The Evaluation Of Oxidative Stress State, Quality Of Life And Curative Effect In The Patients With Graves Disease Before And After ¹³¹I Treatment

BackgroundGraves disease(GD) is a more severe and most common subtype of hperthyroidism. High level of hornmone lead to the disorder of internal environment and harm to multiple systems in patients with GD, including metabolic abnormalities of calcium and phosphorus that may induce osteoporosis, mental and neurological damage and so on. The pathophysiology of GD is associated with activation of immune response, oxidative stress damage, activation of nerve psychological defense mechanism. Taking 131I has been an important and common method for GD. But it is still unable to maintain the function of the ideal state, and may induce subclinical hyperthyroidism or subclinical hypothyroidism, which affects patients’quality of life.There are short of the systematical follow-up study and efficacy evaluation about the role of 131I in GD patients.The purpose of this study was to evaluate the clinical curative effect before and after treatment,oxidative stress state and quality of life for one year in patients with GD who received 131I treatment. The influences of 131I treatment on illness, oxidative stress status and quality of life were explored, which would provided theoretical basis for improving prognosis and quality of life of GD patients.Part 1 the following up design and the losses analysisMethods1. Subjects with a diagnosis of Graves disease(GD) according to ICD-10(E05.0), who voluntarily received 131I treatment, were recruited. The follow-up archives were established, the information of loss were statistically analyzed, the reasons of loss of follow-up were explored.2. The relationships between gender composition, object’s previous treatment situation, status of economy, urban and rural factors and loss of follow-up were analysed using crosstable analysis.ResultsA total of 57 patients lost follow-up, of which 10 cases were male and 47 cases were female, and the rate of loss of follow-up was 15.2%. No statistically significant difference in the rate of loss of follow-up was found between male and female (x2= 1.182, P=0.331); the differences in the rate of loss of follow-up between patients treated with 131I and patients without 131I treatment were statistical significance(x2= 19.137, P=0.000); the differences between urban and rural distribution of patients with loss of follow-up were statistical significance(x2= 5.591, P=0.018), more share from the countryside; there was no statistically significant difference in the two groups devided acording to family income of distribution(x2= 0.453, P=0.501).Part 2 The functional status of thyroid hormone axis and its influencing factors before and after 131I therapy for patients with Graves’ diseaseMethods1. Three hundred and nineteen patients (male 77; female 242) accepted 131I therapy and their blood samples were collected from cubital veins at about 8:00-9:30 before 131I therapy, after treatment 1 moth(1m),3 moths(3m),6months(6m), 9months (9m) and 12 months (12m). The samples were processed by centrifugation and the serum was segregated for detection.2. Srum FT3, FT4, were measured by radioimmunoassay. sTSH levels was measured by using immunoradiometric assay. TRAb and Anti-TPO were detected by chemiluminescence immunoassay.3. According to the serum FT3, FT4, sTSH level, patients with GD who accepted 131I therapy were divided into 5 clinical outcome groups, including normal group, hyperthyroid group, subclinical hyperthyroidism group, subclinical hypothyroidism group and hypothyroidism group.4. Statistical analysis:SPSS 17.0 statistical software was used to analyze all data. General linear model was used to compare the levels of FT3, FT4, sTSH, TSRAb, Anti-TPO at different time points. Bivariate correlation analysis was used to analyze the relationship of the indexes mentioned above. The crosstable analysis was applied to analyze age and gender