Relapse Of Graves' Disease Research Articles

High cut-off value of a chimeric TSH receptor (Mc4)-based bioassay may improve prediction of relapse in Graves' disease for 12months.

There are scarce reports regarding a functional prognostic value of thyroid-stimulating autoantibody (TSAb) levels using a thyroid-stimulating hormone receptor chimera (Mc4) in Graves' disease (GD) in iodine sufficient area. The aim of this study was to investigate whether Mc4-TSAb can predict GD remission/relapse after antithyroid drug (ATD) treatment and to compare Mc4-TSAb with a binding assay using M22 monoclonal antibody (M22-TRAb) in GD patients. We retrospectively reviewed the results of M22-TRAb and Mc4-TSAb in GD patients treated with ATD for 12 months. GD patients who underwent ATD treatment for at least 12 months were included. We compared the predictive values of M22-TRAb and Mc4-TSAb for GD remission and relapse. Of the 92 patients, 60 (65.2%) achieved remission and 32 (34.8%) relapsed within 12 months. In receiver operating characteristic analysis, there were no significant differences in the area under the curves (AUCs) between Mc4-TSAb [AUC=0.79 (95% CI 0.69-0.89)] and M22-TRAb [AUC=0.69 (95% CI 0.58-0.81)]. The optimal predictive cut-off values of M22-TRAb and Mc4-TSAb were 2.23 IU/L and 230%, respectively. At a high Mc4-TSAb cut-off, the better specificity of 85.0% and positive predictive value (PPV) of 69.0% were shown compared with those at the best cut-off for M22-TRAb. In conclusion, a high cut-off for an Mc4 assay may improve the predictive value of relapse with superior specificity and PPV compared with M22-TRAb in treated GD.

Relapse of hyperthyroidism after hemithyroidectomy in concurrent medullary thyroid cancer and Graves’ disease

We present a rare case of concurrent medullary thyroid cancer (MTC) and relapse of Graves' disease (GD). A 26-year-old Chinese female suffered from GD for 1 year. Physical examination demonstrated mildly diffuse goiter with a palpable 1.0 cm nodule in the right thyroid lobe and exophthalmos. Before hemithyroidectomy, calcitonin was elevated and thyroglobulin was normal. After surgery, histopathological findings proved coexistence of MTC and GD. 16 months later, GD relapsed and radioactive iodine 131 therapy was given. Meanwhile, postoperative monitoring showed well controlled calcitonin and carcinoembryonic antigen. Our lesson demonstrates although concomitant of MTC and GD is very rare, yet after hemithyroidectomy for the single nodular MTC lesion, remnant thyroid lobe could be the source of GD relapse very soon. More importantly, the relapse of GD and the following radioiodine therapy and radiation exposure could have been prevented if a better therapy plan of total thyroidectomy was adopted in the first place, instead of hemithyroidectomy (Tab. 1, Fig. 2, Ref. 11).

Decrease in Proportion of CD19+CD24hiCD27+ B Cells and Impairment of Their Suppressive Function in Graves’ Disease

IL-10-producing B cells (B10 cells) have been shown to play a suppressive role in the peripheral blood of humans, with their numbers and function altered in several autoimmune diseases. However, the role of B10 cells in Graves’ disease (GD) remains unknown. In this study, we demonstrated that B10 cells in human peripheral blood belonged to a CD24hiCD27+ B cell subpopulation. The proportion of B10 cells along with the CD19+CD24hiCD27+ B cell subset was significantly lower in new-onset patients compared with healthy individuals. In recovered patients, these proportions were restored to levels similar to those seen in healthy individuals. Additionally, we found that CD19+CD24hiCD27+ B cells from healthy individuals inhibited proliferation and TNF-α production of CD4+ T cells via an IL-10–independent pathway. They also inhibited IFN-γ production by CD4+ T cells, through an IL-10–dependent pathway. In contrast, their suppressive function on CD4+ T cell proliferation and cytokine production was impaired in new-onset and recovered patients compared with healthy individuals. Our study provides evidence that CD19+CD24hiCD27+ B cells may possess the capacity to downregulate immune responses, partially by production of IL-10 in human peripheral blood. Impairment of their immunosuppressive function may contribute to GD pathogenesis and relapse.

