program death 1 ( pd-1 ) and its ligand ( pd - l1 ) have been identified as potential therapeutic targets for solid and hematologic malignancies in recent years . pd-1 is an inhibitory receptor , which prevents overactivation of t - cells and thus prevents autoimmunity by promoting tolerance to self - antigens and to limit damage to normal tissues . pd-1 and its ligands ( pd - l1 and pd - l2 ) have been noted as critical mediators of immunosuppression within the tumor microenvironment.1,2 tumor cells can suppress the activity of t - cells in tissues and the tumor microenvironment by binding pd - l1 to pd-1 on the t - cells to evade immune destruction.3 recently , several antibodies that inhibit the interaction between pd - l1 and pd-1 have demonstrated durable efficacy in a number of solid and hematologic malignancies.47 nivolumab is a fully human monoclonal immunoglobulin g4 anti - pd-1 antibody that has been approved for the treatment of unresectable or metastatic melanoma , advanced non - small - cell lung cancer , and advanced renal cell carcinoma.711 pembrolizumab is another human pd-1-blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma.12 moreover , it is being extensively evaluated as a single agent and as a combination with other therapeutic agents in many advanced refractory solid tumors.13 other antibodies targeting the pd-1/pd - l1 checkpoint in the phase of development include atezolizumab and durvalumab , which have also shown activity against many solid malignancies.1416 however , the very specific mechanism of action of those new medicines brings about some specific immunological adverse event ( ae ) profiles , which is different from toxicities known for cytotoxic drugs or kinase inhibitors.17 for instance , many clinical trials have shown that these side effects affect skin , lung , gastrointestinal tract , liver , endocrine system , and other organ systems.911 hepatic aes mainly manifest as asymptomatic increase of aspartate aminotransferase ( ast ) and alanine aminotransferase ( alt ) levels.18 the contribution of anti - pd-1 therapy to the development of hepatic aes is difficult to assess as individual randomized controlled trials ( rcts ) may be not powered to detect a significant relationship . although a meta - analysis has shown that the use of immune checkpoint inhibitors has a causal relationship to an increased risk of high - grade ( grade 3 or 4 ) elevated alt and ast,19 most rcts included in the analysis evaluated anti - ctla-4 monoclonal antibodies and only three rcts evaluated anti - pd-1 antibody ( nivolumab ) , thus the contributions of anti - pd-1 therapy to hepatic aes are still unclear . as a result , we conducted a meta - analysis of all published rcts to determine the incidence and risk of hepatic aes associated with the use of pd-1 inhibitors in cancer patients . this meta - analysis was performed according to the prisma ( preferred reporting items for systemic reviews and meta - analyses ) recommendations.20 a literature review of pubmed ( data from january 2000 to may 2016 ) and embase ( data from january 2000 to may 2016 ) was conducted to identify relevant clinical trials . the search was conducted using keywords  nivolumab  ,  pembrolizumab  ,  cancer  , and additionally , we searched abstracts presented at the annual meetings of the american society of clinical oncology and the european society of medical oncology annual meetings . moreover , the references cited by the included studies were also used to complete the search . each publication was reviewed , and in cases of multiple publications of the same clinical trial were encountered , only the most complete , recent , and updated report of clinical trials was included in the meta - analysis . the primary objective of this analysis was to determine the overall incidence and relative risk ( rr ) of hepatic aes associated with pd-1 inhibitors . thus , phase i and nonrandomized phase ii trials were excluded from the analysis due to lack of sufficient controls . the relevant clinical trials were selected carefully based on the following criteria : 1 ) prospective rcts evaluating patients with solid tumors , 2 ) patients were allocated to treatment with pd-1 inhibitors ( nivolumab 3 mg / kg , pembrolizumab 2 mg / kg or 10 mg / kg ) or control ( chemotherapy or everolimus or ipilimumab ) , and 3 ) available data regarding events or