Graves' disease in the elderly

Characterization of elderly (> or = 65) patients with Graves' disease (GD) was discussed. Emaciation was the symptom that was most frequently found in elderly patients. The presence of goiter, exophthalmos and increased appetite decreased with age, while weight loss, anorexia and arrhythmia increased. Elderly patients often have serious complications such as congestive heart failure and atrial fibrillation. Serum levels of free T3, free T4 and TSH receptor antibodies were significantly lower in elderly patients. In addition to fewer clinical signs and symptoms of GD in elderly patients, prominent cardiac or gastrointestinal findings may make the diagnosis more difficult. Elderly GD patients should be treated with antithyroid drugs. Radioiodine therapy may be considered after normalization of serum thyroid hormone levels.     

Autoimmunity and Graves' disease

Current treatment options for Graves' hyperthyroidism and the related ophthalmopathy (GO) are not uniformly effective and carry with them potentially serious side effects. As a result, efforts have been focused on the development of novel therapies. Progress has been made, particularly in the production of thyroid-stimulating hormone receptor (TSHR) antagonists, as either monoclonal blocking antibodies or small-molecule ligands. In addition, rituximab (RTX) is the first targeted biological therapy to be studied as treatment for these conditions.     

Hyperthyroidism affects arterial stiffness, plasma NT-pro-B-type natriuretic peptide levels, and subendocardial perfusion in patients with Graves' disease

BACKGROUND: Arterial stiffness is thought to play a critical role in the pathogenesis of cardiovascular events, and in hyperthyroidism increased cardiovascular event rates have been reported. AIM: To investigate markers of systemic arterial stiffness, volume homeostasis, and subendocardial perfusion and its interrelationship in patients with Graves' disease (GD) in hyperthyroidism and euthyroidism. METHOD: Aortic augmentation index (AIx@75) as a measure of systemic arterial stiffness and subendocardial viability ratio (SEVR) as a surrogate measure of subendocardial perfusion were assessed by applanation tonometry in 59 patients with GD in hyperthyroidism and euthyroidism, and measurements were compared to plasma levels of NT-pro-B-type natriuretic peptide (NT-ProBNP). RESULTS: AIx@75 and NT-ProBNP levels were significantly increased in hyperthyroidism compared to euthyroidism and were positively correlated with each other. SEVR was significantly decreased in hyperthyroidism compared to euthyroidism, mainly due to increased heart rates as shown by the heart rate-corrected SEVR75. CONCLUSIONS: In hyperthyroidism, patients with GD exhibited increased systemic arterial stiffness, paralleled by increased levels of NT-ProBNP, a marker of volume overload. The decreased subendocardial perfusion in hyperthyroidism seemed to be mainly due to increased heart rates. The observed unfavorable hemodynamic alterations in hyperthyroidism may serve to explain increased cardiovascular event rates in patients with GD.     

Increased stiffness in common carotid artery in hyperthyroid Graves' disease patients.

The present study was undertaken to assess the effect of hyperthyroidism on stiffness in the common carotid artery (CCA) in patients with Graves' disease (GD) and elucidate the mechanism by which arterial stiffness is increased in hyperthyroidism. The arterial stiffness index beta (stiffness beta) was evaluated in the CCA using an ultrasonic phase-locked echo-tracking system. Stiffness beta was defined as the logarithm of the ratio of systolic to diastolic blood pressure divided by the fractional diameter increase during the cardiac cycle and thus established as a measure of arterial stiffness uninfluenced by the change in blood pressure. Seventy euthyroid GD patients were measured for CCA stiffness beta to determine its relationship to retinal blood flow and plasma levels of vascular injury markers. To investigate the effect of hyperthyroidism, 27 GD patients were measured for changes during antithyroid drug (ATD) therapy in stiffness beta and in hemodynamic parameters, retinal blood flow and plasma vascular injury markers. In euthyroid GD patients, stiffness beta in the CCA showed a significant and positive correlation with systolic blood pressure and pulse pressure, but not with peripheral blood flow in the central retinal artery. ATD therapy significantly reduced stiffness beta from 5.23 +/- 2.10 to 4.36 +/- 1.48. The fractional reduction of stiffness beta during ATD therapy correlated significantly with reductions in pulse pressure and retinal blood flow, but not with the reductions in systolic and mean blood pressure, or any of the plasma injury markers. In summary, the significant increase in stiffness beta in the hyperthyroid state may reflect the harmful effect of hyperthyroidism on the arterial wall, which may in turn result from increased stroke volume.     