Relevant factors in predicting the relapse of Graves disease after treatment with antithyroid drugs

Objective To evaluate the prognostic factors of predicting the outcome of Graves disease (GD) after treatment with antithyroid drugs.Methods A retrospective audit was performed for 306 consecutive patients with newly diagnosed GD.They were divided into successful and failure groups (including recurrent and non-stop subgroups )according to the treatment outcomes.Different prognostic factors after treatment with antithyroid drugs were compared and the state of thyrotropin suppression was observed as the euthyroid state at Months 3,6 and 12 respectively.Results Among them,141patients (46.1％ ) were cured and 165 patients (53.9％) had treatment failures.Age at the time of diagnosis was (46 ±10) years in the successful group and (36 ±9) years in the failure group(t =3.152,P =0.002).Free T3 ( FT3 ) was (25.2 ±8.9) and ( 18.7 ±9.4) pmol/L in the failure and successful groups respectively (t =3.326,P =0.001).The FT3 to FT4 ratio and thyrotrophin receptor antibody (TRAb) levels were higher in the failure group ( t =3.331,3.389,P =0.001).Logistic regression analysis showed that thyroid size,FT3 to FT4 ratio and TRAb at the time of diagnosis were associated with failure outcomes.The ratio of continuing thyrotropin suppression in the recurrent subgroup was more than that in the successful group ( X2 =77.515,114.441,136.232,all P ＜ 0.01).Conclusions The GD patients with a large thyroid size and high pre-mediation levels of TRAb and FT3 to FT4 ratio are more prone to respond unfavorably to antithyroid drug treatment.And those with a large thyroid size and post-medication ophthalmopathy and continuing thyrotropin suppression have a high rate of recurrence. Key words: Graves disease; Recurrence; Antithyroid agents; Prognostic factors

Management of Grave’s Disease Is Improved by Total Thyroidectomy

A retrospective analysis was performed on 267 consecutive patients with Graves' disease (GD). The principal aim of this study was to evaluate the risk for recurrence and complications when changing the surgical method from subtotal (ST) to total thyroidectomy (TT). Information from 267 consecutive patients operated on for GD between 2000 and 2006 was collected at Uppsala University Hospital (143) and Falun County Hospital (128). There were 229 women and 38 men. Four patients were operated on twice. A total of 40 STs and 229 TTs were performed. Results were compared to those of a previous cohort from the same hospital, with a majority of STs (157/176) performed from 1980 to 1992. The risk for relapse of GD was reduced from 20 to 3.3 % after the shift from ST to TT. In terms of surgical complications, 2.2 % demonstrated permanent vocal cord paralysis and 4.5 % had persistent hypocalcemia, not significant when compared to the previous cohort. In spite of TT, there were four recurrences, all due to remnant thyroid tissue high up at the hyoid bone. Changing the surgical method did not affect postoperative progression of dysthyroid ophthalmopathy (DO, 7.0 vs. 7.5 %). There were no differences in outcome with respect to which hospital the patients had their operation. Change from ST to TT dramatically reduced the risk for recurrence of GD without increasing the rate of complications. TT is not more effective than ST in hampering progression of DO as has been advocated by some. Careful surgical dissection up to the hyoid bone is necessary to avoid recurrence.

Clinical implications of thyrotropin receptor antibody measurement

It has been 50 years since the discovery of thyrotropin receptor autoantibody (TRAb). Advances in the knowledge of thyrotropin receptor ( TSHR) structure and function, combined with the elucidation of TSHR signaling and TSHR-autoantibody interaction have greatly facilitated our understanding of TRAb and their clinical applications. Measurement of TRAb activity plays an important role in the diagnosis of Graves' disease ( GD) and Graves' opthalmopathy. It has also been well recognized that TRAb is an effective predictor of GD relapse or remission after antithyroid drug and radioactive iodine treatment. TRAb test is of particular help in pregnant women and lactating mothers with recent iodine load, where radioactive iodine or technetium tests are contraindicated. In addition, it is useful in the diagnosis and differential diagnosis of fetal and neonatal hyperthyroidism as well as some rare forms of thyrotoxicosis in clinical practice. Accumulating evidence also indicates the possible correlation between thyroid cancer occurring in GD patients with positive TRAb and adverse outcomes. However, further innovation and standardization of TRAb tests are required to help pave the way for clinical applications. Key words: Thyrotropin; Thyrotropin receptor antibody; Graves'disease; Methodology

Herpesvirus type 7 infection may play an important role in individuals with a genetic profile of susceptibility to Graves' disease