event rate and sample size of all - grade and high - grade hepatic aes . the data abstraction was conducted by two authors independently , and discrepancies were resolved by consensus . for each study , the following details were extracted : the name of first author , year of publication , trial phase , cancer type , treatment arms and control arms , and patients included for analysis . aes of all grade and high grade were defined according to the national cancer institute s common toxicity criteria ( version 4.0 ; http://ctep.cancer.gov ) ( table 1 ) . study quality of rcts was assessed according to the jadad scale including randomization , blinding , and withdrawals.21 the number of hepatic aes and the total number of patients receiving pd-1 inhibitors were extracted from the safety profiles of all selected studies , and then the proportion of patients with hepatic aes and 95% confidence interval ( ci ) were calculated for each study . studies that had a comparative arm were used to calculate the rr of hepatic aes . for the meta - analysis , both the fixed - effect model and the random - effect model were considered.22,23 the -based q statistic was first applied to estimate between - study heterogeneity , and inconsistency was quantified with the i statistic , which estimates the percentage of total variation across studies because of heterogeneity rather than chance.24 heterogeneity was considered statistically significant when p<0.1 . moreover , the following subgroup analyses were conducted : 1 ) pd-1 inhibitors monotherapy ( nivolumab or pembrolizumab ) versus control ( including chemotherapy or everolimus ) , 2 ) a nivolumab / ipilimumab combination versus ipilimumab control , and 3 ) pd-1 inhibitors monotherapy ( nivolumab or pembrolizumab ) versus ipilimumab control . a two - tailed p - value of < 0.05 was considered statistically significant . all statistical analyses were performed by using version 2 of the comprehensive meta analysis program ( biostat , englewood , nj , usa ) . this meta - analysis was performed according to the prisma ( preferred reporting items for systemic reviews and meta - analyses ) recommendations.20 a literature review of pubmed ( data from january 2000 to may 2016 ) and embase ( data from january 2000 to may 2016 ) was conducted to identify relevant clinical trials . the search was conducted using keywords  nivolumab  ,  pembrolizumab  ,  cancer  , and additionally , we searched abstracts presented at the annual meetings of the american society of clinical oncology and the european society of medical oncology annual meetings . moreover , the references cited by the included studies were also used to complete the search . each publication was reviewed , and in cases of multiple publications of the same clinical trial were encountered , only the most complete , recent , and updated report of clinical trials was included in the meta - analysis . the primary objective of this analysis was to determine the overall incidence and relative risk ( rr ) of hepatic aes associated with pd-1 inhibitors . thus , phase i and nonrandomized phase ii trials were excluded from the analysis due to lack of sufficient controls . the relevant clinical trials were selected carefully based on the following criteria : 1 ) prospective rcts evaluating patients with solid tumors , 2 ) patients were allocated to treatment with pd-1 inhibitors ( nivolumab 3 mg / kg , pembrolizumab 2 mg / kg or 10 mg / kg ) or control ( chemotherapy or everolimus or ipilimumab ) , and 3 ) available data regarding events or event rate and sample size of all - grade and high - grade hepatic aes . the data abstraction was conducted by two authors independently , and discrepancies were resolved by consensus . for each study , the following details were extracted : the name of first author , year of publication , trial phase , cancer type , treatment arms and control arms , and patients included for analysis . aes of all grade and high grade were defined according to the national cancer institute s common toxicity criteria ( version 4.0 ; http://ctep.cancer.gov ) ( table 1 ) . study quality of rcts was assessed according to the jadad scale including randomization , blinding , and withdrawals.21 the number of hepatic aes and the total number of patients receiving pd-1 inhibitors were extracted from the safety profiles of all selected studies , and