Limited genetic susceptibility to severe Graves' ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology.

Graves' disease (GD) is an autoimmune thyroid disease (AITD) characterized by hyperthyroidism and by the occurrence of a distinctive ophthalmopathy (orbitopathy), which presents with varying degrees of severity. Graves' disease clusters in families but the importance of heredity in the pathogenesis of the associated ophthalmopathy is unclear. We have studied the family history of 114 consecutive, ethnically mixed patients with severe Graves' ophthalmopathy (GO). Patients were selected by unambiguous single ascertainment. Seventy-seven percent of patients were female and 59% smoked. The mean age at onset of their GD was 43 years (range 17-78 years). Forty-one patients (36%) had a family history of AITD, defined as a first- and/or a second-degree relative affected with either Graves' disease (GD) or Hashimoto's thyroiditis (HT). The segregation ratio for AITD in nuclear families in our ascertained Graves' ophthalmopathy families was 0.07 (0.12 in Caucasians only). Hence, the higher prevalence of AITD among relatives of Graves' ophthalmopathy patients agreed with the known genetic predisposition to AITD and this predisposition was stronger in women than in men. However, only 3 of the 114 patients had a family history of severe Graves' ophthalmopathy (all second-degree relatives) and the segregation ratio for GO was 0. These data did not support a major role for familial factors in the development of severe Graves' ophthalmopathy distinct from Graves' disease itself. In addition, we tested 4 candidate genes, human leukocyte antigen (HLA), tumor necrosis factor-beta (TNF-beta), CTLA-4 and the thyrotropin receptor (TSHR), for association with Graves' ophthalmopathy. These were negative except for the HLA and CTLA-4 genes, which were found to be weakly associated with GO giving similar relative risk (RR) as in GD patients without ophthalmopathy. These data suggested that environmental factors, rather than major genes, were likely to predispose certain individuals with AITD to severe Graves' ophthalmopathy. Smoking remains one example of such potential external insults.     

Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype

CONTEXT: Both genetic and environmental factors contribute to susceptibility to Graves' disease (GD) and Hashimoto's thyroiditis (HT), as well as disease manifestations. OBJECTIVE: The objective of the study was to define how endogenous/environmental factors contribute to variation in phenotype. DESIGN/SETTING: This was a multicenter cohort study. PATIENTS/OUTCOME MEASURES: We prospectively collected clinical/biochemical data as part of the protocol for a United Kingdom DNA collection for GD and HT. We investigated, in 2805 Caucasian subjects, whether age at diagnosis, gender, family history (FH), smoking history, and presence of goiter influenced disease manifestations. RESULTS: For 2405 subjects with GD, the presence of goiter was independently associated with disease severity (serum free T4 at diagnosis) (P < 0.001). Free T4 (P < 0.05) and current smoking (P < 0.001) were both independent predictors of the presence of ophthalmopathy. Approximately half of those with GD (47.4% of females, 40.0% of males) and HT (n = 400) (56.4% of females, 51.7% of males) reported a FH of thyroid dysfunction. In GD, a FH of hyperthyroidism in any relative was more frequent than hypothyroidism (30.1 vs. 24.4% in affected females, P < 0.001). In HT, a FH of hypothyroidism was more common than hyperthyroidism (42.1 vs. 22.8% in affected females, P < 0.001). For GD (P < 0.001) and HT (P < 0.05), a FH was more common in maternal than paternal relatives. The reporting of a parent with thyroid dysfunction (hyper or hypo) was associated with lower median age at diagnosis of both GD (mother with hyperthyroidism, P < 0.001) and HT (father with hypothyroidism, P < 0.05). In GD and HT, there was an inverse relationship between the number of relatives with thyroid dysfunction and age at diagnosis (P < 0.01). CONCLUSIONS: Marked associations among age at diagnosis, disease severity, goiter, ophthalmopathy, smoking, and FH provide evidence for interactions between genetic and environmental/endogenous factors; understanding these may allow preventive measures or better tailoring of therapies.     