An inherited profile of genes related to the response to aggressive environmental factors such as viruses and chemicals may be related to an increased susceptibility to Graves' disease (GD). This prospective case-control study was designed to examine the relationship between human herpesviruses (HHV) infection, determined by circulating DNA; tumour protein p53 (TP53) apoptotic ability; and detoxification system genes, and GD. We studied 280 confirmed GD patients paired to 284 controls with respect to environmental exposure. Exclusion criteria included medications that could interfere with thyroid function evaluation and a recent history of viral and bacterial infections. A stepwise regression analysis adjusted for age, gender, and ethnicity established the inheritance of glutathione S-transferase pi 1 (GSTP1) (odds ratio (OR)=3.423; 95% confidence interval (CI)=2.120-5.527; P<0.001) and cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) variants (OR=1.649; 95% CI=1.012-2.686; P=0.0445) as significant risk factors for the disease. HHV-7 infection was much more common in GD patients (64.64%) than in controls (38.73%; chi(2), P<0.0001), and it increased the risk for GD more than three times (OR=3.133; 95% CI=1.959-5.011; P<0.0001). The inheritance of less efficient Pro/Pro TP53 gene variants significantly increased the risk of GD development (OR=5.196; 95% CI=2.112-12.783; P<0.0001) and also favored HHV-7 infection (OR=2.835; 95% CI=1.100-7.310; P=0.0275). In addition, 72TP53 variants augmented the risk of GD relapse (OR=1.860; 95% CI=1.015-3.410; P=0.0446). We suggest that an inherited genetic profile involving TP53 may favor HHV-7 infection and maintenance, which, in turn, may initiate and perpetuate GD autoimmune process.

Thyroid blood flow as a useful predictor of relapse of Graves’ disease after normal delivery in patients with Graves’ disease

Objective Measurement of the peak systolic velocity (PSV) in the inferior thyroid artery (ITA) before withdrawal of an anti-thyroid drug (ATD) is useful for predicting relapse of Graves’ disease (GD). We further investigated whether the ITA–PSV can be used for prediction of GD relapse after delivery in euthyroid women with GD who stopped ATD administration during mid- to late pregnancy. Patients and methods ITA–PSV was monitored monthly for three months after delivery in 42 women with GD aged from 24 to 45 years old (mean ± SE: 34.7 ± 0.92 years old) who met the above criteria. To confirm the stability of the measurement, ITA–PSV was also measured monthly in 32 age-matched non-pregnant normal women and for three months after delivery in 10 age-matched women. Results ITA–PSV and thyroid volume were higher in women with GD immediately after delivery compared to normal women, but the levels of TSH receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) did not differ significantly between the two groups. Of the 42 patients, 23 had relapse of GD and the smoker/non-smoker ratio and thyroid volume in these patients immediately after delivery were significantly higher than those in the 19 patients who did not undergo relapse (10/23 vs. 0/19, p < 0.0001; 24280.3 ± 2280.9 vs. 19670.0 ± 2103.7 mm 3, p = 0.046), while ITA–PSV, TRAb and TSAb did not differ between the two groups of patients. The ITA–PSV ratio was calculated by dividing each value in the follow-up period by that obtained immediately after delivery. A significant increase in the mean ITA–PSV ratio occurred at least one month before the time of relapse (1.00 ± 0.00 at –3 months before relapse vs. 1.46 ± 0.12 at –1 month, p = 0.010; 1.00 ± 0.00 at –3 months vs. 1.77 ± 0.13 at the time of relapse, p = 0.0048). In contrast, there were no significant changes in this ratio during the follow-up period in non-relapse patients. Conclusion Monthly measurement of ITA–PSV after delivery in remitted euthyroid women with GD may assist in early prediction of GD relapse.

