Nivolumab is a human monoclonal antibody to programmed cell death receptor 1 (PD-1), which acts as a checkpoint inhibitor and is used in the immunotherapy of several forms of advanced or metastatic cancer. Nivolumab 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 threatening.


Nivolumab (nye vol' ue mab) is a human recombinant monoclonal immunoglobulin G4 antibody to the programmed cell death receptor-1 (PD-1), which has distinctive immunomodulatory activity and is used as a checkpoint inhibitor in cancer immunotherapy. PD-1 is an important checkpoint molecule that modulates and down regulates T cell responses. Inhibition of PD-1 receptors on the surface of activated T cells prevents the down regulation of activation and proliferation of T cells by the programmed cell death pathway. Because PD-1 receptor engagement is prevented by nivolumab, T cell responses remain activated. The subsequent enhancement of cytotoxic reactivity may play a beneficial role in cancer immunotherapy by breaking immunological tolerance to cancer cell associated antigens. In several large multicenter studies, nivolumab 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. Nivolumab was approved for use in advanced melanoma in the United States in 2014. Indications were subsequently extended to many other forms of solid tumors including non-small cell lung cancer (NSCLC), renal cell, hepatocellular, urothelial, colorectal, gastric, esophageal and head and neck carcinoma, Hodgkin disease, and pleural mesothelioma. Nivolumab is available in liquid solution in multiple sizes of single use vials of 10 mg/mL under the brand name Opdivo. The dose and regimen varies by indication, but is typically 240 mg every 2 weeks or 480 mg every 4 weeks. The combination of nivolumab with other chemotherapeutic agents is often recommended, particularly its combination with ipilimumab, a monoclonal antibody to CTLA-4, another checkpoint molecule. This combination, which was first approved as combination immunotherapy for malignant melanoma in 2015, continues to be commonly used.

Side effects of nivolumab 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 nivolumab treated patients develop immune related side effects, including enterocolitis, dermatitis, endocrinopathy, pneumonitis, neuropathy, nephritis and hepatitis. Most of these reactions respond to 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 of nivolumab with ipilimumab. Baseline screening and regular monitoring for these adverse events during nivolumab therapy is recommended. Early recognition and prompt management of side effects is an integral component of proper use of nivolumab and other checkpoint inhibitors such as ipilimumab and pembrolizumab. Checkpoints 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 nivolumab include infusion hypersensitivity reactions and embryo-fetal toxicity.


Mild-to-moderate serum aminotransferase elevations are not uncommon (20% to 30%) during nivolumab therapy, but are usually self-limited and resolve even with continuing cyclic therapy. These rates of serum enzyme elevations are similar to those with other forms of chemotherapy for advanced malignancies. 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 serum enzyme elevations evolve into an immune mediated liver injury that can be clinically apparent and can be severe. The onset of injury is usually after 2 to 4 cycles or 1 to 3 months after starting treatment. The pattern of enzyme elevation is usually hepatocellular but can be mixed or even cholestatic. Liver histology typically demonstrates a panlobular hepatitis with focal or confluent necrosis and prominent lymphocytic infiltrates of activated T cells, compatible with an immune mediated hepatic injury. More severe forms of hepatitis may demonstrate centrilobular (zone 3) necrosis. Despite features of immune related liver injury, autoantibodies are generally not present and immunoglobulin levels are normal. Because of the serious nature of the liver injury, monitoring with routine liver tests (including alkaline phosphatase) is recommended for patients who receive checkpoint inhibitor therapy. Treatment with corticosteroids generally results in a rapid improvement and allows their discontinuation within 1 to 2 months. In some instances, however, the clinical and biochemical response is inadequate, calling for addition of a second immunosuppressive agent such as azathioprine, mycophenolate mofetil, tacrolimus, infliximab or antithymocyte globulin. Restarting nivolumab or another checkpoint inhibitor after resolution of the hepatic injury is sometimes possible, but can result in recurrence of injury and has not been shown to improve outcome of the cancer chemotherapy.

A proportion of patients receiving nivolumab develop cholestatic rather than hepatocellular liver injury. Cholestatic forms of immune mediated liver injury generally arise later than the hepatocellular forms, (after 3 to 10 cycles) and are often accompanied by abdominal pain and jaundice. Alkaline phosphatase levels are markedly elevated while aminotransferase levels are only modestly increased. 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 corticosteroids may improve alkaline phosphatase and bilirubin levels but rarely leads to complete recovery, and long term cholestasis and hepatic failure can occur. Some patients with a cholestatic form of immune related hepatitis do not manifest the large bile duct changes but demonstrate loss and paucity of the smaller, intrahepatic portal bile ducts resulting in a vanishing bile duct syndrome similar to primary biliary cholangitis (PBC).

The effects of PD-1 inhibition on chronic hepatitis B are not well defined but convincing examples of reactivation of hepatitis B have been described with nivolumab. 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 nivolumab 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 immune mediated liver injury and likely cause of reactivation of hepatitis B).