Smoking and thyroid disorders--a meta-analysis

BACKGROUND: Smoking has been associated with Graves' disease, but it remains unclear if the association is present in other thyroid disorders. OUTCOME VARIABLES: Graves' disease, Graves' ophthalmopathy, toxic nodular goitre, non-toxic goitre, post-partum thyroid disease, Hashimoto's thyroiditis, or hypothyroidism. MATERIAL AND METHODS: A search of MEDLINE identified 25 studies on the association between smoking and thyroid diseases. RESULTS: In Graves' disease eight studies were available showing an odds ratio (OR) of 3.30 (95% confidence interval (CI): 2.09-5.22) in current smokers compared with never smokers. In ex-smokers there was no significant excess risk of Graves' disease (OR=1.41, 95% CI: 0.77-2.58). The OR associated with ever smoking in Graves' ophthalmopathy (4.40, 95% CI: 2.88-6.73, six studies) was significantly higher than in Graves' disease (1.90, 95% CI: 1.42-2.55, two-sided P-value <0.01). Ever smoking was not associated with toxic nodular goitre (OR=1.27, 95% CI: 0.69-2.33, three studies), while there was an increased risk of non-toxic goitre in smokers if men were excluded (OR=1.29, 95% CI: 1.01-1.65, eight studies). The risk associated with smoking was significantly lower in men than in women for both Graves' disease and non-toxic goitre. Hashimoto's thyroiditis and post-partum thyroid dysfunction were also associated with smoking while the association with hypothyroidism did not reach statistical significance. CONCLUSIONS: Cessation of smoking seems associated with a lower risk of Graves' disease than current smoking. Smoking increases the risk of Graves' ophthalmopathy beyond the risk associated with Graves' disease alone. Smoking cessation may lead to a decrease in morbidity from Graves' disease, especially in women.     

Clinical experience with a human thyroid cell bioassay for thyroid-stimulating immunoglobulin

A sensitive, specific, and practical bioassay for thyroid-stimulating immunoglobulin (TSI) is now available for clinical use. Fifty-seven of 61 patients with untreated hyperthyroid Graves' disease were TSI positive (sensitivity, 93%). TSI was undetectable in all normal subjects and in patients with Hashimoto's thyroiditis (without concurrent Graves' ophthalmopathy), nontoxic goiter, and toxic nodular goiter (specificity, 100%). The prevalence of TSI in serum declined after therapy, particularly during methimazole or propylthiouracil treatment. TSI correlated well with relapse or remission after antithyroid drug therapy. All 12 patients who were TSI negative at the time of discontinuing antithyroid drug therapy remained in remission (average follow-up of 10 months). TSI values in Graves' disease correlated better with thyroid dysfunction than with ophthalmopathy. Prenatal TSI activity tended to be higher in mothers of infants who developed neonatal Graves' disease than in at-risk mothers who delivered normal infants. However, there was considerable overlap between the two groups.     

Eye signs and serum eye muscle and collagen XIII antibodies in patients with transient and progressive thyroiditis.

BACKGROUND: There have been reports of the development of ophthalmopathy in patients with subacute thyroiditis (SAT) in the absence of Graves' disease and thyroid-stimulating hormone receptor (TSH-r) antibodies. OBJECTIVE: The aim of the study was to determine the prevalences of eye and eyelid signs and positive eye muscle and collagen XIII antibody tests in patients with SAT and silent thyroiditis (ST) and in patients with Hashimoto's thyroiditis (HT) as chronic thyroiditis controls. DESIGN: Ophthalmopathy was classified as Nunery type 1 (orbital inflammation, proptosis, without restrictive myopathy) or Nunery type 2 (with restrictive myopathy). We tested for antibodies against calsequestrin, flavoprotein (Fp), G2s, and collagen XIII in 5 patients with SAT, 6 with ST, and 11 with HT, and in 12 age- and sex-matched healthy subjects, using an optimized and standardized enzyme-linked immunosorbent assay (ELISA). MAIN OUTCOME: At the first visit, eye signs were found in two patients with SAT, one with type 1 ophthalmopathy and one with type 2 ophthalmopathy, and in three patients with ST, two with type 1 ophthalmopathy and one with dominant upper eyelid retraction only. Later in the course of their illness, one other patient with ST developed mild type 1 disease, giving an overall prevalence of any eye signs of 50% in patients with TT. Five patients with HT had mild type 1 ophthalmopathy and dominant upper eyelid retraction. One or more eye muscle antibodies were detected in three patients with SAT, four with ST, and seven with HT, of which calsequestrin and Fp antibodies were the most commonly found. TSH-r antibodies were detected in only one patient with ST, at the time when she developed Graves' hyperthyroidism following an episode of ST. CONCLUSION: The development of mild, but definite, ophthalmopathy or dominant upper eyelid retraction in patients with TT and chronic (Hashimoto's) thyroiditis in the absence of TSH-r antibodies or Graves' hyperthyroidism is an interesting observation that should be further addressed in larger groups of patients, including those with postpartum thyroiditis. These preliminary findings also raise questions about the mechanism for the link between ophthalmopathy and thyroid autoimmunity.     

