intravenous methylprednisolone ( ivmp ) pulse therapy is the first - line treatment for patients with active - phase moderate to severe graves ' orbitopathy ( go ) . ivmp is widely used because it is more effective and better tolerated than oral steroids [ 2 , 3 ] . however , acute and severe liver damage has been reported after pulse therapy , with a roughly estimated morbidity and mortality of 0.8% and 0.3% , respectively . the cumulative dose of ivmp in four patients with fatal liver failure was 8.315  g [ 4 , 5 ] but slightly higher in three patients who died ( 10.8  3.6  g ) than in four patients who recovered ( 7.9  2.9  g ) . therefore , the european group of graves ' orbitopathy ( eugogo ) now recommends that the cumulative dose of mp should be less than 8  g [ 1 , 6 ] . thus , the aim of the present study was to investigate the risk factors for liver dysfunction during and after ivmp pulse therapy for go . this was a retrospective study of 175 japanese patients with moderate to severe go who were treated in one center from 2003 to 2013 . the mean age of the 118 females and 57 males was 51.7  15.5 years . they had been admitted to our university hospital for go and were treated with an intravenous injection of 1  g of mp daily for 3 consecutive days per week , repeated for three to six cycles , and followed by a tapering dose of oral prednisolone ( 20  mg / day for 4 weeks , 15  mg / day for 2 weeks , 10  mg / day for 2 weeks , 5  mg / day for 2 weeks , and 5  mg/2 days for 2 weeks ) . the daily dose of mp was reduced to 0.5  g except in cases with optic neuropathy after the recommendation by eugogo in 2008 . heart rate and ecg were monitored during the intravenous infusion of mp , administered every 2 - 3  h. in addition , 100 of the 175 patients were treated with orbital irradiation therapy ( 2  gy / day , 10 times ; total dose = 20  gy ) either during or after ivmp pulse therapy . thyroid diseases were diagnosed by measuring serum - free triiodothyronine ( ft3 ) , free thyroxine ( ft4 ) , thyroid - stimulating hormone ( tsh ) , thyroglobulin , anti - thyroglobulin antibody , anti - thyroid peroxidase antibody , and anti - thyrotropin receptor antibodies ( trabs ) . trabs were measured using three commercial kits : trab 1st generation ( trab cosmic iii , cosmic , tokyo , japan ) , trab 2nd generation , human trab ( yamasa , tokyo , japan ) and tsab ( yamasa tsab kit ) , and thyroid i uptake on i scintigraphy . orbitopathy was estimated by ophthalmologists using a modified nospecs classification   and the clinical activity score ( cas ) . magnetic resonance imaging was also performed before and after pulse therapy , as previously reported . graves ' disease was detected in 139 patients , 29 patients were euthyroid without a history of graves ' disease , and 7 patients had hypothyroidism without a history of graves ' disease . orbitopathy with nospecs class vi was determined in 8 patients , class v in 3 patients , class iv in 139 patients , class iii in 23 patients , and class ii in 2 patients . liver function tests were performed once a week during pulse therapy and repeated at every visit thereafter for 1 year . hepatitis b surface antigen ( hbsag ) , hepatitis b surface antibody ( hbsab ) , hepatitis b core antibody ( hbcab ) , and hepatitis c virus antibody ( hcvab ) were measured before pulse therapy . the one patient who was hbsag - positive consulted with a hepatologist , who prescribed 0.5  mg of entecavir , during and after pulse therapy . in addition , 43 patients were hbcab - positive and 17 were hcvab - positive . liver dysfunction was classified based on serum alanine aminotransferase ( alt ) and total bilirubin levels as mild ( alt : 40100 u / l ) , moderate ( alt : 100300  u / l ) , or severe ( alt > 300 female and male go patients significantly differed with respect to age , body mass index ( bmi ) , smoking habits , alcohol habits , and hbcab positivity before pulse therapy ( table 1 ) . human trab and tsab levels were significantly higher in female than in male patients before ivmp pulse therapy . statistical analysis was performed using jmp pro software ( version 11.0.0 , sas institute , usa ) . statistical comparisons were performed using student 's t - test , one - way anova , or mann - whitney u test for the analysis of continuous variables . the  test or fisher 's exact probability test was used to analyze 2  2 or 2  4 tables . multivariate logistic regression analyses were carried out to evaluate the risk factors for liver dysfunction , using exact method ( logxact , cytel inc . , usa ) . in all tests , a p value < 0.05 was considered to indicate significance . increases of alt during and/or after pulse therapy were detected in 79 patients ( 45% ) ( table 2 ) . mild ( alt 40100  u / l ) , moderate ( alt 100300 u / l ) , and severe ( alt > 300  u / l ) increases of serum alt were measured in 62 patients ( 35% ) , 10 patients ( 6% ) , and 7 patients ( 4% ) , respectively . her total bilirubin 8 weeks after the cessation of ivmp was 18.45  mg / dl . single and cumulative doses of ivmp were 0.5  g and 3.5  g , respectively . anti - nuclear and anti - single - stranded dna antibodies were also negative , as were anti - smooth muscle antibody , and anti - double - stranded dna antibody in those patients . the hbv carrier taking entecavir prescribed by the hepatologist did not show the elevation of alt . liver dysfunction occurred more frequently in male patients ( p < 0.0012 ) and in patients over the age of 50 years ( p < 0.0009 ) . bmi was significantly higher in patients with mild liver dysfunction than in those without liver dysfunction ( 23.3  4.33  kg / m versus 22.0  3.39  kg / m , student 's t - test , p = 0.043 , data not shown ) . liver dysfunction was not associated with smoking or alcohol habit but it was associated with a high dose of mp ( cumulative dose > 8  g versus < 8  g , 2  2 table ,  = 6.280 , p = 0.0122 ) . preexistent viral hepatitis was significantly associated with liver dysfunction during and after pulse therapy ( p = 0.0035 ) . hbcab was positive in 43 go patients ( 25% ) before pulse therapy . in 28 of them ( 65% ) , alt was significantly increased ( p = 0.01125 ) , although in most the increase was mild . hcvab was positive in 17 go patients ( 10% ) before pulse therapy . in this group , multivariate logistic regression analysis showed that age , gender , and cumulative mp dose ( > 8  g ) were associated with liver dysfunction ( table 2 ) . although ivmp pulse therapy is widely used as the first - line treatment for active moderate - to - severe orbitopathy , severe related side effects have been reported , the most common of which is hepatotoxicity . in the recent review by zang et al . , the morbidity and mortality of go patients treated with ivmp pulse therapy were 6.5% and 0.6% , respectively . fatal hepatotoxicity was reported to be associated with a cumulative dose of ivmp > 8  g. in two studies , the cumulative doses were 8.315  g [ 4 , 5 ] . eugogo now recommends that the cumulative dose of ivmp does not exceed 8  g . in our series of 175 patients , seven patients ( 4.0% ) the cumulative doses of mp were more than 8  g in 5 out of seven patients . however , single and cumulative doses of ivmp in a patient with jaundice were 0.5  g and 3.5  g , respectively . reported two fatal cases of hbv carriers after corticosteroid therapy , and the frequent reactivation of hbv after immune suppressive therapy , such as with rituximab , was noted . therefore , in go patients during ivmp therapy , the reactivation of hbv leading to acute liver failure remains a concern , although its occurrence is rare [ 4 , 9 , 12 , 13 ] . indeed , in the series of le moli et al . , none of the 27 patients with go suffered serious liver damage . wichary and gasiska   concluded that the risk of hbv reactivation is low , based on their experience with 30 patients treated with ivmp . those studies suggest that it is difficult to predict who will develop severe liver failure , such that it is important to carefully monitor patients during and after ivmp therapy . our study identified risk factors for mild to moderate liver dysfunction during and after ivmp therapy for go . among male patients , a mild elevation of alt was associated with a cumulative dose of ivmp > 8  g ; in female patients , a moderate elevation