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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: June 23, 2022.



Ipilimumab is a human monoclonal antibody to the cytotoxic T lymphocyte antigen-4, which acts as an immune checkpoint inhibitor and is used in immunotherapy of several forms of advanced or metastatic cancer. Ipilimumab like other checkpoint inhibitors has major side effects and particularly immune related conditions, including acute hepatocellular and cholestatic liver injury which can be serious and even life-threating.


Ipilimumab (ip” i lim’ ue mab) is a human recombinant monoclonal immunoglobulin G1 antibody to the cytotoxic T lymphocyte antigen-4 (CTLA-4), which has distinctive immunomodulatory activity and is used as a checkpoint inhibitor in cancer immunotherapy. The CTLA-4 antigen is an important checkpoint molecule that modulates and down regulates T cell responses. Inhibition of CTLA on the surface of activated T cells prevents its binding to the costimulatory factor B7 which allows for a continued activation and proliferation of T cells. The subsequent enhancement of cytotoxic reactivity caused by the checkpoint inhibitor can play a beneficial role in cancer immunotherapy by breaking immunological tolerance to cancer neoantigens. In several large multicenter studies, ipilimumab therapy resulted in a prolongation of survival in patients with advanced, metastatic or unresectable malignant melanoma, and a proportion of patients had a long term remission. Ipilimumab was approved for use in advanced malignant melanoma in the United States in 2009, the first monoclonal checkpoint inhibitor approved for use in treating neoplastic diseases. Subsequently, its indications have been expanded to several other forms of advanced or metastatic cancer including renal cell carcinoma, colorectal cancer, esophageal cancer, hepatocellular carcinoma, non-small cell lung cancer (NSCLC) and mesothelioma, usually in combination with nivolumab, a monoclonal checkpoint inhibitor of the programmed cell death receptor-1 (anti-PD-1). Ipilimumab is available in liquid solution in 50 and 200 mg vials (5 mg/mL) under the brand name Yervoy. The dose and regime of ipilimumab varies by indication. The typical regimen is 1 or 3 mg/kg as an intravenous infusion every 3 weeks for a total of four doses. Ipililmumab is also approved for adjuvant therapy of melanoma where it is given in higher doses long term.

Side effects of ipilimumab are common and can include fatigue, headache, musculoskeletal pain, arthralgia, abdominal pain, diarrhea, nausea, vomiting, decreased appetite, weight loss, fever, cough, dyspnea, pruritus, and rash. Importantly, as a result of immune enhancement, between 15% and 25% of ipilimumab treated patients develop immune related side effects, including enterocolitis, dermatitis, endocrinopathy, pneumonitis, neuropathy, nephritis and hepatitis. Most of these reactions respond to stopping ipilimumab and administration of immunosuppressive therapy, but some have resulted in fatalities and some have required permanent discontinuation of checkpoint inhibitor therapy and long term immunosuppressive therapy. These immune related adverse events are more frequent with combination therapy with nivolumab. Baseline screening and regular monitoring for these adverse events during ipilimumab therapy is recommended. Early recognition and prompt management of side effects is an integral component of proper use of checkpoint inhibitors. Checkpoint inhibitors should be used only by health care professionals with training in immunotherapy and experience in management of the side effects of immunomodulatory agents. Other rare but potentially severe adverse effects of ipilimumab also include infusion reactions and embryo-fetal toxicity.


Mild-to-moderate serum aminotransferase elevations are not uncommon (10% to 30%) during ipilimumab therapy, but are usually self-limited and resolve even with continuing cyclic therapy. Serum ALT elevations above 5 times the upper limit of normal (ULN) occur in 1% to 4% of patients and generally lead to temporary discontinuation. Importantly, in 1% to 2% of patients the serum enzyme elevations evolve into an immune mediated liver injury that can be clinically apparent and can be severe. Immune related liver injury is more frequent and severe in patients receiving the combination of ipilimumab and nivolumab. The onset is usually after 2 to 4 cycles, 3 to 9 weeks after initiation of treatment. The pattern of enzyme elevation is most frequently hepatocellular, but can be mixed or even cholestatic. Liver histology demonstrates an acute hepatitis-like pattern with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, which is compatible with an immune mediated hepatic injury. Fibrin ring granulomas have been described in some cases and considered somewhat pathognomic of ipilimumab hepatic immune injury. Despite features of immune mediated injury, autoantibodies are generally not present and immunoglobulin levels are normal. Restarting ipilimumab can result in recurrence of injury, although corticosteroid treatment may block recurrence. Switching to another type of checkpoint inhibitor (anti-PD-1 or anti-PD-L1) may be better tolerated than restarting ipilimumab, but there is little evidence that restarting checkpoint inhibitor therapy after a severe immune related adverse event improves survival or the outcome of cancer chemotherapy.