Oxidative stress peripheral parameters in Graves' disease: the effect of methimazole treatment in patients with and without infiltrative ophthalmopathy

OBJECTIVES: The study was designed to estimate the influence of hyperthyroidism and antithyroid treatment on oxidative stress peripheral parameters in Graves' disease patients with and without infiltrative ophthalmopathy. DESIGN AND METHODS: Free radical generation and scavenging plasma indices were determined in 47 patients with hyperthyroidism due to Graves' disease (22 with and 25 without infiltrative ophthalmopathy), as well as in 24 healthy volunteers after euthyroidism achievement with methimazole. RESULTS: In the hyperthyroid patients, hydrogen peroxide, lipid hydroperoxides, thiobarbituric acid-reacting substances, ceruloplasmin, superoxide dismutase, and catalase were increased. Glutathione peroxidase and glutathione reductase, however, were reduced. Methimazole treatment resulted in all markers being normalized in the patients without infiltrative ophthalmopathy, yet oxidative stress was still present in the ophthalmopathy group. CONCLUSION: We suggest that apart from the thyroid metabolic status influence, it is orbital inflammation that triggers changes in blood extracellular indices of reactive oxygen species metabolism.     

Use of an artificial neural network to predict Graves' disease outcome within 2 years of drug withdrawal

BACKGROUND: Graves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism, which can relapse in many patients after antithyroid drug treatment withdrawal. Several studies have been performed to predict the clinical course of GD in patients treated with antithyroid drugs, without conclusive results. The aim of this study was to define a set of easily achievable variables able to predict, as early as possible, the clinical outcome of GD after antithyroid therapy. METHODS: We studied 71 patients with GD treated with methimazole for 18 months: 27 of them achieved stable remission for at least 2 years after methimazole therapy withdrawal, whereas 44 patients relapsed. We used for the first time a perceptron-like artificial neural network (ANN) approach to predict remission or relapse after methimazole withdrawal. Twenty-seven variables obtained at diagnosis or during treatment were considered. RESULTS: Among different combinations, we identified an optimal set of seven variables available at the time of diagnosis, whose combination was useful to efficiently predict the outcome of the disease following therapy withdrawal in approximately 80% of cases. This set consists of the following variables: heart rate, presence of thyroid bruits, psycological symptoms requiring psychotropic drugs, serum TGAb and fT4 levels at presentation, thyroid-ultrasonography findings and cigarette smoking. CONCLUSIONS: This study reveals that perceptron-like ANN is potentially a useful approach for GD-management in choosing the most appropriate therapy schedule at the time of diagnosis.     

甲状腺功能测定对内分泌突眼的诊断价值

目的探讨三碘甲状腺原氨酸(T3)、游离三碘甲状腺原氨酸(FT3)、甲状腺素(T4)、游离甲状腺素(FT4)、促甲状腺素(TSH)测定对内分泌性突眼的诊断价值。方法采用化学发光法检测130例Graves病(GD)伴眼球突出患者、127例单纯性GD患者、128例正常人血清T3、FT3、T4、FT4、TSH水平,并对检测结果进行比较分析。结果与正常对照组相比,GD伴眼球突出患者和单纯GD患者血清T3、FT3、T4、FT4、TSH水平明显升高(P<0.05),GD伴眼球突出患者和GD患者血清T3、FT3、T4、FT4、TSH水平无明显差异,这些指标水平与突眼呈相关关系。结论甲状腺功能的测定虽然对GO的诊断作用无明显帮助,却有助于临床医生判断突眼的严重程度,从而制定合理的治疗方案。     

Increased level of soluble interleukin-2 receptor in sera of patients with Graves' disease.

Soluble interleukin-2 receptor was studied in 20 patients with Graves' disease before and after methimazole treatment. Soluble interleukin-2 receptor level was significantly increased in newly diagnosed Graves' disease compared to controls (667 +/- 270 vs 205 +/- 45 U/ml) (P less than 0.001). In untreated patients' sera the soluble interleukin-2 receptor levels were higher in patients with active ophthalmopathy than in those without eye symptoms. Soluble interleukin-2 receptor levels were normalized in remission induced by methimazole treatment in the majority of patients except those with infiltrative ophthalmopathy. Furthermore, a correlation was found at the hyperthyroid stage of the disease between soluble interleukin-2 receptor level and titre of anti-TSH-receptor antibodies. However, the association with other parameters including anti-eye muscle, anti-thyroid peroxidase, anti-thyroglobulin antibodies was not significant.     