LYMPHOCYTES IN PERIPHERAL BLOOD AND THYROID TISSUE IN CHILDREN WITH GRAVES' DISEASE

OBJECTIVE: Our goal was to analyze interactions of lymphocytes in peripheral blood and thyroid tissue in children with Graves' disease (GD). METHODS: The prospective study concerned 15 children affected with GD and 15 healthy children. The levels of autoantibodies against thyrotropin receptor, thyroid peroxidase, and thyroglobulin were assayed. Monoclonal antibodies (Ortho Diagnostic Systems, Raritan, NJ) were used to define peripheral blood lymphocyte subsets and analyzed by using a flow cytometer. After thyroidectomy, thyroid specimens were stained with hematoxylin/eosin. T cells were detected by CD3+, CD4+, and CD8+ antibodies and the antigen-presenting dendritic cells with CD1a+ and CD35+ antibodies (DakoCytomation, Glostrup, Denmark). RESULTS: Before treatment, all children with GD had increased thyroid autoantibody levels, an increased percentage of CD4+ helper cells, and decreased levels of CD8+ suppressor/cytotoxic T cells, which resulted in an elevated CD4/CD8 ratio. The percentage of CD19+Cd5+ B cells was increased, although the total population of CD19+ B cells did not differ from that of the control group. The number of lymphocytes in the thyroid was decreased in 10 patients after long-term thiamazole treatment. In 5 patients with short-term therapy (&amp;lt;6 months after relapse of GD), the lymphocytes had formed lymphatic follicles: antigen-presenting dendritic cells CD1a+CD35+ in the germinal center and T-helper CD4+, T-suppressor CD8+, and B cells CD79+ on the edges. CONCLUSIONS: The primary defect of immunoregulation in GD consists of an increase of T-helper lymphocytes with a simultaneous decrease in the number of T-cytotoxic/suppressor cells. Thiamazole therapy probably leads to reduction of the lymphocyte amount in the thyroid.

Serum Selenium Levels in Patients with Remission and Relapse of Graves Disease

Selenium (Se) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase (Gpx) and of the iodothyronine selenodeiodinases that catalyze the extrathyroidal production of tri-iodothyronine (T(3)). Thus, Se deficiency may seriously influence the generation of free radicals, the conversion of thyroxine (T(4)) to T(3) and a thyroidal autoimmune process. The aim of this study was to investigate whether serum Se levels may influence the outcome of Graves' disease (GD). 83 patients (77 women, 6 men) with active GD were retrospectively analyzed (mean age 40,0 years). Twenty-four GD patients went into remission and were euthyroid during follow-up (median follow-up: 20.1 months), whereas 59 patients did not go into remission or developed relapse over the following 24 months. TSH receptor autoantibodies (TRAb) were measured using the second generation assay on the basis of human TSH receptor. Se levels were determined at the first visit in our outpatient clinic and were correlated with TRAb levels and clinical outcome of these patients. Median TRAb levels in the group of remission were significantly (p<0.0001) lower than TRAb values in the relapse group (2.1 as compared to 8.6 IU/l). By comparing mean serum Se levels in the remission and relapse group no significant differences were seen (73.0 vs. 71.7 microg/l). Detailed analyses of both groups of patients, however, revealed that highest serum Se levels (>120 microg/l) were seen in the remission group, indicating a positive effect of Se levels on the outcome of GD. In addition, we also compared these results with TRAb levels of these patients. We could show that TRAb levels and serum Se values were positively correlated in the relapse group, whereas a negative correlation of both parameters were seen in the remission group, supporting the idea of a positive effect of Se on thyroidal autoimmune process. Our data indicate that high serum Se levels (>120 microg/l) may influence the outcome of GD. This is important, as Se administration trials in GD, which are under discussion need to be performed with Se supplementation at higher dosages than used in autoimmune thyroiditis.

