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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: February 16, 2018.



Ipilimumab is a human monoclonal antibody to cytotoxic T lymphocyte antigen-4 which acts as an immune checkpoint inhibitor increases immune reactivity and is used to treat metastatic malignant melanoma. Ipilimumab has major side effects, many of which can be serious and life threatening including acute liver injury.


Ipilimumab (ip” i lim’ ue mab) is a human recombinant monoclonal immunoglobulin G1 antibody to the cytotoxic T lymphocyte antigen-4 (CTLA-4) which is used 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 may play a beneficial role in cancer immunotherapy and can break immunological tolerance. 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. Ipilimumab has also been evaluated in several other forms of cancer, including breast, colon, renal cell and pancreatic cancer, alone and in combination with other checkpoint inhibitors such as nivolumab (anti-PD-1). Ipilimumab is available in liquid solution in 50 and 200 mg vials (5 mg/mL) under the brand name Yervoy. The typical regimen is 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 are common and can be severe, life threatening and even fatal. As many as 70% of treated patients develop immune related side effects as a result of immune enhancement including enterocolitis, dermatitis, endocrinopathy, neuropathy, nephritis and hepatitis. Most of these reactions respond to immunosuppressive therapy. Early recognition and prompt management of these side effects is an integral component of proper use of ipilimumab.


Mild-to-moderate serum aminotransferase elevations are not uncommon (10% to 50%) 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 5% of patients, and a proportion of these individuals (~1%) develop clinically apparent liver injury that can be severe. The onset of injury 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, particularly at the onset of injury. 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 usually not present. Restarting ipilimumab can result in recurrence of injury, although corticosteroid treatment may block recurrence.

The effects of anti-CTLA-4 inhibition on hepatitis B have not been reported, as enrollment criteria in the clinical trials of ipilimumab have usually excluded patients with hepatitis B or C or preexisting liver disease. However, it is possible that anti-CTLA-4 treatment would exacerbate chronic hepatitis B and C by enhancing T cell cytotoxicity to viral antigens.

Likelihood score: A (very likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of liver injury due to ipilimumab is likely to be immunologically mediated and some cases have appeared to respond to corticosteroid or immunosuppressive therapy, allowing for continuation of ipilimumab therapy.

Outcome and Management

Guidelines for management of patients receiving ipilimumab recommend monitoring of liver test results before starting therapy and at the time of each infusion. Corticosteroid therapy is recommended for patients who develop serum aminotransferase elevations above 5 times the ULN, initiating therapy with high doses of intravenous methylprednisolone, switching to oral prednisone after 1 to 2 days, and continuing tapering doses for at least 30 days. Most cases of hepatitis due to ipilimumab resolve with prompt institution of immunosuppressive therapy. In some more protracted and resistant instances, adding a second agent to corticosteroids, such as antithymocyte globulin, tacrolimus, azathioprine or mycophenolate mofetil, has resulted in resolution of the injury. The few fatal cases that have been reported occurred in patients who had other severe immune related adverse events (Stevens Johnson syndrome, capillary leak syndrome) or who had a delay in starting corticosteroid therapy. Restarting ipilimumab after severe liver injury requiring corticosteroid therapy is usually promptly followed by recurrence of liver injury and is not recommended.

Drug Class: Antineoplastic Agents, Monoclonal Antibodies, Checkpoint Inhibitors


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

[Modified from Case 5 in: Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci 2012; 57: 2233-40. PubMed Citation]

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 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.


Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available for review. Most of these reference cases are from the Drug-Induced Liver Injury Network, but others are from users of LiverTox who have submitted data from an actual clinical case. All cases have been reviewed and cleared of personal identifiers and a brief comment added by the LiverTox editors. Click on the following link to view the submitted case reports that have been made publically available.

Submitted Cases on Ipilimumab



Ipilimumab – Yervoy®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Ipilimumab477202-00-9Monoclonal AntibodyNot Available


References updated: 16 February 2018

Abbreviations: CTLA-4, cytotoxic T lymphocyte-associated antigen-4; PD-1, programmed cell death receptor-1.

