Immune reactions in patients with Graves' disease.

Although Graves' disease exhibits many features of an autoimmune disturbance there is uncertainty regarding, in particular, the role of cell-mediated immunity. Therefore, we undertook a sequential study of peripheral lymphocyte responsiveness to phytomitogens, concentrations and ratios of T and B lymphocytes, and skin hypersensitivity to multiple antigens, throughout periods of antithyroid drug therapy in patients with hyperthyroidism of Graves' disease. Careful attention was paid to obtaining control lymphocyte data with blood from normal subjects matched for age and sex. A micromethod using whole blood was applied to measurement of peripheral lymphocyte responses (incorporation of tritiated [³H] thymidine) to phytohemagglutinin (PHA) and to pokeweed mitogen (PWM).Total lymphocyte concentrations and the proportions of T and B cells were normal in 26 patients studied; there was a mild excess of total lymphocytes and T cells in 12 patients with fresh disease versus that in six patients with persisting or recurrent hyperthyroidism. Responses of lymphocytes to pokeweed mitogen were normal but to phytohemagglutinin, significant differences from controls were identified: With one day of culture, cells from the patients were more responsive; with six days of incubation, they were less responsive than were cells from corresponding control subjects. These differences were not found with patients restudied after three to 10 months of treatment with propylthiouracil. The ratio of T:B cells varied with the donor's age, as did responses to pokeweed mitogen. Responses to phytohemagglutinin after one and six days of incubation, and to pokeweed mitogen after three days correlated positively with the concentration of serum thyroxine.Delayed hypersensitivity to four antigens injected intradermally was normal; the degree of skin response to tuberculin purified protein derivative correlated significantly with in vitro lymphocyte responses to that antigen.Our data confirm some abnormalities of lymphocyte function in Graves' disease. It remains unclear to what degree reversion to normal during therapy reflects a change in basic pathogenetic mechanisms or an influence of thyroid hormones per se. The importance of age and sex in studies of this nature is emphasized.     

Immunological findings and thyroid function of untreated Graves' disease patients with undetectable TSH-binding inhibitor immunoglobulin

OBJECTIVE TSH-binding inhibitory immunoglobulin (TBII) is undetectable in about 10% of untreated Graves' disease patients, but the clinical characteristics and immunological significance of this finding are unknown. In this study we evaluated the clinical characteristics of TBII negative Graves' disease. PATIENTS We examined TBII in 1048 untreated patients at Kuma hospital from 1986 to 1990 and found 69 TBII undetectable patients (12 men and 57 women, mean age ± SEM 35 ± 2 years, group A). MEASUREMENTS We compared the clinical characteristics and immunological findings of group A with 57 untreated TBII detectable Graves' patients who were selected randomly (11 men and 46 women, mean age ±SEM 40 ±2 years, group B). T4, TSH, FT4, FT3, 1231 thyroid uptake, TBII, thyroid stimulating antibodies (TSAb) and the volume of the thyroid using ultrasonography were measured at the first visit. RESULTS Serum T4, FT4 and FT3 levels in group A were significantly lower than those in group B (P<0 001). The values of TSAb in group A were significantly lower than those in group B (593±67 (mean±SE) vs 2143±280%, respectively, P < 0001). The 1231 thyroid uptake in group A was significantly lower than that in group B (53 1 ±11 vs 61 -4±14%, respectively, P<0.01).The thyroid volume in group A was significantly smaller than that in group B (391 ±3 0 vs 51 3±3 3 ml, respectively, P<0 01). TSAb was undetectable in about 10% (6) of the TBII negative untreated Graves' patients at their first visit. CONCLUSION In the present study, untreated TBII negative patients with Graves' disease were characterized by mild elevation of thyroid hormones, mildly elevated ¹²³l uptake, weak TSAb activities and small goitres. The finding of both TBII and TSAb negative titres in untreated Graves' disease patients was also confirmed.     