Rarely the liver injury associated with checkpoint inhibitor therapy is characterized by a progressive cholestatic injury accompanied by prominent elevations in serum alkaline phosphatase with modest or only moderate aminotransferase elevations. Imaging studies may show irregular dilatation of the intra- and/or extra-hepatic bile ducts and thickening of the gall bladder and bile duct walls, but without evidence of frank obstruction. Liver biopsy shows portal inflammation and bile duct injury and endoscopic biopsy of the bile duct epithelium shows inflammation and scarring. The general features suggest a secondary form of sclerosing cholangitis referred to as checkpoint inhibitor cholangiopathy. Therapy with immunosuppression may improve alkaline phosphatase and bilirubin levels but rarely causes complete recovery, and long term cholestasis and hepatic failure can occur. Some patients with a cholestatic form of immune related hepatitis do not show the bile duct changes but demonstrate loss and paucity of portal bile ducts resulting in a vanishing bile duct syndrome similar to primary biliary cholangitis (PBC).

The effects of ipilimumab on chronic hepatitis B are not well defined but convincing examples of reactivation of hepatitis B have been described with it as well as with other checkpoint inhibitors. Most cases have occurred in patients with preexisting HBsAg, but rare instances were reported in individuals suspected of having with anti-HBc without HBsAg. Thus, screening patients for HBsAg, anti-HBc and anti-HBs is appropriate before initiating immunotherapy with checkpoint inhibitors. Patients with HBsAg should be considered for prophylaxis with an antiviral agent with potent activity against HBV such as entecavir or tenofovir. In patients with anti-HBc without HBsAg, monitoring and close attention to liver test abnormalities is probably adequate if antiviral therapy can be introduced rapidly for early evidence of reactivation. There has not been adequate experience with ipilimumab in regard to the risk of reactivation of hepatitis B to provide rates of reactivation with and without antiviral prophylaxis.

Likelihood score: A (well known cause of clinically apparent liver injury and likely cause of reactivation of hepatitis B).

Mechanism of Injury

The mechanism of liver injury due to ipilimumab is likely to be immunologically mediated, and most cases appear to respond at least in part to corticosteroid or immunosuppressive therapy. Liver biopsies in cases of hepatocellular injury and bile duct epithelial cell biopsies in cholangiopathic injury demonstrate necrosis and inflammatory cell infiltration with cytotoxic CD8+ T cells, suggesting that the checkpoint inhibition allowed for activation of T cells directed at hepatocyte or cholangiocyte cell surface antigens.

Outcome and Management

Guidelines for management of patients receiving ipilimumab recommend monitoring of liver tests and interrupting therapy for patients who develop serum aminotransferase elevations above 3 times the upper limit of normal (ULN) and discontinuing treatment for values above 5 times the ULN in patients without preexisting abnormalities or HCC involvement of the liver (in whom elevations of 5 and 10 times the ULN are used). Corticosteroid therapy can be considered for patients with high or persistent ALT elevations or if symptoms or jaundice arise, initiating therapy with high dose intravenous methylprednisolone and switching to oral prednisone after 1 to 2 days, continuing tapering doses for at least 30 days.

Most cases of liver injury due to ipilimumab resolve with discontinuation and prompt institution of immunosuppressive therapy which can be discontinued after 1 to 3 months. In some more protracted and resistant instances, corticosteroids have only a limited effect and adding a second agent is needed. Mycophenolate mofetil or azathioprine are most commonly recommended. Other immunosuppressive agents that have been reported to be beneficial include antithymocyte globulin, tacrolimus, infliximab and cycloserine. In refractory cases, immunosuppressive therapy may be needed long term. The few fatal cases due to checkpoint inhibitors have typically occurred in patients who have cholestatic forms of liver injury or have other severe immune related adverse events (Stevens Johnson syndrome, capillary leak syndrome). Restarting ipilimumab after severe liver injury requiring corticosteroid therapy can be followed by recurrence of liver injury and is not recommended. Switching to other checkpoint inhibitors is more likely to be tolerated. Interestingly, survival rates do not seem to be improved by re-introduction of checkpoint inhibitor therapy after severe immune related adverse events. Thus, restarting therapy should be undertaken only after careful evaluation of the residual cancer status.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies, Checkpoint Inhibitors


Case 1. Clinically apparent, acute liver injury due to ipilimumab.(1)

A 43 year old man with metastatic melanoma developed erythema, rash and elevations in serum enzymes 3 days after a third infusion of ipilimumab. He had no history of liver disease, and all liver tests had been normal before starting ipilimumab therapy. Serum ALT was 173 U/L (4 times ULN) and Alk P 131 (1.1 times ULN), while bilirubin levels were normal. The absolute eosinophil count was raised (889/µL) and antinuclear antibody was reactive (2.4 by ELISA), but smooth muscle antibody was not present, and immunoglobulin levels were normal. Over the next few days, liver tests worsened with ALT rising to 2860 U/L, Alk P 410 U/L and total bilirubin 2.2 mg/dL. A liver biopsy showed an acute hepatitis superimposed upon fatty liver disease with steatosis, slight ballooning degeneration, occasional Mallory bodies and slight fibrosis. Initiation of oral prednisone therapy was followed by a slow improvement in enzymes, which fell into the normal range approximately 5 months after onset. Prednisone was later stopped without recurrence of liver injury. He died of progressive metastatic melanoma one year later.