Hyperthyroidism in a hospital environment: 5-year evaluation

Thyroid diseases are an area of particular interest to this Department, constituting 30% of the 3561 patients observed over the last 5 years (when group consultations were set up and outpatient data computerised). To determine the prevalence and aetiologies of Hyperthyroidism (HT) in outpatient clinic and characterise diagnostic and therapy practice. All files of patients diagnosed with HT treated in the department over the last 5 years were reviewed. Of a total of 105 files, 96 were analysed. The data analysed included: demographic data, aetiology of disease, complementary diagnostic test reported, treatment options and follow-up. The data was analysed independently depending on whether 1st consultation occurred before or after 1999. The variables were analysed using descriptive statistical methods, namely frequency and contingency tables for categoric variables and mean, standard deviation, maximum and minimum values for continuous variables. Of the patients evaluated, 72% were female and 28% male, with an average age of 50. 49.0% had Graves' Disease (GD); 14.6% toxic multinodular goitre (TMNG); 11.5% autoimmune HT; 10.4% iatrogenic HT; 7.3% subacute thyroiditis and 7.3% toxic adenoma (TA). Medical treatment was 1st option for 92% of patients with GD (40.4% of cases combined with levothyroxine); 5% received 131Iodine treatment and 3% underwent surgery. In this group, 6 months after suspension of medical treatment, 30.4% had suffered a relapse. Of the patients who suffered a relapse, 42% underwent surgery and 28% received 131Iodine treatment. The remaining 30% made a second attempt with synthetic antithyroid drugs. For patients with TMNG, surgery was the 1st treatment option for the majority of patients (78.5%), followed by 131Iodine (14.2%). 70% of patients with toxic adenoma underwent surgery and 30% 131Iodine treatment. For other pathologies, namely autoimmune HT, iatrogenic HT and subacute thyroiditis, the option was medical treatment. Hyperthyroidism was diagnosed in 3.5% of patients observed as outpatients in this Department. GD was the most prevalent form of HT (49%). Medical treatment is the first treatment option (92%) for GD. 6 months after suspension of medical treatment, 30% of patients had suffered a relapse of GD. For these patients, surgery was the 1st option. For both TMNG and TA, surgery was the first treatment option. The adverse effects that occurred with ATDs (antithyroid drugs) were detected in 4,1% patients; one case of agranulocytosis with propylthiouracil, 2 cases of allergic reactions--rash (one due to the use of methimazole and the other to propylthiouracil), and one case of minor hepatocellular toxicity. In all patients there was improvement after stopping medical treatment.

Improved Prediction of Relapse of Graves' Thyrotoxicosis by Combined Determination of TSH Receptor and Thyroperoxidase Antibodies

Recently, we and others have demonstrated that high levels of auto-antibodies to the human TSH-receptor (TRAb) predict relapse of hyperthyroidism in Graves' disease (GD). Our objective was to extend the outcome of the prediction by combining TRAb with thyroperoxidase antibody (TPO-Ab) measurement. One hundred and thirty-one GD patients (118 females, 13 males) were analysed, of whom 94 patients (71.8%) had relapse, whereas 37 (28.2%) went into remission. Second generation TRAb and TPO-Ab assays were performed in GD patients with relapse and remission in mean 4.3 months after initial diagnosis. The mean anti-TPO-Ab levels were similar in all patients with relapse and remission. However, there was a steady decline from 4047 U/ml to 530 U/ml in the remission group that correlated positively with TRAb values (>2 to >10 IU/l). The relapse group remained at consistently high levels. The positive predictive value (PPV) for relapse in patients with TRAbs >6 IU/l and anti-TPO-Abs >5000 U/ml was 100, whereas TRAbs >6 IU/l and anti-TPO-Abs >500 U/ml were associated with a PPV of 93.7 up to 96 (p=0.008). These Ab constellations accounted for about one third of all GD patients. For patients with TRAbs between >2 and <6 IU/l the PPV was 66.7-90.0. Our follow-up analysis indicates that the prediction of relapse of GD can be improved by a combined measurement of TRAb and TPO-Ab. In patients with moderately increased Abs, determined about 6 months after initial diagnosis, an ablative therapy can be approached without delay.

Binding, Stimulating and Blocking TSH Receptor Antibodies to the Thyrotropin Receptor as Predictors of Relapse of Graves’ Disease after Withdrawal of Antithyroid Treatment

TSH-receptor autoantibodies (TRAbs) are a valuable diagnostic tool for confirming a diagnosis of Graves' disease (GD). While there is evidence that high TRAb levels are associated with relapse of GD, whether a discrimination of TRAb into stimulating (TSAb) and blocking (TBAb) autoantibodies would benefit the clinician in terms of outcome prediction remains unclear. To address this issue, we have determined TRAb, TSAb and TBAb levels in serum samples of ninety-six euthyroid patients with GD taken four weeks after antithyroid drug withdrawal (ATDT). Forty-seven patients (49 %) underwent relapse of GD within two years. Amongst those, forty-one (87 %) had been positive for TRAb and thirty-five (74 %) for TSAb after treatment. All patients except one were negative for TBAb. The correlation between TRAb and TSAb in those treated GD patients was relatively weak (r = 0.268, p < 0.001). Based on a cut-off limit of 1.5 IU/l, the positive and negative predictive values with respect to prediction of relapse were too low for any clinical relevance (TRAb: 49 % and 54 %; TSAb: 51 % and 55 %). However, when a cut-off level above 10 IU/l was used, the positive and negative predictive values increased to 83 % and 62 %. The additional measurement of TSAb or TBAb in those samples after therapy did not add additional information, even at higher decision thresholds. In conclusion, differentiation of TRAb into TSAb and TBAb is of no help in the prediction of relapse of GD in euthyroid patients at the end of ATDT, and only high TRAb levels are associated with relapse.

