = 8.13), but DRB3 was no longer positively associated with the early-onset group. In addition, we found that DRB1*07 was negatively associated with both groups of patients (P = 0.024; chi2 = 5.10 and P = 0.0085; chi2 = 6.93). These data suggest that DRB3*0202 is more likely to be the primary susceptible locus than DRB1*03 for patients with later onset of Graves' disease.

Postpartum autoimmune thyroid syndrome: a model of aggravation of autoimmune disease.

Postpartum thyroid dysfunction is rather a common problem during the postpartum period being found in approximately 5% of mothers in the general population. It occurs from subclinical autoimmune thyroiditis that is aggravated after parturition and causes various types of thyroid dysfunction. Immune activity is physiologically suppressed during pregnancy so that the fetus is not rejected, and rebounds above the normal level after parturition. Graves' disease and Hashimoto's thyroiditis also spontaneously ameliorate during pregnancy, and are often aggravated after parturition. The high-risk mothers for postpartum thyroid dysfunction are well screened by antithyroid microsomal antibody (MCAb) and 60% to 70% of MCAb-positive mothers develop postpartum thyroid dysfunction, which is transient in most cases. New onset of Graves' disease may be screened by thyroid-stimulating antibody (TSAb) and 70% of TSAb-positive mothers develop either transient or persistent postpartum Graves' disease that usually occurs 3 to 6 months postpartum. Immune rebound after parturition may cause not only autoimmune thyroid diseases but other autoimmune diseases, which may be investigated with similar strategies to those in postpartum autoimmune thyroid disease. Thus, we found that postpartum onset of rheumatoid arthritis was found in 0.08% of women in the general population and could be partially predicted by measuring rheumatoid factors in early pregnancy. There are several case reports of other autoimmune diseases that develop after delivery; postpartum renal failure or postdelivery hemolytic-uremic syndrome, postpartum idiopathic polymyositis, postpartum syndrome with antiphospholipid antibodies, postpartum autoimmune myocarditis. Many other possible postpartum autoimmune diseases are still unexplored. Puerperal diseases should be carefully examined in relation to autoimmune abnormalities in the affected organs.

Quinine Hypersensitivity Simulating Sepsis

Little is known about the onset and presymptomatic phase of Graves’ disease. Although it may be characterized by vague symptoms of insidious onset, this case demonstrates that the onset can actually be abrupt. Furthermore, an asymptomatic preclinical phase—which in our patient was associated with tachycardia and increased calorie requirements— can last for more than a month. This case illustrates that the onset of Graves’ disease can be abrupt and have a lengthy presymptomatic phase that may delay diagnosis.