Key Points

Pattern:Mixed initially (R=3.7), hepatocellular at peak (R=20.2)
Severity:1+ (symptoms and liver enzyme elevations without frank jaundice)
Latency:6 weeks
Recovery:5 months
Other medications:None mentioned


The clinical presentation 10 days after a third infusion of ipilimumab and approximately 90 days after starting therapy was typical of the immune related hepatic injury from this monoclonal antibody. Despite discontinuing further infusions, the liver injury worsened and was eventually treated with low doses of corticosteroids, with a slow but eventually complete response.



Ipilimumab – Yervoy®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Ipilimumab 477202-00-9 Monoclonal AntibodyNot Available


Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57:2233–40. [Case 5.] [PMC free article: PMC3792485] [PubMed: 22434096]


References updated: 23 June 2022

Abbreviations used: CPI, checkpoint inhibitor; CTLA-4, cytotoxic T lymphocyte associated antigen 4; HCC, hepatocellular carcinoma; irAE, immune related adverse event; PD-1, programmed cell death receptor 1; PD-L1, programmed cell death receptor ligand-1; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

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    (35 year old woman with refractory metastatic melanoma received 4 infusions of ipilimumab and 4 cyclces of nivolumab with partial response only and death, autopsy showing necrotic melanoma metastases and CD8+ T cell infiltrates in many organs, including liver).
  • Spänkuch I, Gassenmaier M, Tampouri I, Noor S, Forschner A, Garbe C, Amaral T. Severe hepatitis under combined immunotherapy: resolution under corticosteroids plus anti-thymocyte immunoglobulins. Eur J Cancer. 2017;81:203–5. [PubMed: 28641200]
    (49 year old woman with metastatic melanoma developed abdominal pain after 3 cycles of ipilimumab and nivolumab [bilirubin 5.5 mg/dL, ALT 722 U/L, Alk P 449 U/L], responding slowly to methylprednisolone and ATG, and then tolerating pembrolizumab therapy without recurrence).
  • Yildirim S, Deniz K, Doğan E, Başkol M, Gürsoy Ş, Özkan M. Ipilimumab-associated cholestatic hepatitis: a case report and literature review. Melanoma Res. 2017;27:380–2. [PubMed: 28489679]
    (45 year old man with refractory metastatic melanoma developed jaundice 7 days after a 4th dose of ipilimumab [bilirubin 8.5 mg/dL, ALT 96 U/L, Alk P 678 U/L, GGT 1320 U/L], resolving slowly with corticosteroid therapy).
  • Tanaka R, Fujisawa Y, Sae I, Maruyama H, Ito S, Hasegawa N, Sekine I, et al. Severe hepatitis arising from ipilimumab administration, following melanoma treatment with nivolumab. Jpn J Clin Oncol. 2017;47:175–8. [PubMed: 28173241]
    (59 year old man with refractory metasatic melanoma treated with 11 doses of nivolumab developed severe hepatitis after one dose of ipilimumab with fever, chills and fatigue [bilirubin 2.1 rising to 12.6 mg/dL, ALT 1623 U/L, Alk P 1306 U/L, INR 1.45], eventually improving with high doses of methylprednisolone and mycophenolate).
  • Mirza S, Hill E, Ludlow SP, Nanjappa S. Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome. Melanoma Res. 2017;27:271–3. [PubMed: 28146044]
    (46 year old man with refractory metastatic melanoma developed fever, rash and liver test abnormalities while receiving ipilimumab and nivolumab, but also 1 week after a course of levofloxacin [bilirubin and Alk P not given, ALT 116 U/L, eosinophils 1400/uL], resolving with corticosteroid therapy and stopping monoclonal antibodies).
  • Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis. 2017;21:115–34. [PubMed: 27842767]
    (Review of hepatotoxicity of agents newly approved for use in the US including ipilimumab which is associated with ALT elevations in 3-9% of patients [above 5 times ULN in 0.5% to 1.5%], most of which are self-limited in course; however, clinically apparent, largely hepatocellular, injury can also occur, especially when combined with dacarbazine or vemurafenib, usually responding to corticosteroid therapy, but rare deaths from hepatic failure have been reported).
  • Everett J, Srivastava A, Misdraji J. Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis. Am J Surg Pathol. 2017;41:134–7. [PubMed: 27792061]
    (Fibrin ring granulomas were found in liver biopsies from 2 patients with metastatic melanoma treated with ipilimumab who developed fever, rash and elevated liver tests after 3 infusions [bilirubin 0.5 and 0.2 mg/dL, ALT 130 and 643 U/L, Alk P 264 and 70 U/L], resolving with corticosteroid therapy).