of alt was associated with age over 50 years . a history of hbv and hcv infection also contributed to a high prevalence of hepatotoxicity , as approximately 25% of our go patients were hbcab - positive and 10% were hcvab - positive before pulse therapy . within this group , multivariate logistic regression analysis showed that gender , age , and cumulative dose of mp were associated with liver dysfunction . our study in japanese patients suggests that viral hepatitis , gender , age , and cumulative dose are predisposing risk factors for hepatotoxicity during and after ivmp therapy . the current study also supports recommendations of a cumulative dose of mp < 8  g. however , as even this dose may not be completely safe , careful monitoring of go patients receiving ivmp is recommended both during and 12 months after therapy . although the mechanisms of mild to severe hepatotoxicity remain unclear , reactivation of viral hepatitis [ 4 , 10 , 11 ] , a direct toxicity of mp [ 1214 ] , and exacerbation of autoimmune hepatitis have been suggested [ 15 , 16 ] . le moli et al .   reported that mild elevations in liver enzymes following ivmp were dose dependent . the toxic effect of glucocorticoids on hepatocytes , leading to drug - induced steatohepatitis , is thought to involve mitochondrial injury because of the impaired -oxidation of fatty acids , with subsequent generation of reactive oxygen species and atp depletion . reported the exacerbation of autoimmune hepatitis with severe liver dysfunction during ivmp therapy . in our series , two patients were positive for antinuclear and anti - smooth muscle antibodies but in both cases liver dysfunction was mild . however , it allowed us to assess the effect of single and cumulative doses of ivmp , because in line with the eugogo 's recommendation we reduced the single dose of ivmp from 1  g to 0.5  g. another limitation of the study was the small number of patients , which prevented definite conclusions because of the low incidence of severe liver dysfunction . additionally , no histopathological examinations were done and the effectiveness of ivmp for go was not evaluated . therefore , further prospective studies are indicated to assess the hepatotoxicity of ivmp during and after pulse therapy for go . in conclusion , liver dysfunction is frequently associated with pulse therapy for go , both during and after treatment . our study supports the careful evaluation of preexisting risk factors ( especially viral hepatitis , age , gender , body mass index , and smoking history ) before initiating ivmp therapy in go patients . in these patients , strict monitoring of liver function once a week during pulse therapy and every month thereafter for the next 12 months is warranted .
intravenous methylprednisolone ( ivmp ) pulse therapy is the first - line treatment for the active phase of moderate to severe graves ' orbitopathy ( go ) . 
 however , acute and severe liver damage has been reported during and after ivmp therapy . in this retrospective study , we investigated risk factors for liver dysfunction during and after ivmp therapy based on 175 japanese patients with moderate to severe go and treated at our center between 2003 and 2011 . 
 the results showed that seven patients developed severe liver dysfunction with elevated serum alanine aminotransferase ( alt > 300 
 u / l ) . 
 mild ( 40100 
 u / l ) and moderate ( 100300  u / l ) increases of alt occurred in 62 patients ( 35% ) and 10 patients ( 6% ) , respectively . 
 liver dysfunction was more frequently observed in males , in patients receiving high - dose methylprednisolone , and patients aged over 50 years . 
 preexistent viral hepatitis was significantly associated with liver dysfunction ( 65% in patients positive for hepatitis b core antibody and patients positive for hepatitis c virus antibodies ) . 
 our study confirmed the association of liver dysfunction with ivmp during and after treatment . 
 it suggests that , in patients with go , evaluation of preexisting risk factors  including viral hepatitis  and careful weekly monitoring of liver function during ivmp therapy and monthly thereafter for 12 months are warranted .