then the proportion of patients with hepatic aes and 95% confidence interval ( ci ) were calculated for each study . studies that had a comparative arm were used to calculate the rr of hepatic aes . for the meta - analysis , both the fixed - effect model and the random - effect model were considered.22,23 the -based q statistic was first applied to estimate between - study heterogeneity , and inconsistency was quantified with the i statistic , which estimates the percentage of total variation across studies because of heterogeneity rather than chance.24 heterogeneity was considered statistically significant when p<0.1 . the following subgroup analyses were conducted : 1 ) pd-1 inhibitors monotherapy ( nivolumab or pembrolizumab ) versus control ( including chemotherapy or everolimus ) , 2 ) a nivolumab / ipilimumab combination versus ipilimumab control , and 3 ) pd-1 inhibitors monotherapy ( nivolumab or pembrolizumab ) versus ipilimumab control . a two - tailed p - value of < 0.05 was considered statistically significant . all statistical analyses were performed by using version 2 of the comprehensive meta analysis program ( biostat , englewood , nj , usa ) . on the basis of our search criteria , 251 potentially clinical studies evaluating nivolumab or pembrolizumab were identified . after the selection procedure , ten full - text articles were considered for further assessment ; one trial without sufficient data on hepatic aes was excluded . finally , a total of nine rcts5,712,25,26 were considered to be of adequate quality and relevance for the meta - analysis . studies excluded from the analysis and the reasons for their exclusion are shown in figure 1 . in total , nine rcts were available for the meta - analysis including eight phase iii trials and one randomized phase ii / iii trial . four studies evaluated nivolumab monotherapy versus chemotherapy controls,7,9,10,25 one study evaluated nivolumab monotherapy versus everolimus ( data on high - grade hepatic aes),11 one study evaluated pembrolizumab monotherapy versus chemotherapy control,5 two studies evaluated nivolumab / ipilimumab combination versus ipilimumab,8,26 and two studies evaluated pembrolizumab monotherapy or nivolumab monotherapy versus ipilimumab control.12,26 underlying malignancies included melanoma,7,8,12,25,26 renal cell carcinoma,11 and advanced non - small - cell lung cancer.5,9,10 all trials reported the hepatic aes according to the national cancer institute s common terminology criteria for adverse events version four criteria . jadad scores were listed for each trial in tables 1 and 2 ; the mean score was 3.7 ( range , 3.05.0 ) , indicating that the overall methodological quality of the included studies was good and fair . for the incidence analysis , only arms receiving one of the anti pd-1 antibodies were included . a total of 2,442 patients from seven rcts were included for the calculation of the incidence of all - grade hepatic aes . the calculated summary incidence of all - grade hepatic aes was 3.1% ( 95% ci : 2.5%3.9% ) using the fixed - effect model ( heterogeneity test : i=0% , p=0.67 ) for elevated alt and 3.2% ( 95% ci : 2.5%3.9% ) with the fixed - effect model ( heterogeneity test : i=0.82% , p=0.366 ) for elevated ast ( figure 2 ) . data for high - grade hepatic aes included a total of 2,848 patients from eight rcts . the summary incidence of high - grade elevated alt was 0.6% ( 95% ci : 0.4%1.1% ) according to the fixed - effect model ( heterogeneity test : i=0% , p=0.600 ) , and the calculated incidence of high - grade elevated ast was 0.5% ( 95% ci : 0.3%0.8% ) using a fixed - effect model ( heterogeneity test : i=0% , p=0.879 ) ( figure 2 ) . the rr of hepatic aes was calculated by comparing with those assigned to a control treatment in the same trial to determine the specific contribution of pd-1 inhibitors to the development of hepatic aes . a total of 2,587 patients from five rcts were included for calculating the rr of all - grade hepatic aes , and the combined results demonstrated that the use of pd-1 inhibitors monotherapy was associated with a significantly increased risk of developing all - grade hepatic aes with an rr of 2.09 ( 95% ci : 1.13.95 , p=0.024 ) ( heterogeneity test : i=0% , p=0.889 ) for elevated alt and 2.02 ( 95% ci : 1.014.03 , p=0.047 ) ( heterogeneity test : i=0% , p=0.449 ) for elevated ast ( figure 3 ) . as