  • Weber J, Mandala M, Del Vecchio M, Gogas HJ, Arance AM, Cowey CL, Dalle S, et al. CheckMate 238 Collaborators. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824–35. [PubMed: 28891423]
    (Among 905 patients with malignant melanoma after surgical resection given adjuvant therapy for at least 18 months, progression free survival was less with ipilimumab than nivolumab [60.8% vs 70.5% at 12 months] and side effects were greater [serious adverse events in 43% vs 18%] including ALT elevations [15% vs 6% which were above 5 times ULN in 5.7% vs 1.1%]).
  • Koksal AS, Toka B, Eminler AT, Hacibekiroglu I, Uslan MI, Parlak E. HBV-related acute hepatitis due to immune checkpoint inhibitors in a patient with malignant melanoma. Ann Oncol. 2017;28:3103–3104. [PubMed: 28945827]
    (56 year old man with melanoma and HBsAg in serum developed liver injury 12 weeks after starting ipilimumab [bilirubin 0.7 rising to 1.9 mg/dL, ALT 246 rising to 888 U/L, HBV DNA 244,259 IU/mL], responding to tenofovir and was continued on nivolumab).
  • Huffman BM, Kottschade LA, Kamath PS, Markovic SN. Hepatotoxicity after immune checkpoint inhibitor therapy in melanoma: natural progression and management. Am J Clin Oncol. 2018;41(8):760–5. [PubMed: 28749795]
    (Among 218 patients treated with various checkpoint inhibitors at the Mayo Clinic over a 5 year period, 17 developed hepatotoxicity [12 after ipilimumab alone], with onset after median of 52 days [16-151 days] and resolving mostly with corticosteroid therapy after 31 days [6-56 days]).
  • Dueland S, Guren TK, Boberg KM, Reims HM, Grzyb K, Aamdal S, Julsrud L, et al. Acute liver graft rejection after ipilimumab therapy. Ann Oncol. 2017;28:2619–20. [PubMed: 28961840]
    (67 year old woman with ocular melanoma underwent liver transplantation and later had metastases to graft, developed liver test abnormalities 3 weeks after stopping immunosuppression [sirolimus and mycophenolate] and receiving one infusion of ipilimumab [ALT 750 U/L], biopsy showing acute rejection).
  • Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol. 2018;31:965–973. [PubMed: 29403081]
    (Liver histology in 7 cases of hepatotoxicity from checkpoint inhibitors [2 ipilimumab, 7 nivolumab] showed lobular hepatitis with prominence of CD8+ lymphocytes in most, with less eosinophilic infiltration and bile plugs than typical drug induced hepatitis and less plasma cell infiltration and portal inflammation than autoimmune hepatitis).
  • Huffman BM, Kottschade LA, Kamath PS, Markovic SN. Hepatotoxicity after immune checkpoint inhibitor therapy in melanoma: natural progression and management. Am J Clin Oncol. 2018;41:760–765. [PubMed: 28749795]
    (Among 281 patients with cancer treated with checkpoint inhibitors at the Mayo Clinic over a 5 year period, 17 [6%] developed liver injury within 16 to 151 [median=52] days of starting [ipilimumab alone in 12, with nivolumab in 2 and pembrolizumab alone in 3], all with ALT elevations [59 to 2355 U/L], often with Alk P elevations [up to 1728 U/L], 6 with jaundice [bilirubin 2.5 to 15.7 mg/dL], all but one treated with corticosteroids, responding in 6-56 [median 31] days, 2 requiring a second agent [azathioprine or cycloserine], none fatal).
  • Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–168. [PubMed: 29320654]
    (Review of the clinical features, outcomes, pathogenesis and therapy of immune related adverse events of checkpoint inhibitor therapy).
  • Wong GL, Wong VW, Hui VW, Yip TC, Tse YK, Liang LY, Lui RN, et al. Hepatitis flare during immunotherapy in patients with current or past hepatitis B virus infection. Am J Gastroenterol. 2021;116:1274–1283. [PubMed: 33560651]
    (Among 990 patients in Hong Kong with advanced malignancies treated with checkpoint inhibitors between 2014 and 2019 [397 HBsAg positive, 482 with anti-HBc or anti-HBs, 111 negative for both at baseline], 39% of HBsAg-positive vs 30% of HBsAg-negative patients developed ALT elevations during therapy, but only two cases [both HBsAg positive and on prophylaxis] were due to HBV reactivation).
  • Mustafayev K, Torres H. Hepatitis B virus and hepatitis C virus reactivation in cancer patients receiving novel anticancer therapies. Clin Microbiol Infect. 2022:S1198-743X(22)00119-7. [PubMed: 35283317]