Smoking and autoimmune thyroid disease: the plot thickens

New studies have shown that smoking may protect against the development of thyroid peroxidase antibodies, which may result in a decreased risk of Hashimoto's hypothyroidism (HH), whereas it stimulates the development of Graves' hyperthyroidism (GH). According to the above-mentioned hypothesis, to stop smoking would decrease the risk of GH but increase the risk of HH. Also, smoking has been identified as one of the risk factors for the development or worsening of eye changes after 131I treatment of GH. Additionally, the outcome of medical treatment of Graves' ophthalmopathy (GO) is less favourable in smokers as compared to non-smokers. There is concern also about the effect of passive smoking on autoimmune thyroid disease. In a recent study it has been shown that the latter may have a deleterious effect on childhood GO.     

Soluble forms of adhesion molecules sELAM-1 and sICAM-1 in Graves disease and toxic nodular goiter

Intercellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 (ELAM-1) are playing a significant role in an inflammatory process. In patients with autoimmune disorders of thyroid gland an increased expression of ICAM-1 and ELAM-1 was found in thyroid and also in orbital tissue in presence of active ophthalmopathy. Reports concerning concentrations of adhesion molecules soluble forms (sELAM-1 and sICAM-1) in sera of patients suffered from different thyroid gland diseases are controversial. The aim of the project was an estimation of levels of adhesion molecules soluble forms in sera of patients with Graves' disease (GD) and toxic nodular goiter (TNG). In the presented research work sICAM-1 and sELAM-1 were determined in 149 subjects (aged 17-69 years) divided to following groups: group 1--16 hyperthyroid GD patients with active ophthalmopathy (GO) (10 females and 6 males); group 2--25 euthyroid GD patients with GO (17 females and 8 males); group 3--41 hyperthyroid GD patients without GO (22 females and 16 males); group 4--36 patients with TNG (20 females and 16 males) and control group (group 5)--31 healthy subjects (16 females and 16 males). sICAM-1 and sELAM-1 serum concentrations were determined using highly sensitive enzyme linked immunosorbent assay (ELISA). In comparison with control group (group 5) in groups 1--3 significant increase of sICAM-1 and sELAM-1 concentrations was found (p < 0.001). The highest values for both adhesion molecules were demonstrated in the group of hyperthyroid GD patients with GO (group 1) as well as in group of euthyroid GD patients with GO (group 2). In group 1 the values were higher than those in group 2. Lower concentrations were present in group of GD patients with hyperthryroidism without symptoms of GO (group 3). The lowest adhesion molecules concentrations in four examined groups were present in sera of patients with TNG (group 4). The level of sICAM-1 in this group was higher than that in control group, but the difference was not statistically significant (p < 0.01), on the contrary sELAM-1 concentration was markedly elevated in comparison with group 5 (p < 0.002). From the obtained results it may be concluded that elevated sICAM-1 and sELAM-1 concentrations in sera of GD patients are dependent on autoimmunological factors, presence of inflammatory changes in the orbital tissue as well as on hyperthyroidism. Nonautoimmune hyperthyroidism has also influence on increase of sICAM-1 and sELAM-1 levels.     