differences among different clinical outcomes and to analyze the relationships among different course, whether received medications or not, thyroid size and after 131I therapy. Analysis of variance was used to compare differences of the highest iodine absorption rate among five groups.Results1. The patients’thyroid function status before and after taking 131I at different time points:At different time points after 131I therapy, the five groups had different cases. Up to 12-month follow-up, there were 157 cases in normal group,34 cases in hyperthyroid group,42 cases in subclinical hyperthyroidism group,54 cases in subclinical hypothyroidism group and 32 cases in hypothyroidism group, respectively.2. The serum average levels of different indexes were compared at different follow-up time. According to the statistical result of FT3, the result was F=4792.747, P=0.000. LSD method was used to comparing FT3 among the groups. Compared 12m with 9m, P=0.032. Compared FT3 among the other groups, the P value was all less sTSH, F=226.953, P=0.000. Compared lm and 3m with Om, the P value was 0.797 and 0.238, respectively. Compared 3m with lm, there was no statistically significant difference. As for Anti-TPO, F=4792.747, P=0.000. Compared 12m with 9m, P=0.003. Compared among the other groups, the P value was all less than 0.001.3. The correlation analysis of thyroid hormone level changes at different follow-up time points before and after taking 131I.The result showed that FT3 was associated positively with FT4, TRAb and anti-TPO, but showed a negative correlation with sTSH, r value was 0.957,0.905,0.627 and-0.370, respectively. The P value was all less than 0.001. FT4 was associated positively with TRAb and anti-TPO, but it showed a negative correlation with sTSH, r value was 0.859,0.600 and-0.350, respectively. The P value was all less than 0.001. sTSH was associated negatively with TRAb and anti-TPO, r value was-0.370 and-0.230, respectively. TRAb was associated positively with anti-TPO, r=0.604, P=0.000.4. Treatment outcome and related factors analysis at 12 months follow-up.At the end of the follow-up period, there was no statistical difference among five groups in age (F=1.471,P=0.211) under one way analysis of variance, but there was statistical differences among five groups in iodine absorption rate (F=53.759; P=0.000). All patients were stratified by the different course of the disease, medication, thyroid size and family history according to sex and after 1 year treatment. The crosstable analysis was used to compare the constituent ratio of five clinical outcome groups, x2 value was 4.061,2.507,29.372,16.558 and 116.819, and corresponding P values was 0.3980,643,0.000,0.035 and 0.000, respectively.Part Ⅲ Changes in oxidative stress status before and after the treatment of 131I in patients with GDMethod1.319 GD patients in "part 2" of the patient group, and 90 healthy control subjects (22 males and 68 females) who are older or yonger less 2 years than the average age of the patients. Collecting and processing samples was same as in the part 2.2. Detected the level of malondialdehyde(MDA) and superoxide dismutase(SOD) by photoelectric colorimetry, and of the nuclear factor κB (NF-κB) by using the enzyme-linked immunosorbnent assay(ELISA).3. Statistical analysis:compared the changes of the blood serum SOD, MDA and NF-κB by independent sample t-est between the GD group and the control group with the different time points. General linear model to analyse the changes of SOD, MDA, NF-κB in the different follow-up points. One-way analysis of variance to analyse the changes of SOD, MDA, NF-κB in the different groups with the clinical outcome in 12m. Pearson correlation analysis to analyse the SOD, MDA, NF-κB and the correlation between them and the thyroid function axis hormone level.Result1. The differences of serum MDA, Cu/ZnSOD, MnSOD and NF-x B between the patients and the controls were analyzed by independent-samples t-test at different follow-up