The significance of thyroid blood flow at the inferior thyroid artery as a predictor for early Graves’ disease relapse

We investigated the clinical usefulness of thyroid blood-flow measurement in predicting relapse of Graves' disease (GD) in comparison with known risk factors for GD relapse. Thyroid blood flow was measured in pulsed Doppler mode at the inferior thyroid artery (ITA), and the peak systolic velocity (PSV) calculated. ITA-PSV was measured in euthyroid GD patients (n = 79) immediately before withdrawal of anti-thyroid drug (ATD) and in healthy subjects (n = 17). In the 79 euthyroid GD patients, the values of free triiodothyronine (FT3), TSH receptor autoantibody (TRAb), ITA-PSV and thyroid volume were significantly higher in the relapse group (n = 40) than in the nonrelapse group (n = 39) and the Youden index of ITA-PSV was significantly higher than that of FT3, TSH, TRAb and vascular endothelial growth factor (VEGF). ITA-PSV may assist in the prediction of early GD relapse after ATD withdrawal.

Sensitive TSH and TSH-receptor antibody determinations as predictors of relapse in Graves' disease

After primary successful antithyroid drug treatment (ATDT), Graves' disease (GD) has a relapse rate of 30 to 50%. Despite higher sensitivity and specificity of the new second generation human TSH receptor assay, the predictive value of TRAb for relapse of hyperthyroidism is still controversial. In a recent prospective multicenter study we have previously shown that suppressed or low TSH values predict both early (persistence) and late relapse of GD. We now present a more detailed analysis of the predictive value of TSH and TRAb for recurrent hyperthyroidism. Four weeks after withdrawal of ATDT, 96 patients were available for thyroid function tests, including a sensitive third generation TSH assay and a second generation recombinant TSH receptor assay. Relapse of GD was evaluated for a total follow-up of two years. Within two years, 47 of 96 patients (49%) developed relapse of hyperthyroidism. Nine patients relapsed within the first four weeks after withdrawal of ATDT and were thus considered to have persistent GD. Ten of fifteen other patients with TSH levels below 0.3 mU/L without overt hyperthyroidism developed relapse within two years. Twenty-five of 65 patients with normal TSH had recurrent hyperthyroidism. After ATDT cessation, TSH had a positive predictive value of 70% and a negative predictive value of 62% (specificity 85%) for relapse of GD. Mean TRAb levels in the group of patients with relapse were significantly higher (11.1 IU/L±0.17) than TRAb values in the remission group (4.5 IU/L±0.6), p<0.001. Using a cut-off value of 1.5 IU/L, TRAb had low positive and negative predictive values of 49% and 54%, respectively (specificity 14%), but with a cut-off level of 10 IU/L, predictive values improved to 83% and 62%, respectively (specificity 92%). In conclusion, low TSH values four weeks after ATDT withdrawal predict relapse of GD, both early (persistence) and, to a lesser extend, within two years of follow-up. Also, TRAb above 10 IU/L found in a small subset of patients, correlated with a higher relapse rate.

Relationship between cigarette smoking and Graves’ ophthalmopathy

Environmental triggers in the development of Graves' disease (GD) have been suggested from the very first description of the disease. Since 1987 a number of studies from various countries, have assessed the risk for Graves' ophthalmopathy (GO) associated with smoking, and found an odds-ratio of approximately 4 associated with smoking. Smokers have a higher risk for more advanced GO and a dose response relation is evident. Temporality is suggested by a few prospective studies, as is reversibility since former smokers had a lower risk of developing GO than current smokers, even with a comparable lifetime tobacco consumption. In view of the biological plausibility of the association (suggested mechanisms include tissue hypoxia, modulation of circulating pro- and anti-inflammatory cytokines and accentuation of fibroblast HLA-DR expression) it seems that the association is, indeed, causal. Treatment effect of GD/GO is also influenced by cigarette smoking. It is an independent risk factor for relapse of GD after antithyroid drug treatment. Furthermore, it attenuates the effect of orbital radiotherapy and high-dose systemic glucocorticoids in GO and causes a higher rate of progression of eye disease after radioiodine therapy. The possibility of hindering GO or attenuating its course suggests that counselling on smoking cessation should be an integral part of the treatment of any patient with GD.