Graves病患者中与性别相关的临床特点分析

Objective To investigate the gender-related differences in patients with Graves'disease (GD).Methods Seven hundred and eighty-seven consecutive patients with GD treated with anti-thyroid drug in out-patient clinic of department of endocrinology of Chinese PLA general hospital from Oct.2009 to May 2010 were included in the study.The diagnosis of GD WSB made according to common clinical and laboratory criteria.Results (1)In Graves'disease,a marked female preponderance Was found.The female/male ratio was 3.35:1.Female patients with GD presented at a younger age,compared with males[(33.20±13.07 vs 36.75±13.89)year,P=0.002],and the peak incidences of the disease occurred in female and male were 20-29 years and 40-49 years of age respectively.(2)Male patients presented a higher prevalence of weight loss,thyrotoxic cardiopathy,periodic paralysis,and non-invasive ophthalmopathy whereas tachycardia was more common in females.(3)The females presented larger diffuse goiters with higher serum TT4,FT4,and thyrotropin receptor antibody(TRAb)levels.Cases with TRAb>30 U/L were more common in females,whereas those with TRAb 10-30 U/L were frequently seen in males.(4)There was no gender-related difference in the family history of GD.(5)Remission atleast 6 months after anti-thyroid drug therapy in 211 patients,there was a relapse rate of 64.3%(137/211)without gender difference.Conclusion GD appeared at a younger age and with larger diffuse goiters in females,together with more marked elevation of serum TT4,FT4 and TRAb levels.Altogether,these findings depict different patterns for GD in males and females.     

Graves病患者中与性别相关的临床特点分析

Objective To investigate the gender-related differences in patients with Graves'disease (GD).Methods Seven hundred and eighty-seven consecutive patients with GD treated with anti-thyroid drug in out-patient clinic of department of endocrinology of Chinese PLA general hospital from Oct.2009 to May 2010 were included in the study.The diagnosis of GD WSB made according to common clinical and laboratory criteria.Results (1)In Graves'disease,a marked female preponderance Was found.The female/male ratio was 3.35:1.Female patients with GD presented at a younger age,compared with males[(33.20±13.07 vs 36.75±13.89)year,P=0.002],and the peak incidences of the disease occurred in female and male were 20-29 years and 40-49 years of age respectively.(2)Male patients presented a higher prevalence of weight loss,thyrotoxic cardiopathy,periodic paralysis,and non-invasive ophthalmopathy whereas tachycardia was more common in females.(3)The females presented larger diffuse goiters with higher serum TT4,FT4,and thyrotropin receptor antibody(TRAb)levels.Cases with TRAb>30 U/L were more common in females,whereas those with TRAb 10-30 U/L were frequently seen in males.(4)There was no gender-related difference in the family history of GD.(5)Remission atleast 6 months after anti-thyroid drug therapy in 211 patients,there was a relapse rate of 64.3%(137/211)without gender difference.Conclusion GD appeared at a younger age and with larger diffuse goiters in females,together with more marked elevation of serum TT4,FT4 and TRAb levels.Altogether,these findings depict different patterns for GD in males and females.     

Graves病患者中与性别相关的临床特点分析

目的 分析Graves病患者性别相关的临床特点.方法 收集2009年10月至2010年5月在解放军总医院内分泌科门诊就诊的787例Graves病患者临床资料,并按性别进行对比分析.Graves病诊断标准:甲状腺功能亢进(甲亢)同时具有下述2个或多个特征:弥漫性甲状腺肿、甲亢性突眼和促甲状腺激素受体抗体(TRAb)阳性.结果 (1)787例Graves病患者中女性多见,女:男=3.35:1;女性发病年龄更小[(33.20±13.07对36.75±13.89)岁,P=0.002],高峰年龄段明显提前[(20-29对40-49)岁];(2)Graves病常见或少见症状和体征中,男性患者体重减轻、甲亢性心脏病、周期性麻痹和非浸润性突眼更多见,女性则以窦性心动过速和不伴甲亢性突眼更常见、甲状腺弥漫性肿大程度更明显;(3)女性患者血清TT4、FT4、和TRAb水平明显高于男性,其中TRAb显著升高(>30 U/L)者中女性多见,中度升高(10-30U/L)者中则以男性多见;(4)两性患者甲亢家族史无差异,均以母系家族史多见;(5)甲亢治疗预后(问卷调查)显示211例使用抗甲状腺药物治疗至少6个月并停药的患者中复发率为64.3%(137/211),复发率没有性别差异.结论 Graves病临床特点存在明显的性别差异.