Graves病眼型和眼型Graves病临床分析比较

目的比较分析Graves病眼型和眼型Graves病的不同临床特点,以供临床诊断。方法对69例Graves病眼型和38例眼型Graves病病例资料进行了临床分析。结果发现两者具有特征性眼症,眼睑退缩,上睑下落退缓,眼球前突症状。Graves病眼型患者自觉症状明显,且多双眼患病,双眼球突出,病程较长,而眼型Graves病患者多为青状年,约半数无任何自觉症状,且单眼患病多见,主要为单眼球突出。实验室检查眼型Graves病患者三碘甲状腺原氨酸(T3)、甲状腺素(T4)、促甲状腺素(TSH)一般均在正常范围内,Graves病眼型患者T3、T4、TSH常常有不同程度增高。结论Graves病眼型应根据临床表现,实验室检查T3、T4、131I进行确诊,眼型Graves病排除甲状腺功能亢进外,眼眶X线片、B超排除眶内占位性病变以确诊。临床医师应提高对Graves病眼型和眼型Graves病的认识,以减少误诊和漏诊。     

甲状腺相关性眼病与甲状腺自身抗体的关系

目的探讨甲状腺相关性眼病与甲状腺自身抗体的关系。方法对原发甲减组、甲亢组、甲状腺相关性眼病组及对照组均给予促甲状腺激素受体抗体(TRAb)、甲状腺微粒体抗体(TMA)、甲状腺球蛋白抗体(TGA)检测。结果甲状腺相关性眼病组TRAb与其它三组相比差异均具有显著性(P<0.05)。甲状腺相关性眼病组TGA与原发甲减组相比差异具有显著性(P<0.05),与甲亢组相比则差异无显著性(P>0.05)。甲状腺相关性眼病组TMA与原发甲减组、甲亢组相比差异均具有显著性(P>0.05)。甲状腺相关性眼病组、原发甲减组、甲亢组的TRAb、TMA、TG与对照组相比差异均具有显著性(P<0.05)。结论 TRAb与甲状腺相关性眼病具有较好的相关性,对其诊断、治疗及预后有很大的临床价值,TGA、TMA与甲状腺相关性眼病的相关性则较弱。     

Peripheral blood T lymphocyte sensitization to thyroid microsomal antigen from patients with Graves' disease negative for circulating anti-thyroid microsomal antibodies

We have studied thyrocyte HLA-DR expression induced by supernatants of peripheral blood mononuclear cells (PBMC) stimulated by thyroid microsomal antigen (TMA), as an index of sensitization of the T lymphocyte in autoimmune thyroid diseases; we have studied PBMC from 11 normal control persons and 19 patients with Graves' disease (GD) in whom serum anti-thyroid microsomal antibodies (AMA) were either not detectable (9 patients) or were positive (10 patients). Thyrocyte HLA-DR induction in response to TMA-treated PBMC supernatants from GD was significantly different from that of normal controls (p less than 0.05, ANOVA). TMA-stimulated GD PBMC supernatants increased thyrocyte HLA-DR index [TMA 1 ng/ml, SI 143 +/- 82 (mean +/- SD), p less than 0.05], but normal PBMC supernatants did not. However there was no significant difference in response in terms of the thyrocyte HLA-DR expression induced by TMA-stimulated PBMC supernatants between AMA seronegative vs seropositive GD. These results suggest the possibility of some dissociation of the activities of T lymphocytes and B lymphocytes in patients with GD in response to thyroid microsomal antigen with or without anti-thyroid microsomal antibodies.     

The ophthalmopathy of Graves' disease

Fortunately, most patients with thyroid-related eye disease have mild ocular involvement that spontaneously involutes. Less than 5% of patients with hyperthyroidism will develop sufficiently severe ocular abnormalities that will require surgical intervention. Most patients with thyroid eye findings should be symptomatically managed. Some will require use of either topical drops or oral steroids to alleviate their eye problems. In approximately one half of those patients who present acutely with severe thyroid orbital finding, nonsurgical therapies will be sufficient to control their eye disease. In the other half, eventually multiple surgical procedures may be required, and as discussed previously, the timing and sequence of those procedures are crucial to achieve optimal results.     

Thyroid-associated ophthalmopathy: clinical features, pathogenesis, and management