Iodine-131 given for therapeutic purposes modulates differently interferon-gamma-inducible alpha-chemokine CXCL10 serum levels in patients with active Graves' disease or toxic nodular goiter

CONTEXT: The mechanism of activation of the immune system after iodine-131 (131I) treatment of hyperthyroidism is still not fully clarified. Serum levels of CXCL10, a prototype of the CXC family of chemokines, are increased in several endocrine autoimmune conditions, and this chemokine plays a role at least in the initial phases of thyroid autoimmune disease and in Graves' disease (GD). OBJECTIVE, DESIGN, AND PATIENTS: The aim of the present study was to measure the serum CXCL10 levels in 20 patients with GD and 10 patients with toxic nodular goiter (TNG) before and 6 months after 131I treatment, when patients had achieved euthyroidism. Forty healthy subjects and 40 patients with autoimmune thyroiditis served as control groups. RESULTS: Before 131I, mean CXCL10 was significantly higher in patients with GD and thyroiditis than controls or those with TNG. Serum CXCL10 levels significantly decreased in GD patients 6 months after 131I treatment, whereas they remained within normal limits in TNG patients after restoration of euthyroidism by 131I. CONCLUSIONS: In conclusion, our results demonstrate that high serum CXCL10 levels are associated with the hyperthyroid phase in GD but not TNG, providing further evidence for a minimal role of hyperthyroidism per se in determining high CXCL10 levels and showing a strong association with the autoimmune process. The reduction of CXCL10 levels after 131I treatment in GD only shows that the thyroid gland itself is the main source of circulating CXCL10.     

Thyroid cancer in hyperthyroidism: incidence rates and value of ultrasound-guided fine-needle aspiration biopsy in this patient group

Three hundred and thirty-three hyperthyroidism cases were retrospectively investigated to provide information about the association between hyperthyroidism and thyroid cancer. There were 112 cases of toxic multinodular goiter (TMNG), 77 cases of toxic nodular goiter (TNG) and 144 cases of Graves' disease (GD). All nodules detected in GD patients, all nodules greater than 1 cm diameter in nodular goiter patients, nodules 5-10 mm size diameter if they had calcification were fine-needle biopsied (FNAB) under ultrasound guidance (US-guided), and a total of 612 such biopsies were performed. The biopsy samples were cytologically assessed as benign (no.=552; 90.2%), suspicious (no.=6; 1.1%), malignant (no.=13; 2.1%), or inadequate for diagnosis (no.=41; 6.7%). All patients with a biopsy diagnosis of malignant or suspicious nodules underwent surgery. Histological examination confirmed the diagnosis of thyroid cancer in all 13 (2.1%) patients with malignant FNAB findings. Papillary thyroid carcinoma (PTC) was identified in 2 patients with TMNG (%1.8), 5 with TNG (%6.5) and 5 with GD (%3.5). Metastatic follicular thyroid carcinoma (FTC) was identified in a patient with TNG. Thyroid malignancy (micro- or macrocarcinoma) was diagnosed pre-operatively in all 13 cases by US-guided FNAB. Thyroid cancer was diagnosed in 6 (5.5%) of the 109 nodules detected in the TNG group, 2 (0.44%) of the 452 nodules detected in the TMNG group, and 5 (9.8%) of the 51 nodules detected in the GD group. Two (2.6%) of the 77 functioning nodules in the TNG patients were malignant, but none of the 402 functioning nodules in the TMNG patients was malignant. In patients with hyperthyroidism, US-guided FNAB is useful for detecting thyroid cancer in nodules greater than 5 mm diameter before radioiodine therapy or surgery.     