for high - grade hepatic aes , a total of 3,390 patients from six rcts were included for analysis . the combined rr showed that the use of pd-1 inhibitors monotherapy did not significantly increase the risk of high - grade hepatic aes among cancer patients with an rr of 1.47 ( 95% ci : 0.454.86 , p=0.525 ) ( heterogeneity test : i=0% , p=0.745 ) for elevated alt and 1.51 ( 95% ci : 0.435.27 , p=0.515 ) ( heterogeneity test : i=0% , p=0.878 ) for elevated ast ( figure 3 ) . in order to determine whether a nivolumab / ipilimumab combination is associated with a higher risk of developing hepatic toxicities than ipilimumab monotherapy , we calculated the rr according to a nivolumab / ipilimumab combination versus ipilimumab control . the rr of all - grade elevated alt and ast was 4.64 ( 95% ci : 2.668.09 , p<0.001 ) ( heterogeneity test : i=0% , p=0.877 ) and 4.43 ( 95% ci : 2.487.90 , p<0.001 ) ( heterogeneity test : i=0% , p=0.878 ) , respectively ( figure 4 ) . moreover , there was a statistically significant increase in the risk of high - grade hepatic aes with an rr of 5.55 ( 95% ci : 2.2713.57 ; p<0.001 ) ( heterogeneity test : i=0% , p=0.645 ) for elevated alt and 8.98 ( 95% ci : 2.4732.65 ; p=0.001 ) ( heterogeneity test : i=0% , p=0.882 ) for elevated ast ( figure 4 ) . thus , compared with ipilimumab , a nivolumab / ipilimumab combination was associated with higher risk of developing all - grade and high - grade hepatic aes . patients treated with pd-1 inhibitors monotherapy ( nivolumab or pembrolizumab ) might have a lower risk of developing hepatic aes compared with ipilimumab control . the rr of all - grade elevated alt and ast was 0.91 ( 95% ci : 0.521.59 ; p=0.726 ) ( heterogeneity test : i=0% , p=0.737 ) and 1.27 ( 95% ci : 0.702.30 ; p=0.441 ) ( heterogeneity test : i=0% , p=0.570 ) , respectively ( figure 5 ) . additionally , we observed an rr of 0.60 ( 95% ci : 0.191.88 ; p=0.38 ) ( heterogeneity test : i=0% , p=0.374 ) for high - grade elevated alt and an rr of 0.77 ( 95% ci : 0.183.20 ; p=0.716 ) ( heterogeneity test : i=33.3% , p=0.221 ) for high - grade elevated ast ( figure 5 ) . thus , no significant differences in the risk of all - grade or high - grade hepatic aes can be detected between pd-1 inhibitors monotherapy and ipilimumab . when stratified by pd-1 inhibitors monotherapy versus chemotherapy or everolimus control , no significant publication bias was detected for the rr of hepatic aes by either begg test or egger test ( rr of all - grade elevated alt : begg test p=0.46 , egger test p=0.61 ; rr of all - grade elevated ast : begg test p=0.46 , egger test p=0.62 ; rr of high - grade elevated alt : begg test p=0.26 , egger test p=0.42 ; rr of high - grade elevated ast : begg test p=0.85 , egger test p=0.94 ) . on the basis of our search criteria , 251 potentially clinical studies evaluating nivolumab or pembrolizumab were identified . after the selection procedure , ten full - text articles were considered for further assessment ; one trial without sufficient data on hepatic aes was excluded . finally , a total of nine rcts5,712,25,26 were considered to be of adequate quality and relevance for the meta - analysis . studies excluded from the analysis and the reasons for their exclusion are shown in figure 1 . in total , nine rcts were available for the meta - analysis including eight phase iii trials and one randomized phase ii / iii trial . four studies evaluated nivolumab monotherapy versus chemotherapy controls,7,9,10,25 one study evaluated nivolumab monotherapy versus everolimus ( data on high - grade hepatic aes),11 one study evaluated pembrolizumab monotherapy versus chemotherapy control,5 two studies evaluated nivolumab / ipilimumab combination versus ipilimumab,8,26 and two studies evaluated pembrolizumab monotherapy or nivolumab monotherapy versus ipilimumab control.12,26 underlying malignancies included melanoma,7,8,12,25,26 renal cell carcinoma,11 and advanced non - small - cell lung cancer.5,9,10 all trials reported the hepatic aes according to the national cancer institute s common terminology criteria for adverse events version four criteria . jadad scores were listed for each trial in tables 1 and 2 ; the mean score was 3.7 ( range , 3.05.0 ) , indicating that the overall methodological quality of the included studies was good and fair . for the incidence analysis , only arms receiving one