    (Review of the literature on reactivation of HBV and HCV in patients on “novel” anticancer therapy concludes that reactivation can occur with checkpoint inhibitor therapy, but largely among HBsAg positive patients and only rarely in patients with resolved hepatitis B).
  • Yoo S, Lee D, Shim JH, Kim KM, Lim YS, Lee HC, Yoo C, et al. Risk of hepatitis B virus reactivation in patients treated with immunotherapy for anti-cancer treatment. Clin Gastroenterol Hepatol. 2022;20:898–907. [PubMed: 34182151]
    (Among 3,465 patients with advanced malignancies treated with checkpoint inhibitors between 2015 and 2020 at a single referral center in Korean, 511 [15%] were HBsAg positive at baseline, reactivation of HBV occurred in 5 of 511 [1%] HBsAg positive vs none of 2,954 HBsAg negative patients, arising in 2 of 464 [0.4%] patients given prophylaxis [both having stopped antivirals] vs 3 of 47 not given prophylaxis [6.4%]; reactivation arising after 3-141 weeks [median 54 weeks] of nivolumab [n=2], pembrolizumab [n=2] or ipilimumab and nivolumab [n=1] treatment, ALT peak 53 to 1768 IU/mL, HBV DNA 6,100 to 3.9 million IU/mL, resolving with 2 to 6 weeks of starting antiviral therapy).
  • De Martin E, Michot JM, Papouin B, Champiat S, Mateus C, Lambotte O, Roche B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018;68:1181–1190. [PubMed: 29427729]
    (Among 536 patients treated with checkpoint inhibitors, 19 [3.5%] were referred to a liver service for high grade hepatitis and 16 underwent liver biopsy; ages 33 to 84 years, 56% female, injury arising after 1-36 [median=5] weeks and 1-36 [median=2] doses, presenting with fever in 38%, rash in 31%, ALT 266 to 3137 [460] U/L, Alk P 54 to 768 [309] U/L, bilirubin 0.4 to 19 [1.1] mg/dL, enzyme pattern most commonly being mixed, 10 patients treated with corticosteroids and 6 resolving spontaneously and no deaths).
  • Pollack MH, Betof A, Dearden H, Rapazzo K, Valentine I, Brohl AS, Ancell KK, et al. Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol. 2018;29:250–255. [PMC free article: PMC5834131] [PubMed: 29045547]
    (Among 80 patients treated with checkpoint inhibitors who developed immune related adverse events requiring discontinuation who were then restarted on therapy, 31 [39%] had recurrence or toxicities requiring discontinuation again, of the 29 who had hepatitis initially, 5 had recurrence on restarting).
  • Santini FC, Rizvi H, Plodkowski AJ, Ni A, Lacouture ME, Gambarin-Gelwan M, Wilkins O, et al. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC. Cancer Immunol Res. 2018;6:1093–1099. [PMC free article: PMC6125223] [PubMed: 29991499]
    (Among 482 patients with metastatic or advanced NSCLC treated with checkpoint inhibitors at a single US referral center between 2011 and 2016, 68 [14%] developed a serious immune related adverse event [irAE] that required discontinuation of whom 38 were retreated, of whom 18 had no recurrence, 10 had recurrence of the same irAE, 10 had a new irAE [2 of which were fatal]; restarting therapy appeared to be beneficial only in those who had no tumor response before onset of the first event).
  • Tian Y, Abu-Sbeih H, Wang Y. Immune checkpoint inhibitors-induced hepatitis. Adv Exp Med Biol. 2018;995:159–164. [PubMed: 30539511]
    (Review of the clinical, pathological and immunological features of liver injury associated with immune checkpoint inhibitors such as ipilimumab).
  • Karamchandani DM, Chetty R. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective. J Clin Pathol. 2018;71:665–671. [PubMed: 29703758]
    (Review of the gastrointestinal and hepatic adverse events of checkpoint inhibitors with focus on histopathologic features, describes three major histologic patterns: ( 1 ) panlobular hepatitis with mixed inflammatory cell infiltrates, sometimes with microgranulomas; (2) hepatitis with prominent centrilobular [zone 3] necrosis; (3) rarely with prominent biliary injury and cholestasis) .
  • Johnson DB, Chandra S, Sosman JA. Immune checkpoint inhibitor toxicity in 2018. JAMA. 2018;320(16):1702–1703. [PubMed: 30286224]
    (Brief review of the immune mediated adverse effects of checkpoint inhibitors, mentions that hepatitis arises in ~1% of recipients of anti-PD-1 or anti-PD-L1 monoclonal antibodies but in as many as 10% of recipients of anti-CTLA-4 monoclonals such as ipilimumab).