Graves' ophthalmopathy and atrophic thyroiditis: a case report

Graves' ophthalmopathy (GO)--also known as thyroid-associated orbitopathy or ophthalmopathy--usually affects patients with Graves' disease. Antibodies stimulating the TSH receptor are thought to be involved in the pathogenesis of this important and disabling extra-thyroidal manifestation of Graves' disease. Less frequently, GO occurs in subjects who neither have nor have ever shown evidence of thyroid dysfunction ("euthyroid GO"), while the occurrence of GO in patients with autoimmune Hashimoto's thyroiditis is thought to be quite rare and has sporadically been reported. The late and abrupt occurrence of severe GO without hyperthyroidism in an 88-yr-old woman with primary myxedema due to atrophic thyroiditis must be considered as an exceptional event. In this patient, GO was combined with elevated titres of serum auto-antibodies directed against the TSH receptor, while serum levels of anti-thyroglobulin and thyroperoxidase antibodies were within the normal range or only occasionally slightly above the normal values.     

Evidence of extraocular muscle restriction in autoimmune thyroid disease

Patients with Graves' disease lacking eye symptoms frequently have abnormal intraocular pressure (IOP) increases on upward gaze (greater than or equal to 3 mm Hg) indicative of apparent subclinical ophthalmopathy. Because of the close relationship between Graves' disease (GD) and Hashimoto's thyroiditis (HT), we examined 30 patients with a history of HT as well as 26 patients with a history of GD, 4 patients with a history of subacute thyroiditis, 1 patient with a history of silent thyroiditis, and 25 normal subjects for the presence of IOP abnormalities at 15 degrees and 25 degrees upgaze. While all of the patients were asymptomatic, had no exophthalmos, and were euthyroid at the time of the exam, Hertel exophthalmometer readings (mean +/- SD) for the patients with GD were significantly higher (P less than 0.005) than those for either the HT patients or normal subjects (17.1 +/- 2.4 vs. 14.5 +/- 2.3 vs. 14.4 +/- 4.2 mm, respectively). At 15 degrees upgaze, IOP abnormalities occurred in 25% and 13% of patients with GD and HT, respectively. At 25 degrees upgaze, these figures rose to 54% for the GD patients and 37% in HT patients. Only 1 of 25 normal subjects had elevated IOP changes on upgaze, as did the 1 patient with silent thyroiditis, but the patients with subacute thyroiditis did not. These data suggest the frequent presence of extraocular muscle restriction in patients with a history of HT as well as in patients with a history of GD. Maximal detection of these IOP abnormalities requires that patients be examined at 25 degrees upgaze. These data support the belief that the autoimmune bases of both GD and HT are closely linked, at least as manifested by eye muscle involvement.     

定量检测人甲状腺过氧化物酶抗体化学发光酶免疫分析法的临床应用

目的 应用人甲状腺过氧化物酶抗体(hTPOAb)的化学发光酶免疫分析(CLEIA)试剂盒,检测正常人及各类甲状腺疾病患者,探讨该试剂盒在临床应用中的价值.方法 用该试剂盒共测定333例样品血清中的hTPOAb,包括正常人133名,各类甲状腺疾病患者200例,其中桥本甲状腺炎(HT) 94例,Graves病68例,结节性甲状腺肿19例,亚急性甲状腺炎10例,单纯性甲状腺肿9例.结果 确立本试剂盒hTPOAb阳性切限值为3.22 IU/ml,hTPOAb浓度以中位数表示,分别为HT5.48 IU/ml,阳性率为91.50％;Graves病1.88 IU/ml,阳性率为29.40％;结节性甲状腺肿1.83 IU/ml,阳性率为10.50％,亚急性甲状腺炎2.54 IU/ml,阳性率为20.00％;单纯性甲状腺肿2.21 IU/ml,阳性率为0.HT患者血清hTPOAb阳性率高于其他患者(x2=67.22,60.13,35.49,49.89,P均＜0.01).结论 该定量检测hTPOAb的CLEIA试剂盒在HT中有很高的阳性率,可作为HT有效的诊断手段.     