time points. There was significant difference of all of them between patent group and control group, for MDA and NF-κB, the difference was exist at the end of 9m,, the t value was-2.614,-2.369, and the P value was 0.010,0.019, respectively. But at the end of 12m, there was no significant difference between them,the t value was-0.750,-0.608, and the P value was 0.453,0.543, respectively. The serum level of MDA and NF-κB in the other time points and Cu/ZnSOD, MnSOD in all of the time points compared with the control group, all the P values were less than 0.001.2. The mean comparison differences were significant of the serum MDA level, Cu/ZnSOD, MnSOD and NF-κB activity of the patient group with 131I treatment in the different follow-up points by two factors analysis of variance, FMDA=35586.594, P=0.000; FCu/ZnSOD=39.699, P=0.000;FMnSOD=6813.408,P=0.000; FNFB =7032.432,P=0.000.3. Pearson correlation analysis analysed the correlation of the index in patient group. Positive correlation was found between the level of serum FT3 and serum FT4, TRAb, Anti-TPO, MDA, Cu/ZnSOD, MnSOD in the patient group, the r value was 0.957,0.905,0.627,0.487,0.664,0.228, respectively, P value was all less than 0.001, an inverse association between the level of serum FT3 and sTSH, NF-κB,the r value was 0.370,0.384, the P value was all less than; the level of FT4 has positive correlation with TRAb, Anti-TPO, MDA, Cu/ZnSOD, MnSOD and NF-κB, r=0.859,0.600,0.476,0.648,0.203,0.372, the P value was all less than 0.001, and the FT4 has the inverse association with sTSH, r=-0.350, P=0.000; sTSH has the inverse association with TRAb, Anti-TPO, MDA, Cu/ZnSOD, MnSOD and NF-κB, r value was-0.370,-0.330,-0.489,-0.506,-0.430 and-0.365, respectively, and the P value was 0.000,0.034,0.000,0.000,0.010 and 0.000 respectively; TRAb has a positive correlation with Anti-TPO, MDA, Cu/ZnSOD, MnSOD, r=0.604,0.382, 0.592,0.256, the P value was all less than 0.001, there was no significant correlation between TRAb and NF-κB, r=0.208, P=0.056; Anti-TPO and MDA, ZnSOD, MnSOD, NF-κB has a direct association, r=0.464,0.440,0.236,0.230, P value was all less than 0.001; MDA and Cu/ZnSOD, MnSOD, NF-κB has a direct association, r=0.323,0.327,0.235, P value was all less than 0.000, Cu/ZnSOD and MnSOD also has a direct association, r=0.476,P=0.000; NF-κB and Cu/ZnSOD, MnSOD did not have statistically significant correlation, r=0.223,0.106,P=0.053,0.329.4. At the end of 12m, compared with the oxidative stress parameters in healthy control group, hyperthyroidism group, subclinical hyperthyroidism group, subclinical hypothyroidism group and hypothyroidism group, there were statistically significant differences in MDA, Cu/ZnSOD, MnSOD and NF-κB, and the F value was 21.540, 1923.347,142.134,32.887, respectively, the P was less than 0.000. Differences of MDA between the healthy control group, subclinical hyperthyroidism group and hyperthyroidism group have the significant, the normal group has a low serum level, and the P value was less than 0.001. there was no significant difference between the normal group, subclinical hypothyroidism group and hypothyroidism group, and the P was 0.055,0.161; Cu/ZnSOD was the lowest in the normal group and was higher than the other groups, and the differences have the statistically significant, P value was less than 0.001; the level of MnSOD in subclinical hyperthyroidism group^ hyperthyroidism group and hypothyroidism group was higher than the normal group, and there was no significant differences in hyperthyroidism group and hypothyroidism group (P=0.405), NF-κB which in the hyperthyroidism group was higher than the other groups (P<0.001).Part IV Appraisal of the Life Quality of the Patient with Hyperthyroidism who were treated with 1311MethodsMesured the Quality of life in patient’s with GD by using Quality of life scale(QLS, SF-36), Self-Rating Anxiety Scale (SAS), Self-RatingDpression Scale(SAS) and Social Disability Screening Schedule (SDSS) and the Ssikness Impact