  • Namikawa K, Kiyohara Y, Takenouchi T, Uhara H, Uchi H, Yoshikawa S, Takatsuka S, et al. Efficacy and safety of nivolumab in combination with ipilimumab in Japanese patients with advanced melanoma: An open-label, single-arm, multicentre phase II study. Eur J Cancer. 2018;105:114–126. [PubMed: 30447539]
    (Among 30 Japanese subjects with advanced melanoma treated with nivolumab and ipilimumab, overall survival was 66% at 24 months and adverse events occurred in all patients including ALT elevations in 37% which were above 5 times ULN in 10%).
  • Zhang HC, Luo W, Wang Y. Acute liver injury in the context of immune checkpoint inhibitor-related colitis treated with infliximab. J Immunother Cancer. 2019;7:47. [PMC free article: PMC6380028] [PubMed: 30777137]
    (79 year old man with metastatic prostate cancer treated 3 cycles of nivolumab and ipilimumab developed corticosteroid-refractory immune mediated enterocolitis and was treated with a single infusion of infliximab and one month later developed jaundice [bilirubin 7.5 mg/dL, ALT 291 U/L, Alk P 677 U/L, ANA negative], which was attributed to infliximab and eventually resolved without corticosteroid therapy).
  • Cheung V, Gupta T, Payne M, Middleton MR, Collier JD, Simmons A, Klenerman P, et al. Immunotherapy-related hepatitis: real-world experience from a tertiary centre. Frontline Gastroenterol. 2019;10(4):364–371. [PMC free article: PMC6788136] [PubMed: 31656561]
    (Among 453 patients treated with checkpoint inhibitors for cancer between 2022 and 2018, 20 [4%] developed immune related hepatitis, with highest rates with the combination of ipilimumab and nivolumab, 18 treated with immunosuppression using corticosteroids, 8 with addition of mycophenolate and 2 with infliximab, none fatal).
  • Zen Y, Yeh MM. Checkpoint inhibitor-induced liver injury: A novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019;36:434–440. [PubMed: 31358424]
    (Liver histology from 7 patients with checkpoint inhibitor [CPI] induced hepatitis [4 nivolumab, 2 ipilimumab, arising after 1-6 doses] and classical autoimmune hepatitis showed similar rates of lobular hepatitis, but less confluent necrosis with CPIs and absence of autoantibodies and IgG elevations).
  • Vozy A, De Martin E, Johnson DB, Lebrun-Vignes B, Moslehi JJ, Salem JE. Increased reporting of fatal hepatitis associated with immune checkpoint inhibitors. Eur J Cancer. 2019;123:112–115. [PubMed: 31678768]
    (Review of the VigiBase registry of adverse drug reactions through September 2018 identified 531 cases of immune related hepatitis, 85% due to CPIs alone with an increase in fatality rate over time, being 14% between 2011 to 2016 and 34% in 2017-2018, time to onset median of 42 days, arising after 1-4 courses [median 2] and with concurrent other organ immune related injury in 31%, usually thyroid or skin).
  • Zhang D, Hart J, Ding X, Zhang X, Feely M, Yassan L, Alpert L, et al. Histologic patterns of liver injury induced by anti-PD-1 therapy. Gastroenterol Rep (Oxf). 2019;8:50–55. [PMC free article: PMC7244961] [PubMed: 32467761]
    (Liver histology in 8 cases of immune mediated liver injury after monoclonal anti-PD-1 therapy revealed a lobular hepatitis without features of autoimmune hepatitis).
  • Imoto K, Kohjima M, Hioki T, Kurashige T, Kurokawa M, Tashiro S, Suzuki H, et al. Clinical features of liver injury induced by immune checkpoint inhibitors in Japanese patients. Can J Gastroenterol Hepatol. 2019;2019:6391712. [PMC free article: PMC6935806] [PubMed: 31929981]
    (Among 343 Japanese patients with cancer treated with checkpoint inhibitors, 56 [16%] developed evidence of liver injury, arising after 21 to 94 [median=46] days, with initial ALT 39 to 136 [mean 60] U/L, Alk P 263 to 857 [471] U/L, bilirubin 0.4 to 1.0 [0.7] mg/dL, and thus a cholestatic pattern was found in most patients, and there was a low rate of high grade liver injury [3.2%] and no fatalities).
  • Jennings JJ, Mandaliya R, Nakshabandi A, Lewis JH. Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies. Expert Opin Drug Metab Toxicol. 2019;15:231–244. [PubMed: 30677306]
    (Review of the incidence, clinical features, histopathology, diagnosis, grading, and management of the liver injury associated with checkpoint inhibitor therapy which occurs in up to half of patients, but ALT values above 5 times ULN in 1-20% being highest with ipilimumab and particularly when given in combination with nivolumab or other PD-1 or PD-L1 inhibitors).
