Prospective Research On Effects And Adverse Reactions Of Initiating Different Dosage Of Methimazole Therapy For Patients With Hyperthyroidism Caused By Graves Disease

Objective:Hyperthyroidism is a kind of thyrotoxicosis caused by excessive thyroid hormones secreted by the thyroid itself.The most common cause of hyperthyroidism is Graves disease(GD).At present,antithyroid drugs(ATD)are the first choice for the treatment of hyperthyroidism in China.However,ATD may also cause different degrees of adverse reactions,such as hepatic damage,agranulocytosis,minor rash,drug-induced hypothyroidism,etc.In the past,large dose of ATD was used as the initial treatment to control hyperthyroidism as soon as possible,it is also recommended to start treatment with low-dose ATD,which is believed to control hyperthyroidism slowly but with fewer adverse reactions.At present,there are few prospective studies on the optimal starting dose of ATD in China.In this study,by prospectively observing the effects and adverse reactions after treatment with different initial doses of Methimazole(MMI)in patients with hyperthyroidism and normal liver profile and baseline complete blood count,this study explored the optimal initial dose of MMI that could effectively control hyperthyroidism without increasing the risk of adverse reactions,providing reference for rational clinical application of ATD.Methods:This trial was performed in the outpatient service of endocrinology and metabolism department and thyroid diagnosis and treatment center of the First Affiliated Hospital of Dalian Medical University,from January 2021 to December 2022.A total of 95 patients were included according to the inclusion and exclusion criteria.According to the level of serum free thyroxine(FT4)before initiating ATD therapy for GD,they were divided into group A(n=45)and group B(n=50).Group A: FT4 was less than twice the upper limit of normal value(FT4 range is 24~48 pmol/L);group B: FT4 was more than twice the upper limit of normal(FT4 > 48 pmol/L).The treatment dose was randomly determined by the outpatient physician according to the odd and even number of the order of treatment.In group A and group B,according to the different treatment doses of MMI,group A was divided into two subgroups of 10 mg/d and 15 mg/d.Group B was divided into two subgroups of MMI 15 mg/d and MMI 20 mg/d.At baseline,gender,age,past history,family history,MMI initial dose of all subjects were recorded.Prior to initiating ATD therapy for GD,the levels of thyroid stimulating hormone(TSH),free triiodothyronine(FT3),FT4,antithyrotropin receptor antibody(TRAb),alanine aminotransferase(ALT),aspartate aminotransferase(AST),white blood cell(WBC)and neutrophil(N),the number,presence of allergies(rashes),type and time of adverse reactions after ATD therapy were measured.Data were analyzed with the SPSS 26.0 statistical software package.The comparison of measurement data between the two groups was consistent with the normal distribution using t test.Rank sum test for non-normal distribution;chi-square test was selected for comparison of count data;Spearman analysis was used to analyze the relationship between measurement variables.Respectively to To "GD patients after therapy of serum liver enzymes levels(ALT,AST)is normal or not" and To "GD patients after therapy of serum complete blood count levels(WBC,N)is normal or not" as the dependent variable,with "initial MMI dosage,initial TSH,TRAb,FT4,FT3,ALT,AST,WBC,N level,gender,age,previous history of hyperthyroidism" as independent variables line logistic regression analysis.P<0.05 is considered statistically significant.Results:1.Group A(1)Thyroid function after ATD therapy: compared with the MMI 10 mg/d group,the serum FT4 level in the MMI 15 mg/d group was significantly lower in the first month(19.00±1.74 pmol/L vs 25.19±1.14 pmol/L,P<0.05)and the second month(15.87±1.13 pmol/L vs 19.98±1.10 pmol/L,P<0.05).Serum FT3 level was significantly decreased in the third month(4.59±0.43 pmol/L vs 5.71±0.28 pmol/L,P<0.05).The proportion of FT4 returning to normal increased significantly in the first month(63.2% vs 30.8%,P<0.05)and the second month(84.2% vs 46.2%,P<0.05).The recovery time of FT4([29.00(28.0,53.5)d vs 72.0(30.0,90.0)d,P<0.01])was significantly shorter.FT3,FT4 and TRAb showed a downward trend in the two different dose subgroups,TSH showed an overall upward trend,and the overall downward trend of MMI 15 mg/d was greater than that of MMI 10 mg/d.(2)There was no significant difference in liver function(blood ALT,AST)levels and blood routine(blood WBC,N)counts in the two dose subgroups of group A before and after ATD therapy.