immune checkpoint inhibition with anti - ctla-4 blockade ( e.g. , ipilimumab ) and anti - pd-1 antibodies ( e.g. , nivolumab ) has improved the poor prognosis of unresectable malignant melanoma [ 1 , 2 ] .
these newly approved medications induce many types of immune - related adverse events ( iraes ) , including pneumonitis , colitis , hepatitis , and endocrinopathies such as hypophysitis and thyroiditis .
although iraes induced by ipilimumab have occasionally been reviewed in the literature , studies on nivolumab are also gradually being described .
a 52-year - old male with lung and liver metastasis of malignant melanoma was put on nivolumab therapy ( 3 mg / kg every 3 weeks ) . after approximately 34 weeks of nivolumab administration ( fig .
1 ) , laboratory tests revealed a sudden elevation of liver enzymes ( ast / alt ) to 1,225/824 u / l ( grade 4 ) .
computed tomography detected the exacerbation of liver metastasis , identifying a lesion that was slightly larger than the nondiffuse , localized lesion that had been observed 3 months earlier ( fig .
2 ) . therefore , we suspected hepatitis associated with nivolumab because this drug has a low probability of causing serious liver damage to localized lesions , even when they are large .
the patient stopped taking nivolumab and was treated with 70 mg / day ( 1.0 mg / kg / day ) of systemic corticosteroids .
his ast / alt level promptly improved to 112/389 u / l within 3 days .
the median onset of ipilimumab - related hepatitis is approximately 812 weeks after initial treatment .
therefore , the interval from nivolumab initiation to the occurrence of hepatitis was much longer than that reported in previous cases .
hepatitis induced by nivolumab was also observed at 712 weeks in a pooled analysis of a nivolumab phase iii trial .
however , the incidence of grade 23 nivolumab - induced hepatitis was approximately 1% in a phase iii clinical study . in that study ,
the liver function test improved to grade 1 within 415 days of initiation of corticosteroid treatment .
the liver dysfunction caused by long - term nivolumab therapy in this case is noteworthy .
although many diseases induce liver dysfunction , in this case , we definitively excluded other causes of hepatitis such as viral infection ( e.g. , hbv , hcv , hsv , cmv , and ebv ) , medication other than nivolumab , and other forms of autoimmune hepatitis . to manage hepatitis associated with nivolumab , these possibilities must be excluded as causes of the disease .
the recommended initial treatment of hepatitis in the risk evaluation and mitigation strategy ( rems ) is to administer systemic corticosteroids ( 12 mg / kg / day of prednisone ) .
if the symptoms continue after 35 days , alternative immunosuppressive therapy , such as 500 mg of oral mycophenolate mofetil every 12 h , must be considered . in this case , because the laboratory test showed an ast / alt level > 20 the upper limit of normal , we considered systemic corticosteroids to be the most appropriate treatment .
fortunately , the ast / alt level rapidly improved to grade 12 in 3 days , and modification was not necessary .
it is very important to note that severe hepatitis can occur despite long - term nivolumab therapy . in this case ,
it was possible to quickly reach a correct diagnosis because we were aware of the possibility of drug - induced hepatitis , even though the period of occurrence of nivolumab - induced hepatitis had passed .
therefore , we believe that this report may be very informative when treating hepatitis as an irae of nivolumab . in addition , to our knowledge , this patient exhibited the longest time between nivolumab administration and the onset of hepatitis that has been reported to date .
 immune checkpoint inhibitors have drastically changed in the treatment of many kinds of malignancies , especially malignant melanoma . 
 the focus of the recent experiments has not only been on their efficacy but also immune - related adverse events ( iraes ) . 
 we report a case of fulminant hepatitis due to nivolumab . in this case 
 , the patient had undergone long - term nivolumab therapy . 
 he did not complain of any symptoms but his liver enzyme levels were extremely elevated ( grade 4 ) . 
 we promptly decided to start oral corticosteroids in the patient . 
 his liver function rapidly improved . 
 the dose of corticosteroids was gradually reduced . 
 our case demonstrates that sudden onset fulminant hepatitis can occur despite the safe use of long - term nivolumab therapy . 
 the irae can improve rapidly with proper corticosteroid treatment . 
 this report will be useful for the physicians who always use immune checkpoint inhibitors . 
Introduction
Case Report
Discussion
Statement of Ethics
Disclosure Statement