Thyroid-associated ophthalmopathy (TAO) is a progressive eye disorder characterized by immune-mediated inflammation of the extraocular muscles and orbital connective tissue. TAO is linked, in a unique way, with thyroid autoimmunity, in particular Graves' hyperthyroidism. Our working hypothesis for the pathogenesis of TAO is that recognition of a thyrotropin receptor (TSHR)-like protein in the orbital preadipocytes by antibodies may be the initial event leading to homing of lymphocytes into the orbital tissues. In the course of thyroid inflammation, antibodies and T cells reactive against G2s expressed in thyroid membranes cross-react with the protein in the eye muscle fiber, leading to eye muscle damage and dysfunction. Those patients with anti-G2s antibodies develop ocular myopathy. Antibodies against flavoprotein, the 64-kDa protein, which are produced in the context of eye muscle fiber damage and mitochondrial rupture, are sensitive markers of immune-mediated fiber necrosis in patients with ophthalmopathy but do not directly damage the eye muscle. Antibodies against type XIII collagen, which is localized in the plasma membranes of orbital fibroblast, may be a new marker for the congestive ophthalmopathy subtype of TAO. The measurement of antibodies against key eye muscle and orbital connective tissue autoantigens may have a role in the management of active ophthalmopathy and its prediction in patients with Graves' hyperthyroidism.     

Graves' disease in interferon-alpha-treated and untreated patients with chronic hepatitis C virus infection.

An association between Graves' disease (GD) and chronic hepatitis C (C-HC) has been observed both in the presence and the absence of recombinant interferon-alpha (rIFN-alpha) treatment. rIFN-alpha-induced GD is characterized by suppressed thyroid-stimulating hormone levels; normal or elevated free triiodothyronine (FT3) and free thyroxine (FT4) values; the presence of thyroid peroxidase antibodies, antithyroglobulin antibodies, and thyroid receptor antibodies; and high iodine thyroid uptake. In contrast, GD developed during C-HC without rIFN-alpha is less clearly defined. In this study, we examined two groups of patients: group A, 28 patients with C-HC treated with rIFN-alpha who developed GD after 1 to 9 months, and group B, 10 patients with C-HC who developed GD without a previous rIFN-alpha treatment. At the time of GD, both groups started methimazole therapy; thyroid function was reevaluated after 3, 6, 9, and 12 months. Group A patients continued IFN. After 12 months, all patients of group A were euthyroid, and 21 of them (75%) had already stopped methimazole treatment, whereas all patients of group B were euthyroid and only 2 (20%) had stopped methimazole. In conclusion, the data show a better course of GD, with a more precocious and significantly higher number of recoveries in patients with rIFN-alpha-induced GD than in rIFN-alpha-unrelated disease. Further studies are needed to establish whether the two types of GD differ not only from a clinical point of view but also because of different underlying pathogenetic mechanisms.     

药物治疗对Graves病甲亢患者血清脂联素表达水平的影响

目的对药物治疗Graves病甲亢患者后血清脂联素水平的变化情况进行分析研究。方法选择108例Graves病甲亢患者为研究对象,将其分成GD1和GD2两个亚组,GD2组患者接受甲亢药物治疗;另取同期来我院行健康检查的50例体检健康者为健康对照组,全面探究Graves病甲亢患者治疗前后血清脂联素水平的变化情况。结果血清脂联素水平变化:和健康对照组相比,GD1组患者较高,GD2组较低,各组数据之间的差异具有统计学意义(P0.05)。TSH水平变化:GD组患者比对照组低,GD1组的TSH水平低于GD2组(P0.05)。FT3水平变化:和健康对照组相比,GD两个亚组患者均显著升高,且GD1组高于GD2组(P0.05)。FT4水平变化:和健康对照组相比,GD1组患者血清FT4水平显著升高(P0.05);GD2组的FT4水平稍低(P0.05)。各组血清脂联素水平和TSH呈负相关,和FT4,FT3为正相关,与其余基线资料不存在相关性。结论 Graves病甲亢患者脂联素水平上升,在经过药物治疗之后,其水平下降且低于健康体检组,同时与甲状腺激素水平保持相关性,这说明脂联素水平受甲状腺激素调控。     

Serum laminin in Graves' disease

Abstract. We determined serum levels of laminin in 23 patients with Graves' disease (GD) and in 24 patients with toxic nodular goiter (TNG). Elevated levels of soluble laminin were observed in patients with GD prior to treatment (median concentration 1376 ng mL^-1 [range 712–2402]), compared to patients with TNG (median 442 ng mL^-1 [284–891]), and normal controls (median 492 ng mL^-1 [range 235–675], n = 26) respectively. In GD patients serum laminin levels decreased during thiamazole treatment and normalized within 8 weeks of therapy. There was no correlation between serum laminin levels and serum levels of thyroid hormones and/or auto-antibodies, respectively. Whether serum laminin is a marker for alterations of extracellular matrix during GD and release of basement membrane components in the circulation and/or reflects an impaired clearance remains to be elucidated.     

Thymic hyperplasia in patients with Graves' disease. Identification of thyrotropin receptors in human thymus.