of the anti pd-1 antibodies were included . a total of 2,442 patients from seven rcts were included for the calculation of the incidence of all - grade hepatic aes . the calculated summary incidence of all - grade hepatic aes was 3.1% ( 95% ci : 2.5%3.9% ) using the fixed - effect model ( heterogeneity test : i=0% , p=0.67 ) for elevated alt and 3.2% ( 95% ci : 2.5%3.9% ) with the fixed - effect model ( heterogeneity test : i=0.82% , p=0.366 ) for elevated ast ( figure 2 ) . data for high - grade hepatic aes included a total of 2,848 patients from eight rcts . the summary incidence of high - grade elevated alt was 0.6% ( 95% ci : 0.4%1.1% ) according to the fixed - effect model ( heterogeneity test : i=0% , p=0.600 ) , and the calculated incidence of high - grade elevated ast was 0.5% ( 95% ci : 0.3%0.8% ) using a fixed - effect model ( heterogeneity test : i=0% , p=0.879 ) ( figure 2 ) . the rr of hepatic aes was calculated by comparing with those assigned to a control treatment in the same trial to determine the specific contribution of pd-1 inhibitors to the development of hepatic aes . a total of 2,587 patients from five rcts were included for calculating the rr of all - grade hepatic aes , and the combined results demonstrated that the use of pd-1 inhibitors monotherapy was associated with a significantly increased risk of developing all - grade hepatic aes with an rr of 2.09 ( 95% ci : 1.13.95 , p=0.024 ) ( heterogeneity test : i=0% , p=0.889 ) for elevated alt and 2.02 ( 95% ci : 1.014.03 , p=0.047 ) ( heterogeneity test : i=0% , p=0.449 ) for elevated ast ( figure 3 ) . as for high - grade hepatic aes , a total of 3,390 patients from six rcts were included for analysis . the combined rr showed that the use of pd-1 inhibitors monotherapy did not significantly increase the risk of high - grade hepatic aes among cancer patients with an rr of 1.47 ( 95% ci : 0.454.86 , p=0.525 ) ( heterogeneity test : i=0% , p=0.745 ) for elevated alt and 1.51 ( 95% ci : 0.435.27 , p=0.515 ) ( heterogeneity test : i=0% , p=0.878 ) for elevated ast ( figure 3 ) . in order to determine whether a nivolumab / ipilimumab combination is associated with a higher risk of developing hepatic toxicities than ipilimumab monotherapy , we calculated the rr according to a nivolumab / ipilimumab combination versus ipilimumab control . the rr of all - grade elevated alt and ast was 4.64 ( 95% ci : 2.668.09 , p<0.001 ) ( heterogeneity test : i=0% , p=0.877 ) and 4.43 ( 95% ci : 2.487.90 , p<0.001 ) ( heterogeneity test : i=0% , p=0.878 ) , respectively ( figure 4 ) . moreover , there was a statistically significant increase in the risk of high - grade hepatic aes with an rr of 5.55 ( 95% ci : 2.2713.57 ; p<0.001 ) ( heterogeneity test : i=0% , p=0.645 ) for elevated alt and 8.98 ( 95% ci : 2.4732.65 ; p=0.001 ) ( heterogeneity test : i=0% , p=0.882 ) for elevated ast ( figure 4 ) . thus , compared with ipilimumab , a nivolumab / ipilimumab combination was associated with higher risk of developing all - grade and high - grade hepatic aes . patients treated with pd-1 inhibitors monotherapy ( nivolumab or pembrolizumab ) might have a lower risk of developing hepatic aes compared with ipilimumab control . the rr of all - grade elevated alt and ast was 0.91 ( 95% ci : 0.521.59 ; p=0.726 ) ( heterogeneity test : i=0% , p=0.737 ) and 1.27 ( 95% ci : 0.702.30 ; p=0.441 ) ( heterogeneity test : i=0% , p=0.570 ) , respectively ( figure 5 ) . additionally , we observed an rr of 0.60 ( 95% ci : 0.191.88 ; p=0.38 ) ( heterogeneity test : i=0% , p=0.374 ) for high - grade elevated alt and an rr of 0.77 ( 95% ci : 0.183.20 ; p=0.716 ) ( heterogeneity test : i=33.3% , p=0.221 ) for high - grade elevated ast ( figure 5 ) . thus , no significant differences in the risk of all - grade or high - grade hepatic aes can be detected between pd-1 inhibitors monotherapy and ipilimumab . when stratified by pd-1 inhibitors monotherapy versus chemotherapy or everolimus control , no significant publication bias was detected for the rr of hepatic aes by either begg test or egger test ( rr of all - grade elevated alt : begg test p=0.46 , egger test p=0.61 ; rr of all - grade elevated ast : begg test p=0.46 , egger test p=0.62 ; rr of high - grade elevated alt : begg test p=0.26 , egger test p=0.42 ; rr of high - grade elevated ast : begg test p=0.85 , egger test p=0.94 ) . our meta - analysis