Profile(SIP) before and after treatment with 131I for 6m and 12m. the differences of the score of SAS, SDSS, SF-36, SIP and their agents at different time were analyzed by performing General linear model. The differences of the score among the groups with different clinical outcome were compared by performing one way ANOVA program. Bivariate correlation analysis was used to analyzed the correclation between the scale’s score. The influencing factors on life quality state at the end of one year was analyzed by using Logistic regression programme.Results1. There was significant difference of SAS, SDS, SDSS, SIP and SF-36 and their agent score among every three groups before and 6m and 12m after 131I treatment in the 319 patients. After treatment with 131I, SAS, SDS, SDSS and SIP score was lower, SF-36 total and agent score was higher. There was no significant defference between the score of SAS, SDS, SDSS, SIP total score and it’s agent score of SD-II, SR, W, SF-36 agent score of RP, BP, VT, SF at the end of 12m compared to the score at the end of 6m. But there was significant defference between the score of SIP agent score of SD-I, HM, RP, SF-36 total score and it’s agent score of PF, GH, RE, HT at the end of 12m compared to the score at the end of 6m.2. At the end of 6m and 12m after treatment the subjects were divided five groups:normal, subclinical hyperthyroidism, hyperthyroidism, subclinical hypothy-roidism and hypothyroidism. Not only at the end of 6m, but also at the end of 12m, there was significant difference of SAS, SDS, SDSS, SIP total score, and it’s agent score of SD-Ⅰ, SD-Ⅱ, SR, W, RP, SF-36 total score and it’s agent score PF、RP、BP、 GH、VT、SF、RE、HT, respectively, among the five groups. P<0.001, There was no significant difference of HM among five groups.At the end of 6m, for every scale, comparision every two groups out of five groups by performing SNK programme. As for SAS, four equilibrium subsets were appeared:normal; subclinical hyperthyroidism and subclinical hypothyroidism (P=0.058); subclinical hypothyroidism and hypothyroidism (P=0.426); hyper-thyroidism. As for SDS, three equilibrium subsets formed:normal; subclinical hyperthyroidism, subclinical hypothyroidism and hyperthyroidism (P=0.060); hypothyroidism. As for SDSS, three equilibrium subsets formed:normal; subclinical hyperthyroidism, subclinical hypothyroidism and hypothyroidism (P=0.273); hyperthyroidism. Three equilibrium subsets formed as for SIP total score:normal; subclinical hyperthyroidism, subclinical hypothyroidism and hypothyroidism (P=0.393); hyperthyroidism. Three equilibrium subsets formed as for SD-I:normal and subclinical hypothyroidism (.P=0.086); subclinical hypothyroidism, subclinical hyperthyroidism and hypothyroidism (P=0.315); hyperthyroidism. Two equilibrium subsets formed as for SD-Ⅱ:normal; subclinical hyperthyroidism, subclinical hypothyroidism, hypothyroidism, hyperthyroidism (P=0.409). Two equilibrium subsets formed as for SR:normal; subclinical hyperthyroidism, subclinical hypothyroidism, hypothyroidism, hyperthyroidism (P=0.065). One equilibrium subsets formed as for SD-Ⅱ and HM, P=0.057 and 0.577, respectively. Two equilibrium subsets formed as for RP of SIP:normal, subclinical hyperthyroidism, subclinical hypothyroidism and hypothyroidism (P=0.127); subclinical hyperthyroidism, hypothyroidism, hyperthyroidism(P=0.070).Two equilibrium subsets formed as for SF-36 total score:normal; hyperthyroidism, hypothyroidism, subclinical hyperthyroidism and subclinical hypothyroidism(P=0.863). Two equilibrium subsets formed as for PF:subclinical hyperthyroidism, subclinical hypothyroidism, hypothyroidism and hyperthyroidism (P=0.880); normal. Two Equilibrium subsets formed as for RP:hyperthyroidism, hypothyroidism, subclinical hyperthyroidism and subclinical hypothyroidism (P=0.690); normal. Two equilibrium subsets formed as for GH:hyperthyroidism, hypothyroidism, subclinical hyperthyroidism and subclinical hypothyroidism (P=0.128); normal. Two