Prediction of remission or relapse for Graves' hyperthyroidism by the combined determination of stimulating, blocking and binding TSH-receptor antibodies after the withdrawal of antithyroid drug treatment.

The most likely reasons for the low predictive value of TSH-receptor antibodies (TRAbs) determinations in previous investigations are the biological heterogeneity of TRAbs and changes of the different stimulating (TSAb) or blocking (TSBAb) antibody bioactivities of TRAbs during the course of Graves' disease (GD), which have not been taken into account in most previous studies. Furthermore, in a recent study it has been demonstrated that the decline of TRAb values detected with highly sensitive hTBII or TSAB assays is not useful in evaluating remission or relapse of GD at the end of antithyroid drug treatment (ATDT). In order to make a thorough investigation of the predictive values of all different TRAb qualities for the recurrence for GD after the withdrawal, we investigated hTBII, TSAbs and TSBAbs in 54 consecutive patients with GD at the end of ATDT and 12 - 13.5 months after stopping ATDT. Using the TRAb values at the time of reinvestigation in a model, recurrence for GD was better predicted compared to the determination at the time of withdrawal of ATDT. Furthermore, using this model, the combined determination of hTBII, TSAbs, and TSBAbs revealed the highest level of significance for the prediction of remission or relapse of GD (OR = 15; p < 0.0001) compared to the detection of hTBII, TSAbs and TSBAbs alone. Therefore, significant changes of TSAbs after the end of ATDT and the biological heterogeneity of TRAb define the conditions for predicting remission or relapse of GD after ATDT by TRAb determinations. Consequently, our results suggest that the prediction of the individual course of GD can only be improved by combined determinations of all TRAb qualities (hTBII, TSAbs and TSBAbs) after the end of ATDT.

Thyroid hypoechogenicity after methimazole withdrawal in Graves' disease: a useful index for predicting recurrence?

A characteristic thyroid ultrasonographic picture with diffuse or scattered low echogenicity has been described in Graves' disease (GD). Thyroid hypoechogenicity in GD at onset has been considered a prognostic index of relapse after medical treatment; moreover, thyroid hypoechogenicity is regularly observed in GD at the onset, but not in patients with 'burned-out' disease. The aim of this study was to evaluate the usefulness of thyroid hypoechogenicity changes in predicting GD relapse. Longitudinal prospective study of previously untreated patients with GD. Thirty-nine consecutive patients aged 10-72 years were treated with methimazole (MMI) for 12-24 months on a titration regimen. Evaluation of patients in remission or with relapse was done 12 and 24 months after MMI withdrawal. Thyroid ultrasonography and TSH receptor antibodies (TRAb) were evaluated in basal conditions and then one month after MMI withdrawal. Thyroid hypoechogenicity score (assessed by the same observer with the same equipment) was graded as: 0 absent; 1 mild; 2 moderate; 3 marked. At the withdrawal evaluation a score < 2 and a TRAb value < 10 U/l were considered as normal. Twelve and 24 months after withdrawal, there were 10 (25.6%) and 17 (44.7%) relapses, respectively. Neither thyroid hypoechogenicity score nor TRAb values evaluated in basal conditions, showed significant differences between patients remaining euthyroid and those who became again hyperthyroid. In the whole group, the thyroid hypoechogenicity score was significantly lower at the withdrawal than in basal conditions (1.1 +/- 1.1 vs 2 +/- 0.8; P < 0.0001); it was significantly lower in patients in remission (P < 0.001), but not in those who relapsed. The thyroid hypoechogenicity score at withdrawal was normal in 23/29 (79.3%) of patients still euthyroid and in 4/10 (40%) of those who relapsed up to the 12th month (P < 0.05); it was normal in 19/21 (90.4%) of patients still euthyroid and in 7/17 (41.2%) of those who relapsed up to the 24th month (P < 0.05). A normal thyroid hypoechogenicity score at withdrawal of MMI had a higher specificity (0.95) and sensitivity (0.59) with respect to TRAb values (0.86 and 0.53, respectively) for the prediction of the relapse of hyperthyroidism at the 24th month. Basal thyroid hypoechogenicity cannot be used as an index of relapse of GD. MMI treatment induces evident changes in thyroid hypoechogenicity, mainly in patients who subsequently go into remission. The absence or a low grade of thyroid hypoechogenicity after MMI treatment seems to be a favourable prognostic index of remission of hyperthyroidism in GD.