Liver Injury Is Related With The Dosage Of Antithyroid Drugs And Initial Serum Free Thyroxine Level In Patients With Hyperthyroidism

Objective:Diffuse toxic goiter disease（Graves disease,GD）is the most common cause of hyperthyroidism.Antithyroid drug（ATD）is the main method for hyperthyroidism.Graves hyperthyroidism itself can cause liver injury,and ATD can also cause drug-induced liver injury.At present,it is confirmed that liver injury in patients with GD be affected by gender,age,metabolic characteristics,drug interactions and other factors in multiple studies.The previous study of our group found that the initial serum level of free thyroxine（FT₄）when hyperthyroidism was diagnosed without any treatment was associated with drug-induced liver injury after the application of ATD.Patients with higher level of initial FT₄ were more likely to develop liver injury after the application of ATD.However,there is no clinical research on the total dosages and average daily dosage of ATD on the occurrence of liver injury.Therefore,this study retrospectively analyzed the relevant clinical data of GD patients with liver injury,and explored the effect of ATD dosage and initial serum FT₄ level on liver function,so as to provide references for guiding the rational application of ATD in clinical.Methods:From January 2002 to January 2018,patients who were admitted to the endocrinology department of the First Affiliated Hospital of Dalian Medical University and diagnosed with GD and with liver injury were included.A total of 282 patients were included according to the inclusion and exclusion criteria.There were 161 cases of hyperthyroidism-induced liver injury,56 cases of ATD-induced liver injury,and 65cases of the mixed liver injury（mild liver injury caused by hyperthyroidism and ATD-induced liver injury）.A total of 47 patients with hyperthyroidism who did not have liver injury after ATD treatment were selected from the outpatient clinic of the the First Affiliated Hospital of Dalian Medical University from January 2017 to December2019 as the control group.Record sex,age,thyroid stimulating hormone（TSH）,free triiodothyronine（FT₃）,FT₄,antithyrotropin receptor antibody（TRAb）,types of ATD,initial ATD dosage,total ATD dosages,average daily ATD dosage,alanine aminotransferase（ALT）,aspartate aminotransferase（AST）,alkaline phosphatase（ALP）,γ-glutamyl transpeptidase（γ-GT）,total bilirubin（T-Bil）and direct bilirubin（D-Bil）.SPSS 22.0 software was used for statistical processing to compare the above indicators among the four groups of patients.Spearman’s test was used to analyze the correlation between age,initial thyroid hormone and TRAb level,ATD drug dosage and liver injury.To"whether liver injury occurred in patients with Graves disease"as the dependent variable,With age,initial FT₃ and FT₄level,and initial ATD dosage"as independent variables line logistic regression analysis.P<0.05 is considered with statistically significant.Results:1.Compared with the group without liver injury,the ATD-induced liver injury group has higher level of initial serum FT₄levels（63.31±31.00 pmol/L vs 50.31±34.23pmol/L,P=0.041）and initial ATD dosage（18.43±7.40 mg/d vs 13.99±7.49mg/d,P=0.010）.The hyperthyroidism-induced liver injury group has higher level of initial serum FT₃（31.12±10.93 pmol/L vs 20.98±14.29 pmol/L,P=0.001）and FT₄（74.32±22.58 pmol/L vs 50.31±34.23 pmol/L,P=0.001）.The mixed liver injury group has higher level of age（42.49±11.87 years old vs 36.94±12.30 years old,P=0.033）,initial serum FT₃（28.24±14.53 pmol/L vs 20.98±14.29 pmol/L,P=0.014）and FT₄（69.80±27.88 pmol/L vs 50.31±34.23 pmol/L,P=0.001）and lower level of total ATD dosages[180（105,260）mg vs 400（300,590）mg,P<0.001].Compared with the drug-induced liver injury group,the mixed liver injury group has lower level of the initial ATD dosage（15.35±7.14 mg/d vs 18.43±7.40 mg/d,P=0.037）and the total ATD dosages[180（105,260）mg vs 270（140,567）mg,P=0.030].2.The liver function of the patients:compared with the ATD-induced liver injury group,the hyperthyroidism-induced