equilibrium subsets formed as for VT:subclinical hyperthyroidism, hypothyroidism, hyperthyroidism, subclinical hypothyroidism (P=0.264); normal. Two equilibrium subsets formed as for SF:subclinical hyperthyroidism, hyperthyroidism, subclinical hypothyroidism and hypothyroidism (P=0.143); normal. Three equilibrium subsets formed as for RE:hypothyroidism, subclinical hyperthyroidism, subclinical hypothyroidism (P=0.133); hyperthyroidism; normal. Two equilibrium subsets formed as for HT:hyperthyroidism,hypothyroidism, subclinical hyperthyroidism and subclinical hypothyroidism (P=0.286); normal.At the end of 12m, for every scale, comparision every two groups out of five groups by performing SNK programme. As for SAS, three equilibrium subsets were appared:normal; subclinical hyperthyroidism and subclinical hypothyroidism (P=0.513); hypothyroidism and hyperthyroidism (P=0.185). As for SDS, three equilibrium subsets formed:normal; subclinical hyperthyroidism, subclinical hypothyroidism (P=0.378); hyperthyroidism and hypothyroidism (P=0.349). As for SDSS, three equilibrium subsets formed:normal; subclinical hyperthyroidism, subclinical hypothyroidism (P=0.956); hypothyroidism and hyperthyroidism (P=0.098). Four equilibrium subsets formed as for SIP total score:normal; subclinical hyperthyroidism and subclinical hypothyroidism (P=0.523); hypothyroidism; hyperthyroidism. Two equilibrium subsets formed as for SD-Ⅰ: normal, subclinical hypothyroidism and subclinical hypothyroidism (P=0.089), hyperthyroidism and hypothyroidism (P=0.681). Four equilibrium subsets formed as for SD-Ⅱ:normal; subclinical hyperthyroidism and subclinical hypothyroidism (P=0.080); subclinical hyperthyroidism and hypothyroidism (P=0.196); hyperthyroidism. Three equilibrium subsets formed as for SR:normal, subclinical hypothyroidism, subclinical hyperthyroidism (P=0.524); hypothyroidism; hyperthyroidism. Two equilibrium subsets formed for W:subclinical hyperthyroidism, normal and subclinical hypothyroidism (P=0.686); hypothyroidism and hyperthyroidism (P=0.870). One equilibrium subsets formed for HM:normal, subclinical hyperthyroidism, subclinical hypothyroidism, hypothyroidism, hyperthyroidism (P=0.102). Three equilibrium subsets formed as for RP of SIP: normal; subclinical hyperthyroidism and subclinical hypothyroidism (.P=0.797); hypothyroidism and hyperthyroidism(P=0.297).Four equilibrium subsets formed as for SF-36 total score:hyperthyroidism; hypothyroidism; subclinical hyperthyroidism and subclinical hypo-thyroidism (P=0.984); normal. Three equilibrium subsets formed as for PF:hyperthyroidism; hypothyroidism, subclinical hyperthyroidism and subclinical hypothyroidism (P=0.903); normal. Three equilibrium subsets formed as for RP:hyperthyroidism; hypothyroidism, subclinical hyperthyroidism and subclinical hypothyroidism (P=0.385); normal. Three equilibrium subsets formed as for BP:hyperthyroidism and hypothyroidism(P=0.964); subclinical hyperthyroidism and subclinical hypothyroidism(P=0.376); normal. Three quilibrium subsets formed as for GH: hyperthyroidism; hypothyroidism and subclinical hyperthyroidism and subclinical hypothyroidism (P=0.966); normal. Four equilibrium subsets formed as for VT: hypothyroidism and hyperthyroidism(P=0.426); subclinical hypothyroidism; subclinical hyperthyroidism; normal. Two equilibrium subsets formed as for SF: hyperthyroidism, hypothyroidism, subclinical hypothyroidism and subclinical hyperthyroidism(P=0.053); normal. Two equilibrium subsets formed as for RE: hypothyroidism, hyperthyroidism, subclinical hyperthyroidism and subclinical hypothyroidism(P=0.056); normal. Three equilibrium subsets formed as for HT: hyperthyroidism; hypothyroidism, subclinical hyperthyroidism and subclinical hypothyroidism(P=0.123); normal.3. Comparision of the difference of SF-36 total score and it’s agent score between control group and GD group before and after treatment with 131I for 6m, 12m by performing ANOVA. The results indicated:there was