Thymic size and density were studied in 23 untreated patients with Graves' disease and 38 control subjects using computed tomography. Both thymic size and density were higher in untreated patients with Graves' disease than in control subjects in the age-matched group. After treatment with antithyroid drugs, both thymic size and density were significantly reduced, with a concomitant decrease in thyrotropin receptor antibodies. PCR of human thymic cDNA using primers for human thyrotropin receptor amplified a fragment in a size expected for the receptor, and its nucleotide sequence was identical to human thyrotropin receptor cDNA in the thyroid. Northern blot analysis of human thymic poly(A)+ RNA demonstrated the presence of the full length form of thyrotropin receptor mRNA. Western blot analysis of human thymic membrane using anti-thyrotropin receptor peptide antibodies demonstrated a band of 100 kD that was also observed in the thyroid membrane. Immunohistochemistry of thymic tissue using mouse antihuman thyrotropin receptor monoclonal antibodies demonstrated the immunostaining of epithelial cells. These results indicate that thymic hyperplasia is apparently associated with Graves' disease and suggest that thymic thyrotropin receptor may act as an autoantigen that may be involved in the pathophysiology of development of Graves' disease.     

Clinical studies of the reactivity of serum IgG from patients with Graves' ophthalmopathy with porcine orbital tissue preparations

The clinical utility of ELISA assays for antibodies reactive with a variety of porcine orbital tissue antigen preparations is described using sera from large numbers of patients. Use of such assays does not allow reliable identification of patients with Graves' ophthalmopathy (GO) due to the overlap between patients with and without eye involvement and normal individuals. In 5/6 patients showing high levels of reactivity with porcine eye muscle membrane antigen, a considerable but variable proportion of the binding was found to be species, rather than tissue, specific. No consistent pattern of change in ELISA reactivity with time was seen in studies of serum samples from patients treated medically for hyperthyroidism and patients who received immunosuppressive therapy with cyclosporin A for active, severe ophthalmopathy. Use of previously published ELISA methods using the crude antigen preparations described is therefore not likely to be of use in the routine clinical management of GO patients.     

Postpartum thyroiditis presenting as a cold nodule and evolving to Graves' disease

We describe the case of a 30-year-old woman who, five months after giving birth, was referred with a solitary nodule in her anterior neck. Laboratory analysis, ultrasonography, pertechnetate (Tc99m) thyroid scan and cytological examination of fine needle aspiration biopsy performed on the nodule led us to diagnose postpartum thyroiditis (PPT). Twenty-eight months after parturition, overt hyperthyroidism developed, with raised thyroperoxidase and thyroid stimulating hormone receptor antibody titres, diffuse high uptake of Tc99m at thyroid scan, and high vascular flow throughout the gland at Color-Power imaging. The diagnosis of Graves' disease (GD) was established. The differential diagnosis of thyrotoxicosis in the postpartum period, and the possible aetiological relationships between PPT and GD are discussed. To our knowledge, this is the first published report of a PPT presenting as a cold nodule, and evolving to GD.     

Prediction of remission after antithyroid drug treatment in Graves' disease

A prospective study was carried out to determine the factors which influence response to antithyroid drug treatment in Graves' disease and to assess their predictive value. Eleven variables were included in the assessment and were subjected to discriminant analysis, log rank test and "survival" analysis. The patients were observed for a considerable period (mean duration 51 months). Carbimazole (mean total dose 8 g) was given in combination with thyroxine for an average of eight months to 72 patients. Thirty-five patients relapsed and 37 remain in remission. Thyrotrophin binding inhibiting immunoglobulins (TBII) were detectable in 74 per cent of patients at diagnosis and thyroid stimulating antibodies detectable in 70 per cent. At the end of treatment thyrotrophin binding inhibiting immunoglobulins and thyroid stimulating antibodies were present in 36 and 27 per cent of patients respectively. Levels of thyrotrophin binding inhibiting immunoglobulins were significantly higher both before and after treatment in the group who relapsed, but were not of prognostic significance in an individual patient unless the value was extremely high (TBII index greater than 70). The presence of thyroid stimulating antibodies was of no value in predicting outcome. HLA typing confirmed the known association of Graves' disease with HLA B8 and HLA DR3 but neither of these antigens conferred and increased likelihood of relapse. The likelihood of relapse is shown to be directly related to the severity of the disease at the time of diagnosis, as measured by the serum total T3, and to the size of the thyroid gland; it is not affected by age, family history of thyroid disease or ophthalmopathy. The data indicate that antithyroid drug treatment can be expected to induce long-term remission in patients with mild disease (T3 less than 5 nmol/l) and small thyroids; carbimazole at this dose level is inappropriate for patients with severe disease (T3 greater than 9 nmol/) and large goitres.