(3)In the two dose subgroups of group A,there were 3 cases of liver damage(11.5%),1 case of drug-induced hypothyroidism(3.8%)and 1 case of rash(3.8%)in the MMI 10 mg group.There were 3 cases(15.8%)of liver damage and 1 case(5.3%)of neutropenia in MMI 15 mg group.The proportion of liver damage in the MMI 15 mg group was higher than that in the 10 mg group(15.8% vs 11.5%),but there was no statistical difference.(4)Among the time of appearance of adverse reactions,the time of appearance of liver damage in the MMI 10 mg/d treatment group in group A was 0~8w in 3 cases;the time of appearance of drug hypothyroidism was 0~2w in 1 case;the time of appearance of skin rash was 2~4w in 1 case.The time of appearance of liver damage in the MMI 15 mg/d treatment group was 0~4w in 3 cases;the time of appearance of granulocytopenia was 0~2w in 1 case.2.Group B(1)Thyroid function after treatment: compared with the MMI 15 mg/d group,the blood FT4 level in the MMI 20 mg/d treatment group was significantly lower in the second month(17.37±1.39 pmol/L vs 27.47±2.21 pmol/L,P<0.01)and the third month(16.70±1.89 pmol/L vs 22.18±1.49 pmol/L,P<0.05),and no difference at month 4(18.26±1.68 pmol/L vs 18.56±1.42 pmol/L,P>0.05).The proportion of FT4 returning to normal increased significantly in the second month(80% vs 50%,P<0.05)and not different at month 4(90% vs 65%,P=0.071).The decreasing trend of MMI 20 mg/d during the first 3 months of treatment was generally more obvious than that of MMI 15 mg/d group.After 4 months’ treatment,there was no difference in blood FT3,FT4,TSH,TRAb levels and the proportion of normal recovery in different dose groups.(2)There was no significant difference in liver function(blood ALT,AST)levels and blood routine(blood WBC,N)counts in the two dose subgroups before and after treatment.(3)In the two subgroups,8 cases(40%)of liver damage occurred in the MMI 15 mg/d group.There were 13 cases(43.4%)of liver damage,4 cases(13.3%)of neutropenia,2 cases(6.7%)of drug-induced hypothyroidism and 1 case(3.3%)of rash in MMI 20 mg/d group.The proportion of liver damage in the MMI 20 mg/d group(43.3% vs 40.0%)was higher than that in the MMI 15 mg/d group,but there was no statistical difference.(4)In the two subgroups of group B,the time of appearance of liver damage in the MMI 15 mg/d treatment group was 0~4w in 8 cases.The time of appearance of liver damage in the MMI 20 mg/d treatment group was 0~4w in 10 cases and 4~24w in 3 cases;the time of appearance of granulocytopenia was 0~12w in 4 cases;the time of appearance of drug hypothyroidism was 0~12w in 2 cases;the time to appearance of rash was 0~2w in 1 case.It can be seen that there were more adverse reactions in the MMI 20 mg/d group during the first 3 months after ATD therapy.3.Among the 95 patients followed up,27 cases(28.4%)developed liver damage,5 cases(5.3%)developed granulocytopenia,3 cases(3.2%)developed drug-induced hypothyroidism,and 2 cases(2.1%)developed rash after the application of MMI treatment.This shows that most of the adverse reactions caused by MMI appeared within the first 3 months after therapy,and liver damage and agranulocytosis were the main ones.4.Spearman correlation analysis of TRAb and TSH,FT3 and FT4 showed that there was no significant correlation between TRAb and TSH,FT3 and FT4.5.Spearman correlation analysis was performed on patients with hepatic damage and agranulocytosis and their initial FT3,FT4,TSH,TRAb,ALT,AST,WBC and N levels.6.Respectively to To "GD patients after therapy of serum liver enzymes levels(ALT,AST)is normal or not" and To "GD patients after therapy of serum complete blood count levels(WBC,N)is normal or not" as the dependent variable,with "initial MMI dosage,initial TSH,TRAb,FT4,FT3,ALT,AST,WBC,N level,gender,age,previous history of hyperthyroidism" as independent variables line logistic regression analysis;Age is an independent risk factor for agranulocytosis in GD patients after treatment.Conclusions:1.Different doses of MMI are used to treat GD patients,and it is found that after 6 months of therapy with MMI 10 mg/d,15 mg/d and 20 mg/d,most of the patients could be effectively controlled,and the efficacy was similar among all dose groups.2.In patients with mild hyperthyroidism,TH decrease faster in the first 3 months after MMI 15 mg/d therapy,which is conducive to faster remission of hyperthyroidism symptoms;in patients with moderate to severe hyperthyroidism,TH decrease faster in the first three months after MMI 20 mg/d therapy,but the incidence of adverse reactions is also relatively increased.3.The adverse reactions after ATD therapy mostly occur within 3 months after therapy,and the high-dose group is more likely to have adverse reactions.Agranulocytosis in GD patients after MMI therapy may be related to aging.4.MMI 15 mg/d may be the best and safe dose for the therapy of GD patients with hyperthyroidism.