significant difference of the total score of SF-36 and it’s agent score PF、RP、VT、SF、RE、HT between GD group and the control group, respectively. At the end of 6m, the total score of SF-36 and it’s agent score RP、VT、SF、RE、HT in GD group were lower than those in control group. At the end of 12m, the total score of SF-36 and it’s agent score PF、SF、 RE、HT in GD group were lower than those in control group. the score of PF and RE at 6m were lower than those at 12m, but the score RP、VT、SF at 6m were higher than those at 12m, respectively.4. Under the corrclation analysis programme, the positive correlation of score exist between SAS and SDS, SDSS, SIP. r value was 0.975,0.913,0.891, respectively. There was the negative correlation of score between SAS and SF-36 total score, r value was-0.567. the positive correlation of score exist between SDS and SDSS, SIP. r value was 0.901,0.884, respectively. There was the negative correlation of score between SDS and SF-36 total score, r value was-0.563. There was positive correlation between SDSS and SIP total score(r=0.924), but negative correlation between SDSS and SF-36, P<0.001. Nagative correclation exist between SIP and SF-36, r=-0.640, P<0.001.5. At the end of 12m, the subjects were divided two groups according to SDSS score(2 as demarcation):normal social function group and deficent social function group. Took the size of thyroid, taking 131I ratio, the levels of FT3, FT4, TSH, TRAb, TPO, MDA, ZnSOD, MnSOD, NF-κB, at the beginning, ophthalmopathy as concomitant variable, Logistic regression programme was performed. Significant variances were taking 131I ratio, ophthalmopathy,the levels of FT3, TSH, TPO, MDA, NF-κB. Homologus regression coefficient was 0.054,-1.077,0.239,20.703,0.316, 2.788 and-219.715, respectively. The P value was 0.041,0.044,0.006,0.004,0.000, 0.000,0.000, respectively.Conclusion1. Taking 1311 is a safe and effective method with low recurrence rate for Graves disease.2. After taking 131I, thyroid axis function is in a relatively unstable condition, it can appear five different clinical outcomes such as "hyperthyroidism, hypothyroidism, hyperthyroidism,subclinical hyperthyroidism,subclinical hypothyroidism, and normal thyroid function", and the greatest volatility exists between 3-6 months, but the clinical outcome can be mutual transformation during the first year. The incidence rate of subclinical thyroid disease which is caused by 131I therapy is high, so there may be long-term adverse outcomes. Autoimmune derangement may exist after131I therapy with one year, so making corresponding intervention measures may be the important aspect to improve prognosis.3. There is a pathological process of oxidative stress enhanced in GD patients, and in this process, the cellular damage, immune activation and the enhance of oxygen radical scavenging activity may coexist at the same time, and may interact, to cause the clinical symptoms of thyroid dysfunction; The treatment of 131I can change the serum level of oxidative stress related factors in GD patients, balance the oxidative stress status of organism, and this process and hypothyroidism may interact with immune activation.All of hyperthyroidism, hypothyroidism and the subclinical thyroid disease can result in the enhanced oxidative stress activity. Therefore, the subclinical thyroid functional status and the hypothyroidism which caused by 131I treatment also need to pay more attention.4. Quality of life of patients with GD is decrease.131I treatment can improve it. Physical function can be improved, but part of social-psycho fuction can not significantly. So many factors can influce the quality of life. The most damaged quality of life is in the clinical state of hyperthyroid. The damage exist in hypothyroidism, subclinical thyropathy, even in recovered GD patcients within a period of time. It is necessary to care patients with GD from multidemention, especially mental intervention, in order to improve the quality of life completely.