  • Abu-Sbeih H, Tran CN, Ge PS, Bhutani MS, Alasadi M, Naing A, Jazaeri AA, et al. Case series of cancer patients who developed cholecystitis related to immune checkpoint inhibitor treatment. J Immunother Cancer. 2019;7:118. [PMC free article: PMC6499962] [PubMed: 31053161]
    (Among 4253 patients treated with checkpoint inhibitors at the MD Anderson Cancer Center between 2010 and 2018, 25 [0.6%] developed acalculous cholecystitis attributed to the immunotherapy most frequently with anti-CTLA-4 agents alone [1.6%], than anti-PD-1/PD-L1 [0.4%] and combination [0.9%], mean age of patients was 60 years, 60% male, 64% white, median peak ALT 55 U/L, bilirubin 1.4 mg/dL, 20% underwent cholecystectomy, all recovered, 10 [40%] restarted therapy, all without recurrence).
  • Mizuno K, Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, Kawashima H, et al. Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies. J Gastroenterol. 2020;55:653–661. [PubMed: 32124082]
    (Among 546 patients with advanced malignancies treated with checkpoint inhibitors at two Japanese referral centers between 2014 and 2019, high grade, immune mediated liver injury occurred in 29 [5%], mean age 69 years, 73% male, mean onset 52 [range 1-273] days, after 3 [1-15] doses of ipilimumab [6%], nivolumab [54%], pembrolizumab [30%], atezolizumab [6%], durvalumab [2.4%], combination [1.3%], presenting with hepatocellular [21%], cholestatic [59%] or mixed [21%] enzyme elevations, 4 with cholangitis and biliary dilatation without obstruction, only 1 case fatal; predictive factors for injury included ipilimumab [hazard ratio 4.2]).
  • Zen Y, Chen YY, Jeng YM, Tsai HW, Yeh MM. Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes. Histopathology. 2020;76:470–480. [PubMed: 31550390]
    (Description of 10 cases of second generation checkpoint inhibitor induced immune liver injury mentions 3 patterns, hepatocellular, cholestatic and granulomatous injury, the cholestatic form often with a delayed latency and poor response to corticosteroids).
  • Peeraphatdit TB, Wang J, Odenwald MA, Hu S, Hart J, Charlton MR. Hepatotoxicity from immune checkpoint inhibitors: a systematic review and management recommendation. Hepatology. 2020;72:315–329. [PubMed: 32167613]
    (Review of the clinical features, biochemical findings, histology, pathogenesis, diagnosis and management of immune related liver injury due to the checkpoint inhibitors).
  • Li M, Sack JS, Rahma OE, Hodi FS, Zucker SD, Grover S. Outcomes after resumption of immune checkpoint inhibitor therapy after high-grade immune-mediated hepatitis. Cancer. 2020;126:5088–5097. [PMC free article: PMC7655516] [PubMed: 32888341]
    (Among 102 patients with advanced melanoma treated with checkpoint inhibitors at 3 Boston medical centers between 2010 and 2019 who developed high grade liver injury, 31 were rechallenged with a checkpoint inhibitor of whom 15 [48%] developed an immune related adverse event, but only 6 [20%] required drug discontinuation, 4 with recurrence of liver injury most commonly with ipilimumab).
  • Miller ED, Abu-Sbeih H, Styskel B, Nogueras Gonzalez GM, Blechacz B, Naing A, et al. Clinical characteristics and adverse impact of hepatotoxicity due to immune checkpoint inhibitors. Am J Gastroenterol. 2020;115:251–261. [PubMed: 31789632]
    (Among 5762 recipients of checkpoint inhibitor therapy of cancer at the MD Anderson Cancer Center between 2010 and 2018, 433 [8%] developed ALT levels and 100 had levels above 5 times ULN [2%), the rate being 8% with combination therapy, 1.7% with anti-CTLA agents and 1.1% with PD1 and PDL1 blockers, the abnormalities arising after a median of 59 days; all had the checkpoint inhibitor therapy held, 67 received corticosteroids [for a median of 43 days], 3 with mycophenolate, and 31 were rechallenged after resolution of the hepatitis, of whom 8 [26%] had a recurrence).
  • Kitagataya T, Suda G, Nagashima K, Katsurada T, Yamamoto K, Kimura M, Maehara O, et al. Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan. J Gastroenterol Hepatol. 2020;35:1782–1788. [PubMed: 32187734]
    (Among 202 patients with cancer treated with checkpoint inhibitors at a single referral center in Japan, 17 [8.5%] developed immune related hepatitis which was severe in 8 [4.5%] often requiring corticosteroids, 2 receiving mycophenolate as well, but none died).