Hodgkin's disease and hyperthyroidism

In recent years we have had the occasion to observe hyperthyroidism in 6 patients with Hodgkin's disease. All patients had received Mantlefield irradiation and were disease-free when hyperthyroidism appeared. Hyperthyroidism allows three different pictures to be distinguished: 1 case report of Graves' disease without ophthalmopathy, 1 case report of Hashimoto's thyroiditis corresponding to a particular form called hashitoxicosis, and 4 case reports of atypical silent thyroiditis. Reports concerning case studies of postirradiation Graves' disease or Hashimoto's thyroiditis during Hodgkin's disease are only to be found exceptionally. Atypical silent thyroiditis was recently individualized, but no postirradiation case studies have been reported. It is suggested that these 6 cases represent a radiation-induced immune thyroid disease: physiopathology and predisposing factors are discussed.     

Sibling recurrence risk in autoimmune thyroid disease.

There is abundant evidence for a genetic influence on the development of autoimmune thyroid diseases (AITD). One measure of the magnitude of genetic contribution to the development of a disease is the sibling risk ratio (lambda(s)). Recent accurate prevalence data for hypothyroidism and hyperthyroidism in the United States reported from the National Health and Nutrition Examination Survey III (NHANES III) study have now allowed us to compute the sibling recurrence risk for AITD. Patients were recruited from our endocrine clinic on the basis of having AITD. The inclusion of patients in this study was unambiguously single ascertainment. We studied 155 patients (131 with Graves' disease [GD] and 24 with Hashimoto's thyroiditis [HT]) who had reliable information on the presence or absence of AITD in siblings. Nine probands had siblings with GD and 13 probands had siblings with HT. Using the prevalence rates from NHANES III for clinical hyperthyroidism and hypothyroidism, the calculated lambda(s) was 16.9 for AITD, 11.6 for GD, and 28.0 for HT. These results confirm the significant contribution of genetic factors to the development of AITD.     

Soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease

In Hashimoto's thyroiditis, Fas-induced apoptosis is one of the mechanisms leading to cell destruction, whereas thyroid tissue in Graves' disease is prevented from it. The soluble form of the Fas molecule produced by alternative splicing prevents from apoptosis. We measured soluble Fas in the sera of 112 patients with Graves' disease, 21 patients with toxic goiter, and 24 patients with subclinical hyperthyroidism due to suppressive therapy with levothyroxine after near-total resection of the thyroid gland for nodular goiter. Soluble Fas was increased in thyrotoxic patients, toxic goiter, and patients with subclinical hyperthyroidism. Decreased levels of soluble Fas were found in euthyroid patients with Graves' disease after surgery, whereas soluble Fas was normal in euthyroid patients with Graves' disease receiving antithyroid drug treatment and in patients in stable remission. There was a good correlation between soluble Fas with free T(3) (r = 0.6) and free T(4) (r = 0.5). Our results show that soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.     

Heterogeneity of TSH receptor-binding antibodies in Hashimoto's thyroiditis and Graves' disease

The possible heterogeneity of TSH receptor antibodies in Graves' disease (GD) and Hashimoto's thyroiditis (HT) with respect to the binding site on the receptor and corresponding biological effect was studied. Employing an immunoprecipitation assay (IPA), the sera of 80% of the patients with GD (24 out of 30) and 76% of the patients with HT (16 out of 21) contained TSH receptor-binding antibodies, compared to none of the sera from 17 normal volunteers and 8 patients with nontoxic multinodular goiter. TSH inhibited immunoprecipitation by GD and HT sera. In HT sera (n = 9), but not in GD sera (n = 5), heterogeneity of the TSH-induced inhibition was observed. Four HT sera showed complete inhibition of immunoprecipitation at a saturating concentration (19.8 nM) of TSH. Five HT sera, like the 5 GD sera, showed partial inhibition of immunoprecipitation by 19.8 nM TSH. Thyroid stimulating immunoglobulins (TSI) were found in four of the five GD sera and in only one of the nine HT sera. The results suggest that different subpopulations of TSH receptor antibodies, characterized by other receptor binding sites or different affinities, are associated with autoimmune thyroid disease.     