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    (Clinical and histological features of 5 patients with liver injury due to ipilimumab; 3 men and 2 women, ages 43 to 76 years, arising after 2 to 4 courses, 39-71 days after initial dose [peak bilirubin 1.5-5.1 mg/dL, ALT 326-3070 U/L, Alk P 206-427 U/L], only one had autoantibodies, resolving with immunosuppressive therapy within 1-4 months; one had recurrence on rechallenge; liver biopsies showed acute hepatitis usually with prominent inflammation, interface hepatitis and confluent necrosis: Case 1).
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  • Voskens CJ, Goldinger SM, Loquai C, Robert C, Kaehler KC, Berking C, Bergmann T, et al. The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the Ipilimumab Network. PLoS One 2013; 8: e53745. [PMC free article: PMC3544906] [PubMed: 23341990]
    (Retrospective review of adverse reactions seen in 752 patients with metastatic melanoma treated with ipilimumab in 19 major cancer centers in Europe; 120 events were summarized including 11 involving the liver, which usually presented 3-6 weeks after starting therapy, with marked elevations in serum enzymes; one fatal case described in detail).
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    (Six patients with ipilimumab hepatitis, ages 44-82 years, five men and one woman, treated with 2-4 cycles presenting with fatigue, fever and nausea [bilirubin 0.5-19.6 mg/dL, ALT 168-975 U/L], resolving within 34-147 days of stopping, many were treated with corticosteroids).
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    (Among 11 patients with malignant melanoma treated with ipilimumab, 6 [54%] developed some degree of ALT elevation after 1 to 4 courses, but only one had values above 5 times ULN and all resolved with temporary delay in therapy).
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    (Among 676 patients with melanoma enrolled in the phase III trial of ipilimumab, 94 [20%] survived for 2 years and 42 [16%] for 3 years; late onset immune related adverse events occurred in 11 patients [14%], but were usually mild and none were hepatic).
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    (Among 53 patients with metastatic uveal melanoma treated with ipilimumab, response rates were poor and side effects were common, ALT elevations occurred in 7% and were above 5 times ULN in 4%).
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    (Among 245 patients with metastatic melanoma treated with ipilimumab with or without sargramostim [GM-CSF] found improved objective responses with the combination and lower rates of severe adverse events, ALT elevations above 5 times ULN occurring in 5.1% vs 5.8% of patients).
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    (Among 9 patients with metastatic melanoma and either chronic hepatitis C [n=4] or B [n=5] treated with ipilimumab, viral levels and serum ALT levels did not change in a consistent manner; most with hepatitis B were on antiviral prophylaxis).
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    (Among 834 patients with advance melanoma treated with pembrolizumab [Pem: 10mg/kg every 2 or 3 weeks] or ipilimumab [Ipil: 3 mg/kg every 3 weeks], 6 month progression free survival was higher with Pem [47% and 46%] than Ipil [26.5%] and adverse events were less; thyroiditis was more common with Pem, whereas colitis and hypophysitis were more common with Ipil; ALT elevations occurred in 3% [Pem] vs 3.5% [Ipil] and were above 5 times ULN in 0.2% vs 0.8%).
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    (50 year old woman with metastatic melanoma developed fever and liver test abnormalities after a first infusion of ipilimumab [bilirubin 0.9 rising to 1.8 mg/dL, ALT 640 to 4700 U/L, Alk P 366 to 604 U/L], treated with corticosteroids and then ATG and mycophenolate and resolving in 4 weeks, not restarted).
  • Johncilla M, Misdraji J, Pratt DS, Agoston AT, Lauwers GY, Srivastava A, Doyle LA. Ipilimumab-associated Hepatitis: Clinicopathologic characterization in a series of 11 cases. Am J Surg Pathol 2015; 39: 1075-84. [PubMed: 26034866]
    (Among 11 patients with metastatic melanoma treated with ipilimumab who developed liver injury and had liver biopsy, age range 33-71 years, 10 men, arising after 1-4 doses, all with ALT elevations and 3 with jaundice [bilirubin 0.7 to 15.6 mg/dL, ALT 185 to 3075, Alk P 48 to 453 U/L], 9 biopsies showed panlobular or central hepatitis, one showed NASH, one cholangitis; all resolved in 2-12 weeks with corticosteroid therapy).
  • Morales RE, Shoushtari AN, Walsh MM, Grewal P, Lipson EJ, Carvajal RD. Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation. J Immunother Cancer 2015; 3: 22. [PMC free article: PMC4469313] [PubMed: 26082835]
    (67 year old man with liver transplant for hepatitis C developed metastatic melanoma treated with 4 doses of ipilimumab and 2 weeks later had ALT elevations without jaundice that resolved without corticosteroids or antirejection therapy).
  • Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, Schmidgen MI, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 2016; 60: 190-209. [PubMed: 27085692]
    (Review of the major immune mediated side effects of anti-PD-1 therapy, with characteristics of 11 cases of hepatitis due to pembrolizumab or nivolumab, arising 1-4 weeks after initial infusions, resolving mostly with corticosteroid therapy and stopping drugs).
  • Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist 2016; 21: 1230-40. [PMC free article: PMC5061539] [PubMed: 27401894]
    (Review of immune mediated adverse events from anti-PD-1 therapy and their management; ALT elevations are reported in 2-4% of patients with higher rates with combinations; recommend stopping therapy if ALT elevations are above 5 times ULN or bilirubin is raised and use of methylprednisolone, but merely delay in therapy and increased frequency of monitoring if ALT elevations are above 3 times but below 5 times ULN).
  • Koelzer VH, Rothschild SI, Zihler D, Wicki A, Willi B, Willi N, Voegeli M, et al. Systemic inflammation in a melanoma patient treated with immune checkpoint inhibitors-an autopsy study. J Immunother Cancer 2016; 4: 13. [PMC free article: PMC4791920] [PubMed: 26981243]
    (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%]).
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