  • Ruggiero R, Fraenza F, Scavone C, di Mauro G, Piscitelli R, Mascolo A, Ferrajolo C, et al. Immune checkpoint inhibitors and immune-related adverse drug reactions: data from Italian Pharmacovigilance Database. Front Pharmacol. 2020;11:830. [PMC free article: PMC7295943] [PubMed: 32581796]
    (Among 2088 safety reports of check point inhibitors enrolled in an Italian pharmacovigilance registry, 801 were immune related including gastrointestinal [33%], skin [17%] and liver [2.7%] due to nivolumab [70%], pembrolizumab [11%], ipilimumab [15%], atezolizumab [4%] and avelumab [<1%]).
  • Riveiro-Barciela M, Barreira-Díaz A, Vidal-González J, Muñoz-Couselo E, Martínez-Valle F, Viladomiu L, Mínguez B, et al. Immune-related hepatitis related to checkpoint inhibitors: clinical and prognostic factors. Liver Int. 2020;40:1906–1916. [PubMed: 32329119]
    (Among 414 patients treated with checkpoint inhibitors, 28 [6.8%] developed high grade liver injury but 19 were considered mild, 7 moderate, 1 severe and only 1 fatal).
  • Gauci ML, Baroudjian B, Bédérède U, Zeboulon C, Delyon J, Allayous C, Madelaine I, et al. PATIO group. Severe immune-related hepatitis induced by immune checkpoint inhibitors: Clinical features and management proposal. Clin Res Hepatol Gastroenterol. 2021;45:101491. [PubMed: 32773362]
    (Among 339 patients treated at a single French referral center with checkpoint inhibitors, 21 [6.2%] developed high grade liver toxicity, including 8% [7/86] receiving ipilimumab, 3% [3/105] nivolumab, 1% [1/122] pembrolizumab and 38% [10/26] combination therapy; 13 patients received corticosteroids, all except one with severe biliary lesions recovered and 8 restarted therapy none of whom relapsed).
  • Cho YA, Han JM, Kang SY, Kim DC, Youn YJ, Choi KH, Gwak HS. Analysis of risk factors for hepatotoxicity induced by immune checkpoint Inhibitors. J Immunother. 2021;44:16–21. [PubMed: 33290362]
    (Among 194 patients with cancer treated with checkpoint inhibitors at two Korean referral centers, 125 [64%] developed liver test abnormalities, more frequently in younger patients vs older [30-50 years - 80% vs 50-70 years - 72%, and >70 years - 50%] and in men than women [68% vs 58%]).
  • Au M, Body A, Mant A, Nicoll A. Checkpoint inhibitor induced steroid refractory drug-induced liver injury. Intern Med J. 2021;51:810–811. [PubMed: 34047030]
    (75 year old man with metastatic melanoma developed ALT elevations [peak 451 U/L] starting 4 weeks after starting ipilimumab and nivolumab treated with corticosteroids, with a prompt improvement but relapse once predniosone was tapered [ALT 647 U/L], which responded with addition of mycophenolate).
  • Ortland I, Mirjalili M, Kullak-Ublick GA, Peymani P. Drug-induced liver injury in Switzerland: an analysis of drug-related hepatic disorders in the WHO pharmacovigilance database VigiBaseTM from 2010 to 2020. Swiss Med Wkly. 2021;151:w20503. [PubMed: 34000058]
    (Among 2042 cases of drug induced liver injury reported from Switzerland to VigiBase between 2010 and 2020, average age 57 years, males and females similar proportions, 10% were fatal and the most common causes included acetaminophen [5.8%], amoxicillin/clavulanate 3.1%, esomeprazole [2.0%], atorvastatin [1.9%], and nivolumab [1.3%]).
  • Yamamoto A, Yano Y, Ueda Y, Yasutomi E, Hatazawa Y, Hayashi H, Yoshida R, et al. Clinical features of immune-mediated hepatotoxicity induced by immune checkpoint inhibitors in patients with cancers. J Cancer Res Clin Oncol. 2021;147:1747–1756. [PubMed: 33222015]
    (Among 250 patients with cancer treated with checkpoint inhibitors, 21 [9.5%] developed immune mediated liver injury, most frequently with ipilimumab [60%], ipilimumab and nivolumab [57%] compared to nivolumab alone [7%] or pembrolizumab [3%], and rates were higher in patients with melanoma [35%] compared to renal cell cancer [10%] and others).
  • Purde MT, Niederer R, Wagner NB, Diem S, Berner F, Hasan Ali O, Hillmann D, et al. Presence of autoantibodies in serum does not impact the occurrence of immune checkpoint inhibitor-induced hepatitis in a prospective cohort of cancer patients. J Cancer Res Clin Oncol. 2022;148:647–656. [PMC free article: PMC8881258] [PubMed: 34874490]
    (Among 131 patients with melanoma or NSCLC treated with checkpoint inhibitors between 2016 and 2019, 11 developed high grade hepatitis [8.4%] which did not correlate with existence or titer of autoantibodies in pretreatment serum samples).


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