| Objective:To evaluate the efficacy of Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction combined with MMI on patients newly diagnosed with of Graves’ disease(GD); To study the effect of Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction on intrathyroid vascularity(ITV),serum vascular endothelial growth factor(VEGF) levels and interferon-inducible protein-10(IP-10) in patients with new diagnoses of Graves’ disease(GD); To investigate longitudinally T-helper(th)1/th2 balance in untreated hyperthyroid patients with Graves’ disease(GD) after treatment of Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction.Methods:This study was conducted as an open prospective randomized trial, with an observation period of 12 wk. To compare the methimazole(MMI) combined with Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction treatment with MMI alone treatment in terms of efficacy and adverse reactions. 100 patients with new diagnoses of GD were divided into two groups: Treatment Group was treated with Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction(50ml, TID, PO) combined with MMI(15-30mg/d) and Controlled Group was treated with MMI alone(15-30mg/d). Patients were scheduled to visit the hospitals at 2, 4, 8, and 12 wk after initiation of their treatment. Adverse effects of the drugs were looked for systematically by careful health interview and clinical examinations. Aspirate aminotransferase(AST), alanine aminotransferase(ALT), glutamyl transpeptidase, and hematological values were measured for evaluation every visit to the outpatient clinic. Serum FT4 and FT3 with TSH were assayed and intrathyroid vascularity(ITV) was measured by thyroid duplex sonography(TDS) at 4, 8, and 12 wk. When serum FT4 and FT3 were both within normal ranges, the dosages of ATD were lessened. Thyroid volumes, superior thyroid artery peak systolic velocity(STA-PSV), thyroid vascularity index(TVI) and serum VEGF levels in patients were also observed in Treatment Group and Controlled Group before and after treatment. The correlation between thyroid volumes and serum VEGF levels in patients was analyzed. To detect intracellular cytokines in single T lymphocyte by flow cytometry and assay serum interferon-inducible protein-10(IP-10) and thymus and activation-regulated chemokine(TARC) levels by ELISA before and after treatment.Results:1 Co mparisons of the efficiency of Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction combined with MMI with MMI alone.After 2 weeks of treatment, the Traditional Chinese Medicin(TCM) syndrome scores were decreased significantly compared with pretreatment in treatment group(P<0.01); But no significant change of syndrome scores was found in the control group after treatment(P>0.05); There was significant difference between the two groups(P<0.01). The effect on improving symptom scores in the treatment group was better than that in the control group at 4,8 or12 week(respectively, P<0.01).Treatment group normalized FT4 in more patients than control group at 4 and 2 week(54 vs. 32%; P<0.05; 84 vs. 62%, P<0.05, respectively). No remarkable difference between the treatments was observed at 12 wk.Serum FT4 in both groups were significantly reduced at 4 and 8 weeks after beginning treatment, treatment group was significantly lower than control group(36.02±15.22 vs 47.96±16.24,P <0.01; 21.12±8.12 vs 30.64±10.68,P <0.01). The same tendency of FT3 was observed at 4 and 8wk also(16.04±9.68 vs 21.78±10.22,P <0.05; 9.14±6.32 vs 12.88±7.24,P <0.01).Thyroid volumes(TV) and superior thyroid artery peak systolic velocity(STA-PSV) in treatment group were significantly reduced at 4,8 and 12 weeks after beginning treatment, treatment group was significantly lower than control group(P<0.05, respectively).Treatment group caused significantly fewer adverse events than control group(P<0.05).There were fewer doses of MMI in treatment group than control group at 4, 8 and 12 wk(P<0.05).2 Effect of Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction on intrathyroid vascularity(ITV)The parameters of GD were were significantly higher than those in the normal group(P<0.01). There were positive correlation between thyroid volumes and thyroid vascularity index(TVI) or serum VEGF levels in patients(r=0.57, 0.59, respectively P<0.05). The parameters in Treatment Group and Control Group were decreased after treatment(P<0.01). Thyroid volumes, superior thyroid artery peak systolic velocity(STA-PSV), thyroid vascularity index(TVI) and serum VEGF levels were decreased more in Group A than in Group B after treatment(23.88±9.46 vs.31.70±18.90.;67.37±38.85 vs. 85.60±43.80;0.203±0.108 vs. 0.250±0.075;159.69±52.72 vs.195.55±66.79, P<0.05, respectively).3 Changes in th1/th2 balance before and after treatment Both plasma IP-10 and TARC concentrations at the baseline were significantly higher in hyperthyroid patients with Graves’ disease than in control subjects(P<0.05, respectively). The percentage of INF-γ-expressing CD4+ T lymphocytes and the IFN-γ+/IL-4+ratio was significantly higher in hyperthyroid patients with Graves’ disease than in control subjects(P<0.05), while we found no significant difference in IL-4-expressing cells among CD4+T lymphocytes between patients with hyperthyroid, patients with Graves’ disease and control subjects. After treatment, the percentage of IFN-γ-expressing CD4+ T lymphocytes in both groups decreased at 12 weeks(P<0.05,respectively). Furthermore, the percentage of IFN-γ-expressing cells was significantly lower in treatment group than in control group(P<0.05).On the other hand, the percentage of IL-4-expressing CD4+ T lymphocytes in both groups increased significantly at 12 weeks(P<0.05,respectively), the percentage of IL-4-expressing cells was significantly higher in treatment group than in control group(P<0.05). After initiation of MMI treatment, plasma concentrations of IP-10 decreased significantly at 12 weeks(P<0.05), plasma concentrations of IP-10 was significantly lower in treatment group than in control group(P<0.05).On the other hand, plasma concentrations of TARC decreased significantly at 12 weeks(P<0.05).Conclusion:1. Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction can improve clinical symptoms of resent-onset Graves’ disease more quickly. Our RCT showed that the Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction combined with methimazole(MMI) treatment is clearly superior in the effectiveness to achieve normal thyroid hormone(TH) than MMI alone treatment, especially at 4 wk and 8 wk. The Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction combined with methimazole(MMI) treatment can normalize TH more rapidly than MMI alone treatment. On the other hand, it is clearly superior in the effectiveness to improve goiter than MMI alone treatment. Both are advantages of traditional Chinese medicine in the treatment of Graves’ disease. Treatment group caused significantly fewer adverse effects, and need fewer doses of MMI to achieve normal TH than control group.2. Increased intrathyroid vascularity(ITV) can occur in resent-onset Graves’ disease, which has been shown to correlate with serum VEGF and IP-10 levels. Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction can improve goiters more effectively than only traditional western medicine by decreasing serum VEGF and IP-10 levels of patients with GD.3. Th1 rather than Th2 cells were predominant among peripheral blood lymphocytes in hyperthyroid patients in the active phase of Graves’ disease, suggesting that Th1 dominance is responsible for disease induction. After treatment with Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction and MMI, a progressive transition from Th1 to Th2 dominance was evidently found. Our RCT showed that the Nourishing-Yin Removing-Fire and Dissipating-Stagnation Decoction combined with methimazole(MMI) treatment is clearly superior in the effectiveness to achieve th1/th2 balance than MMI alone treatment. Thus, INF-γ-expressing peripheral blood lymphocytes and increased serum IP-10 levels correlate with activity of Graves’ disease, suggesting that the prevalence of such cells among peripheral blood lymphocytes and serum IP-10 would be useful surrogate markers for thyroid autoimmune activity in this disease.
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