Abstract：

Objective To investigate the gender-related differences in patients with Graves'disease (GD).Methods Seven hundred and eighty-seven consecutive patients with GD treated with anti-thyroid drug in out-patient clinic of department of endocrinology of Chinese PLA general hospital from Oct.2009 to May 2010 were included in the study.The diagnosis of GD WSB made according to common clinical and laboratory criteria.Results (1)In Graves'disease,a marked female preponderance Was found.The female/male ratio was 3.35:1.Female patients with GD presented at a younger age,compared with males[(33.20±13.07 vs 36.75±13.89)year,P=0.002],and the peak incidences of the disease occurred in female and male were 20-29 years and 40-49 years of age respectively.(2)Male patients presented a higher prevalence of weight loss,thyrotoxic cardiopathy,periodic paralysis,and non-invasive ophthalmopathy whereas tachycardia was more common in females.(3)The females presented larger diffuse goiters with higher serum TT4,FT4,and thyrotropin receptor antibody(TRAb)levels.Cases with TRAb>30 U/L were more common in females,whereas those with TRAb 10-30 U/L were frequently seen in males.(4)There was no gender-related difference in the family history of GD.(5)Remission atleast 6 months after anti-thyroid drug therapy in 211 patients,there was a relapse rate of 64.3%(137/211)without gender difference.Conclusion GD appeared at a younger age and with larger diffuse goiters in females,together with more marked elevation of serum TT4,FT4 and TRAb levels.Altogether,these findings depict different patterns for GD in males and females.     

Clinical studies on abnormal thyroid stimulators in patients with Graves' disease. II. Clinical significance of measuring TSAb and TBII in patients with euthyroid Graves' disease and patients with hyperthyroid Graves' disease during antithyroid drug treatment

To evaluate the clinical significance of TBII and TSAb activities in euthyroid and hyperthyroid Graves' disease, these two activities were measured in 8 patients with euthyroid Graves' disease and 29 patients with hyperthyroid Graves' disease during treatment with antithyroid drugs. In 8 patients with euthyroid Graves' disease, TBII activity was detectable only in one patient and TSAb activity detected in 3 patients, these detectabilities being much lower than those in hyperthyroid Graves' disease. However, 2 of 4 patients who had either TSAb or TBII came to have both activities, and one of them became overt hyperthyroid. In patients with hyperthyroid Graves' disease, detectabilities of these activities became lower as they became euthyroid with antithyroid drug treatment, but TSAb tended to be higher than TBII when they remained euthyroid for more than 4 months. Although the majority of the patients who had TSAb and/or TBII activities were T3 non-suppressible, patients with no TSAb and TBII activities did not necessarily show remission of the disease. The present results suggest that patients with euthyroid Graves' disease with both TBII and TSAb may be apt to become hyperthyroid, and that TSAb and TBII activities and T3 suppressibility may not be a definite criteria for the remission of Graves' disease.     

Ileal function in patients with untreated adult coeliac disease.

A double-lumen perfusion technique has been used to investigate jejunal and ileal absorption of glucose, water, and electrolytes in a group of patients with untreated adult coeliac disease. Correct positioning of the tube was confirmed by measuring the differential jejunal and ileal handling of bicarbonate. Eight control subjects and eight patients with coeliac disease were perfused with an isotonic electrolyte solution containing 50 mM glucose and 25 mM bicarbonate. The group of coeliac patients had impaired jejunal absorption of glucose (P less than 0.001), water (P less than 0.01), sodium (P less than 0.02), and chloride (P greater than 0.05) compared with the control group. In contrast the group of coeliac patients had normal ileal glucose and water absorption and increased ileal sodium (P greater than 0.01) and chloride (P greater than 0.05) absorption compared with the controls. Evidence for ileal adaptation was found in three individual patients who had absorptive values outside 2SD of the normal mean. The results indicate that the distal small intestine in coeliac disease has the ability to adopt to the damage and loss of absorptive capacity in the proximal small intestine.     

Thyroid cancer yield in patients with Graves' disease

The management of thyroid nodules in patients with Graves' disease remains an issue both of concern and controversy for those who care for these patients. At one time, thyroid cancer in patients with thyrotoxicosis was considered to be extremely rare, but this perception has proven to be incorrect. Several studies have demonstrated both an increased incidence of nodules and of thyroid cancer in patients with Graves' disease, with cancer rates varying from as low as 1% to as high as 9% of cases. These divergent estimates of malignancy rates in Graves' disease have predictably led to variability in management recommendations. Considerable controversy also exists as to whether or not thyroid cancer behaves more aggressively in patients with Graves' disease. Anecdotal experience and a number of studies have suggested an increased aggressiveness of papillary and follicular thyroid cancer in patients with Graves' disease, but these findings are not universal. Underlying both issues of the incidence and aggressiveness of thyroid cancer is the role of thyrotropin (thyroid stimulating hormone, TSH) in the development and stimulation of thyroid cancer. The association between TSH and thyroid cancer has long been known. TSH has a central role in thyroid growth and normal functioning and appears to play a similar part in the growth and development of thyroid cancer. The close relationship of TSH to the stimulating TSH-R antibodies (TSH-R AB) seen in Graves' disease has led to the perception that thyroid cancer occurring in the setting of Graves' disease may become more aggressive as a result of stimulation by these autoantibodies. This article will summarize the existing literature pertaining to thyroid cancer in Graves' disease, and suggest an evidence-based approach to the management of these patients.     