Graves'' ophthalmopathy in relation to cigarette smoking and ethnic origin

OBJECTIVE: We aimed to study the effect of cigarette smoking on the prevalence and severity of Graves' ophthalmopathy (GO). PATIENTS: One hundred and fifty-five newly diagnosed patients with Graves' disease (GD) were diagnosed clinically and by routine biochemical methods. Twenty-five per cent (39) were of Asian origin. METHODS: Eye signs were classified according to the American Thyroid Association Classification. A detailed smoking questionnaire and data from hospital notes were used to calculate an index of cigarette consumption. RESULTS: Thirty-four per cent of all patients had Graves' ophthalmopathy, and the prevalence in males (26%) and females (36%) did not differ significantly. There was a prevalence of 42% among Europeans compared to 7.7% in Asians (P = 0.0002). The overall risk for Europeans for developing Graves' ophthalmopathy was 6.4 (1.78-22.7 confidence interval) times higher than for Asians. Corrected for the ethnic factor the increased risk from smoking for Europeans was 2.4 (1.12-5.18, 95% confidence interval) times higher. There was a significant dose effect (P = 0.008). CONCLUSIONS: The present findings confirm an effect of cigarette smoking on Graves' ophthalmopathy and in addition show that Europeans have a substantially greater risk of developing Graves' ophthalmopathy than have Asians.     

The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves' disease identifies a group at markedly increased risk of ophthalmopathy.

Among Graves' Disease (GD) patients, we have observed an unexpectedly high prevalence of antithyroperoxidase antibody (TPOAb) and antithyroglobulin antibody (TgAb) negativity in those with severe ophthalmopathy. To study the possible role of thyroid autoantibodies in the pathogenesis of Graves' ophthalmopathy (GO), TPOAb, TgAb, thyroid-stimulating immunoglobulin (TSI), and thyrotropin-binding inhibitory immunoglobulin (TBII) levels were measured, and the presence or absence of GO was assessed by a single observer in 100 consecutive patients with newly diagnosed, untreated GD who were nonsmokers. Ophthalmopathy was present in 43 patients. TSI levels (p = 0.001), and the prevalence of TPOAb-negativity (p = 0.002) were significantly higher in patients with ophthalmopathy compared to those without. Logistic regression analysis showed that TSI levels (p = 0.005) and the absence of TPOAb (p = 0.0025) were independent predictors of GO. No correlation between TBII or TgAb and eye disease was found. The prevalence of GO increased with each quartile of TSI levels. The prevalence was 20%, 36%, 52%, and 64% in the first, second, third and fourth quartiles of TSI, respectively. The odds ratio of GO (with 95% confidence intervals) when TSI levels were above the median level (1640%) was 3.6 (1.5-8.0), when TPOAb was negative it was 5.0 (1.7-14.4), and with both risk factors it was 36.6 (4.3-313.5). The prevalence of ophthalmopathy in this last group was 92.9%. The combination of negative TPOAb and high TSI levels appears to be associated with a markedly increased risk of clinically evident ophthalmopathy.     

Color flow Doppler sonography for the etiologic diagnosis of hyperthyroidism.

Color flow Doppler sonography (CFDS) is gaining importance for the functional evaluation of the thyroid disorders. We aimed to determine the value of CFDS for the etiological diagnosis of hyperthyroidism. Fifty-five patients with hyperthyroidism (29 Graves' disease [GD] and 26 toxic adenoma [TA]), 24 patients with Hashimoto's thyroiditis (HT), and 39 euthyroid controls were included. Etiological diagnoses were carried out using standard methods. Conventional gray scale sonography was performed, followed by CFDS. Doppler patterns of the glands were scored and peak systolic velocity (PSV) measurements were obtained from intrathyroidal, perithyroidal, and perinodular vasculature. Vascular patterns were significantly more prominent, and the mean PSV values were significantly higher in the GD patients compared to the HT patients ( p < 0.001) and controls ( p < 0.001). Perinodular and intranodular signals and the mean perinodular PSV values were significantly higher in TAs compared to controls. CFDS could differentiate the untreated GD from the HT, which had similar gray scale findings. Hot nodules could also be differentiated from cold nodules with more prominent vascular patterns and significantly higher PSV values. As an inexpensive, fast, and noninvasive imaging procedure, CFDS could be helpful in the initial clinical evaluation and may avoid scintigraphy in a substantial number of thyrotoxic patients.