liver injury group has higher level of T-Bil[15（12.6,20）μmol/L vs 11.95（7.975,19.075）μmol/L,P=0.016],while the mixed liver injury group has lower level of ALP[82（65.25,123.5）μmol/L vs 126（92.5,177）μmol/L,P=0.009].Compared with the hyperthyroidism-induced liver injury group,the mixed liver injury group has higher level of ALT[146（97.5,206.5）IU/L vs 103（65,153）IU/L,P<0.001],AST[67.5（57,98.5）IU/L vs 62（44.5,83.5）IU/L,P=0.012]and lower level of D-Bil[3.6（2.975,5.2）μmol/L vs 5.2（4,7.7）μmol/L,P=0.007].3.Among the patients with ATD-induced liver injury,after ATD treatment,23patients（40.5%）had liver injury in less than 2 weeks,and 16 patients（28.0%）had liver injury in 2 weeks to 4 weeks,9 patients（16.6%）had liver injury in 4 to 8 weeks,5patients（8.9%）had liver injury in 8 weeks to 12 weeks,and 3 patients（6.0%）had liver injury after more than 12 weeks.Among the patients with hyperthyroidism-induced liver injury,because of the obvious aggravation of liver injury,31 patients（47.7%）were discontinued with ATD in less than 2 weeks,and 23 patients（35.4%）were discontinued with ATD in 2 to 4 weeks,6 patients（9.2%）were discontinued with ATD in 4 to 8 weeks,3 patients（4.6%）were discontinued with ATD in 8 to 12 weeks,2patients（3.1%）were discontinued with ATD after more than 12 weeks.4.Correlation analysis of liver enzymes level with age,serum thyroid hormone levels and TRAb levels between the group without liver injury and the hyperthyroidism-induced liver injury group showed that serum ALT level was positively correlated with initial serum FT₄ level（P<0.05）,AST and ALP were positively correlated with initial FT₃ level and initial FT₄ level（P<0.05）,γ-GT was positively correlated with age,initial FT₃ level and initial FT₄ level（P<0.05）,there was no correlation between liver enzymes level and TRAb（P>0.05）.5.Correlation analysis of liver enzymes level with age,drug dosage,serum thyroid hormone and TRAb levels in the group without liver injury and the ATD-induced liver injury group showed that ALT was positively correlated with initial serum FT₃,FT₄level and initial ATD dosage（P<0.05）.Serum AST level was positively correlated with age,initial serum FT₄ level and initial ATD dosage（P<0.05）.Serumγ-GT level was positively correlated with age,initial TRAb level（P<0.05）.Serum ALP level was positively correlated with initial TRAb level（P<0.05）.6.Correlation analysis of liver enzymes level with age,drug dosage,serum thyroid hormone levels and TRAb level in the group without liver injury and the mixed liver injury group showed that serum ALT and AST levels were positively correlated with initial serum FT₃ and initial FT₄ levels（P<0.05）,and negative correlated with total ATD dosages（P<0.05）.Serumγ-GT level was positively correlated with the initial FT₃（P<0.05）.7.Correlation analysis of liver enzymes level with age,ATD dosage,serum thyroid hormone levels and TRAb level in the ATD-induced liver injury group and mixed liver injury group showed that serum ALT,AST,γ-GT and ALP levels were positively correlated with the total ATD dosages（P<0.05）.8.To"whether liver injury occurred in patients with Graves disease"as the dependent variable,With"age,initial serum FT₃ level,initial serum FT₄level,and initial ATD dosage"as independent variables line logistic regression analysis,the results showed that age and initial serum FT₄ level were independent risk factors for liver injury（P<0.05）.Conclusions:1.Age,initial serum FT₃ level,initial serum FT₄ level,and initial ATD dosage are the risk factors for liver injury in patients with hyperthyroidism.Among them,age and initial serum FT₄ level are independent risk factors for liver injury.Gender,initial TRAb level,types of ATD and average daily dosage are not associated with liver injury.2.Higher serum liver enzymes levels（ALT,AST,γ-GT,ALP）from older patients,higher level of initial serum thyroid hormone levels to higher initial ATD dosage and total ATD dosages.3.The recommended initial dosage of MMI is 15mg/d,but for patients who had liver injury,a lower dosage of ATD should be selected.