Changes in cytokine production during pregnancy in patients with Graves' disease.

In order to investigate the role of type 1 and type 2 cytokines in the remission of Graves' disease (GD) during pregnancy, spontaneous and mitogen-stimulated production of interleukin (IL)-4, IL-6, IL-10, IL-12, interferon-gamma (IFN-gamma), and tumour necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunospot assay of peripheral blood mononuclear cells from 10 pregnant women with GD, 8 healthy pregnant women, and 10 healthy nonpregnant women. Tests were performed in the first, second, and third trimesters of pregnancy and 10-17 weeks after delivery. IL-4 production was not affected greatly by normal or GD pregnancy, whereas IFN-gamma production was suppressed throughout pregnancy but returned to normal levels after delivery in both controls and patients. IL-6 and TNF-alpha tended to be higher in GD pregnancy than normal pregnancy, especially in the second and third trimesters. Controls had raised IL-10 in the first trimester with a return to normal levels by the third trimester, whereas patients had raised levels throughout pregnancy. IL-12 levels were suppressed to a greater extent in control than Graves' pregnancy, especially during the second and third trimesters. Ratios of IL10:IL12 in phytohemaglutinin (PHA)-stimulated cultures were much lower in GD than normal pregnancy and cross-regulation of IL-10 and IL-12 may be deficient in GD.     

Increased serum anti-carbonic anhydrase II antibodies in patients with Graves' disease.

Carbonic anhydrase II (CA II) has an important role in thyroid hormone synthesis via regulating iodide (I-) transport across thyroidal cell membranes and the existence of autoantibodies against CA I and/or CA II have been shown in sera from patient with various autoimmune diseases such as Sj?gren's Syndrome, Systemic Lupus Erythmatosus, type 1 diabetes, primary biliary cirrhosis and ulcerative colitis. The aim of this study was to investigate the presence of anti-CA I and CA II antibodies in autoimmune thyroid disease and the relationships between the autoantibodies and other clinical parameters. We studied 40 autoimmune thyroid patients (20 Hashimoto's thyroiditis, HT and 20 Graves' disease, GD ) and 21 healthy control subjects. Serum anti-CA I and CA II antibodies were screened by ELISA. Positive rate of anti-CA II (25%) antibody was significantly higher in GD patients as compared to HT patients and control subjects (p<0.05). There were no significant changes in positive rate of anti-CA I antibody. In addition, a significant correlation between serum anti-CA antibodies titers and other studied clinical parameters was not found. The results suggest that anti-CA II antibodies may be involved in the pathogenesis of GD.     

Increased serum concentration of eosinophil-derived neurotoxin in patients with Graves' disease.

Eosinophil-derived neurotoxin (EDN) is released after activation and stimulation of eosinophils in allergic disease, which is a T(H)2-predominant condition. We previously reported that Graves' thyrotoxicosis develops or relapses after an attack of allergic rhinitis. In this study, to confirm the relation between Graves' disease and the allergic condition, we determined the serum level of EDN in 30 untreated patients with Graves' disease, 50 patients with Hashimoto's thyroiditis, and 39 normal controls. Compared to the serum level in normal subjects (30.1 +/- 15.6 ng/mL), EDN was increased in untreated patients with Graves' disease (52.4 +/- 27.6 ng/mL), but not in patients with Hashimoto's thyroiditis (thyrotoxic, 30.9 +/- 13.4 ng/mL; euthyroid, 30.0 +/- 11.9 ng/mL; hypothyroid, 23.4 +/- 10.2 ng/mL). A significant correlation was observed between the EDN level and the serum activity of thyrotropin (TSH) receptor antibody (r = 0.541, p < 0.0001). These data suggest that the allergic condition is closely related to Graves' disease and that a T(H)2-type immune response is crucial in the pathogenesis of Graves' disease.     

Hyperthyroidism due to Graves' disease in aged patients.

Hyperthyroidism due to Graves' disease is more prominent in older patients than was originally thought. Aged patients with this disorder have characteristic clinical and hormonal features that are different from those in younger patients. Thus, Graves' disease in aged patients is not merely a milder form of the disease seen in youth, but is qualitatively different in many aspects. Owing in part to incomplete understanding of the etiology of Graves' disease, the pathophysiologic reasons for these differences are unknown.