of data from phase ii / iii and iii rcts demonstrated that treatment with pd-1 inhibitors was associated with a significant increase in the risk of developing all - grade hepatic aes , but not for high - grade hepatic aes , which are different from the results previously reported by abdel - rahman et al.19 in their analysis , the use of immune checkpoint inhibitors ( pd-1 inhibitors and ctla-4 inhibitors ) had a causal relationship to an increased risk of high - grade elevated alt and ast . the reason for this discrepancy could be partly explained by the distribution of treatment agents . all rcts included in our study used pd-1 inhibitors as treatment drugs , while only three of ten rcts in the study of omar abdel - rahman et al evaluated pd-1 inhibitors ( three rcts evaluated nivolumab and seven rcts evaluated ctla-4 inhibitors ) . although no significant differences in the risk of developing hepatic aes can be detected between pd-1 inhibitors and ipilimumab in our analysis , these results should be interpreted cautiously as only two rcts were included for the rr calculation . moreover , it has been reported that anti - ctla-4 monoclonal antibodies were associated with elevated ast and alt levels in 10% of patients or less,2729 while this was < 5% for pd-1 inhibitors confirmed by our study . additionally , we found that a nivolumab / ipilimumab combination was associated with significantly increased risk of developing all - grade and high - grade hepatic aes compared with ipilimumab monotherapy . similar to our results , wolchok et al30 reported that high - grade treatment - related hepatic aes were one of the most common aes in patients who received ipilimumab plus nivolumab with 11% of patients for alt and 13% of patients for ast . hepatic aes induced by pd-1/pd - l1 inhibitors commonly present as asymptomatic increase of ast and alt , rarely total bilirubin.18 a proportion of patients may be presenting with fatigue , fever , and radiologic appearances including hepatomegaly , periportal lymphadenopathy , and periportal edema.31 pathologic signs of pembrolizumab - induced hepatitis have been reported with periportal and lobular hepatitis , eosinophils , and some other inflammatory cell infiltrates.32 the median time to the onset of hepatic aes was highly variable , such as 25 weeks ( range 431 weeks ) in lung cancer patients , 4 weeks ( range 0.123 weeks ) in melanoma patients treated with nivolumab , and 19 weeks ( range 0.393 weeks ) in patients treated with pembrolizumab.33 the risk of hepatic aes with anti - pd-1 therapy seems to be increased not only by combination use of anti - pd-1 and anti - ctla-4 monoclonal antibody but also by combination use of pd-1 inhibitors and targeted therapy or chemotherapy.34 for example , nivolumab combined with either sunitinib or pazopanib was associated with increased incidence of high - grade ast / alt elevations in metastatic renal cell carcinoma.35 in addition , higher rates of ast / alt elevation have been noted in advanced hepatocellular carcinoma patients treated with nivolumab . in a prospective analysis conducted by el - khoueiry et al,36 41 patients were enrolled , 17% of patients experienced all - grade ast increase , and 15% of patients experienced all - grade alt elevation . as for high - grade hepatic aes , 12% of patients suffered ast elevation and 10% of patients suffered alt elevation . given hypothesized risk of triggering exacerbations of autoimmune diseases and/or chronic viral infections , patients with chronic hepatitis b / c ( hbv / hcv ) , human immunodeficiency virus ( hiv ) infection , or autoimmune diseases have been excluded from clinical trials evaluating checkpoint blocking antibodies pd-1 and ctla-4 . interestingly , davar et al37 reported two patients with advanced melanoma and concomitant hcv or / and hiv infections treated with pembrolizumab and found that this drug was well tolerated with no exacerbation of underlying hcv / hiv infection or hepatic toxicity in both cases . although the results of only two patients is in no way generalizable to other patients , it may indicate an important area for future investigation of the systematic evaluation of pd-1/pd - l1 inhibitors in patients with chronic hbv / hcv and/or hiv infection and other entities including autoimmune disease requiring systemic immunosuppression . management of immune checkpoint inhibitor - related hepatic aes consists of dose interruption and/or dose reduction and treatment with corticosteroids . monitoring of patients for liver function before , during , and after anti - pd-1 therapy is essential , but at the same time , the malignant disease in the liver , viral hepatitis , or another drug - induced toxicity should be excluded . several algorithms have already been proposed for hepatic aes with immune checkpoint blockade.28,33 the grade of the ae should be conducted to guide therapeutic decisions . in asymptomatic patients with ast or alt 2.5 upper limit of normal , treatment with immunotherapy may continue without dose adjustment , but patients should be monitored closely for liver function . immunotherapy should be held or reduced for grade 2 , and oral prednisone may be involved in treatment . if a patient presents with grade 3 or 4 hepatic aes , then discontinuation of immunotherapy should be considered in addition to methylprednisolone 24 mg / kg / d , and occasionally additional immune suppression with mycophenolate mofetil 5001,000 mg every 12 hours is recommended.38 infliximab , as confers its own risk of hepatotoxicity , should be avoided in this setting.1 however , there are several potential limitations needed to be considered in our meta - analysis . first , all the included studies were conducted at academic centers or major institutions , excluding patients with poor renal , hematological , and hepatic functions , so the true incidences and risk of pd-1 inhibitors - related hepatic aes might be higher in daily clinical work . second , this is a meta - analysis at study level and not on the patients data , then confounding factors at the patient level including patients comorbidities , previous therapeutic exposure , and concomitant treatments that affect liver function can not be assessed properly and incorporated into the analysis . third , this analysis is not powered to detect significant difference in the risk of developing hepatic aes between pd-1 inhibitors monotherapy and ipilimumab control , while the observation might be influenced by sample size . fourth , in this retrospective analysis , different tumor types , drug types , and dosage of pd-1 drug may increase the clinical heterogeneity among included trials and make the interpretation of the meta - analysis more problematic . however , the heterogeneity of pooled rr was not significant for both all - grade and high - grade hepatic aes . this meta - analysis of rcts demonstrates that the use of pd-1 inhibitors is associated with an increased risk of hepatic aes in cancer patients , which is primarily for lower grade events . and the risk of hepatic aes is higher in patients treated with a nivolumab / ipilimumab combination compared with ipilimumab control . these findings would help clinicians and patients to recognize the risk of hepatic aes of pd-1 checkpoint inhibitors to avoid delays in diagnosis and treatment .
purposeanti - programmed cell death receptor-1 ( pd-1 ) antibodies have demonstrated antitumor activity in many cancer entities . 
 hepatic adverse events ( aes ) are one of its major side effects , but the overall risks have not been systematically evaluated . 
 thus , we conducted this meta - analysis to investigate the overall incidence and risk of developing hepatic aes in cancer patients treated with pd-1 inhibitors.methodspubmed , embase , and oncology conference proceedings were searched for relevant studies . 
 eligible studies were randomized controlled trials of cancer patients treated with pd-1 inhibitors with adequate data on hepatic aes.resultsa total of nine randomized controlled trials with a variety of solid tumors were eligible for the meta - analysis . 
 the use of pd-1 inhibitors significantly increased the risk of developing all - grade hepatic aes but not for high - grade hepatic aes in comparison with chemotherapy or everolimus control . 
 additionally , the risk of all - grade and high - grade hepatic aes with a nivolumab / ipilimumab combination was substantially higher than ipilimumab . 
 no significant differences in the risk of all - grade and high - grade hepatic aes were found between pd-1 inhibitors monotherapy and ipilimumab.conclusionwhile the use of pd-1 inhibitors is associated with an increased risk of developing hepatic aes in cancer patients , this is primarily for lower grade events .