Mechanism of Injury

The mechanism of liver injury due to nivolumab is likely to be immunologically mediated and is usually at least partially responsive 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 nivolumab 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 8 times the ULN in patients without preexisting abnormalities or tumor 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 nivolumab resolve with discontinuation and prompt institution of immunosuppressive therapy which can be discontinued in 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 nivolumab after severe liver injury requiring corticosteroid therapy can be followed by recurrence of liver injury and is not recommended. Switching to other checkpoint inhibitors (ipilimumab or anti-PD-L1 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



Nivolumab – Opdivo®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



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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    (79 year old man with NSCLC developed jaundice after 4 infusions of nivolumab [day 62] with bilirubin 10.5, ALT ~480 U/L, Alk P~950 U/L, jaundice resolving 14 weeks after stopping therapy and with corticosteroid treatment, but patient died of progressive cancer shortly thereafter and before Alk P and GGT were completely normal).
  • Mirza S, Hill E, Ludlow SP, Nanjappa S. Checkpoint inhibitor-associated drug reaction with eosinophilia and systemic symptom syndrome. Melanoma Res. 2017;27:271–273. [PubMed: 28146044]
    (46 year old man with melanoma developed fever, rash, eosinophilia with elevations in ALT [115 U/L] and creatinine [1.2 mg/dL] while being treated with ipilimumab and nivolumab, but also shortly after courses of doxycycline and levofloxacin, responding rapidly to corticosteroid therapy).
  • 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;81:203–205. [PubMed: 28641200]
    (49 year old woman with metastatic melanoma developed hepatitis after 3 cycles of ipilimumab and nivolumab [bilirubin 5.8 mg/dL, ALT 772 U/L, Alk P 449 U/L], with inadequate response to corticosteroids but eventual response after starting antithymocyte globulin, later tolerating pembrolizumab without recurrence on low doses of prednisone).
  • Kawakami H, Tanizaki J, Tanaka K, Haratani K, Hayashi H, Takeda M, Kamata K, et al. Imaging and clinicopathological features of nivolumab-related cholangitis in patients with non-small cell lung cancer. Invest New Drugs. 2017;35:529–536. [PubMed: 28317087]
    (Among 91 Japanese patients with advanced NSCLC treated with nivolumab, 3 developed severe cholangitis arising after 6, 9 and 12 cycles in 2 women and 1 man, ages 64 to 82 years with marked elevations in Alk P (peak 1769, 1947 and 2996 U/L], modest ALT elevations [144, 101 and 70 U/L], no autoantibodies, and imaging showing localized common bile duct dilatation with distal breaking but no obstruction, hypertrophy of bile duct wall and no intrahepatic duct abnormalities, all with poor or only moderate response to corticosteroids).
  • Doherty GJ, Duckworth AM, Davies SE, Mells GF, Brais R, Harden SV, Parkinson CA, et al. Severe steroid-resistant anti-PD1 T-cell checkpoint inhibitor-induced hepatotoxicity driven by biliary injury. ESMO Open. 2017;2:e000268. [PMC free article: PMC5652580] [PubMed: 29081991]
    (Three cases of checkpoint inhibitor induced cholestatic liver injury in 2 women and 1 man, ages 47, 59 and 76 years, who developed liver injury after 1-3 cycles of pembrolizumab or nivolumab, one with severe ductopenia who died of liver failure, one with focal ductopenia who eventually recovered, and one with prolonged cholestasis who died of progressive cancer, all with poor or only moderate response to corticosteroids).
  • Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, Sznol M, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients With advanced melanoma. J Clin Oncol. 2017;35:785–792. [PubMed: 28068177]
    (Among 576 patients with advanced melanoma treated with nivolumab [every two weeks] for an average of 6 months, 4.2% developed liver abnormalities, most commonly ALT elevations [1.9%] but few [0.7%] were above 5 times ULN).
  • Schadendorf D, Wolchok JD, Hodi FS, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, et al. Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: a pooled analysis of randomized phase II and III trials. J Clin Oncol. 2017;35:3807–3814. [PMC free article: PMC5791828] [PubMed: 28841387]
    (Among 407 patients with advanced melanoma treated with the combination of ipilimumab and nivolumab for 4 cycles and then nivolumab alone, 156 discontinued therapy because of adverse events, including 13 with liver toxicity, but progression-free survival was similar in those who continued and those who discontinued therapy, largely during the induction period).
  • El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, Kim TY, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492–2502. [PMC free article: PMC7539326] [PubMed: 28434648]
    (Among 262 patients with advanced hepatocellular carcinoma [HCC] treated with nivolumab in dose escalation and expansion studies, objective responses were achieved in 15-20% of patients and toxicity was “manageable” with ALT elevations in 15% that were above 5 times ULN in 6%; among 51 patients with HBV all were receiving antiviral prophylaxis and none had HBV reactivation).
  • Lake AC. Hepatitis B reactivation in a long-term nonprogressor due to nivolumab therapy. AIDS. 2017;31:2115–2118. [PubMed: 28906278]
    (72 year old man with HIV infection, recurrent metastatic lung cancer and anti-HBc without HBsAg was started on dolutegravir and abacavir and then on nivolumab and was found to have acute liver injury 1 month later [bilirubin 0.5 mg/dL, ALT 332 UL, Alk P 205 U/L, HBsAg positive and HBV DNA > 170 million IU/mL], started on tenofovir and later tolerated restarting nivolumab).
  • 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).
  • 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).
  • Zarrabi K, Wu S. Risk of liver toxicity with nivolumab immunotherapy in cancer patients. Oncology. 2018;94:259–273. [PubMed: 29539626]
    (Meta-analysis of 27 clinical trials of nivolumab cancer chemotherapy found incidence of any ALT elevation to be 5% and ALT elevation above 5 times ULN 1.7%, with higher rates of any ALT elevations in 3 trials of its combination with ipilimumab [24%] vs in 17 trials of nivolumab monotherapy [3.5%]).
  • 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 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).
  • Matsubara T, Nishida T, Higaki Y, Tomita R, Shimakoshi H, Shimoda A, Osugi N, et al. Nivolumab induces sustained liver injury in a patient with malignant melanoma. Intern Med. 2018;57:1789–1792. [PMC free article: PMC6047996] [PubMed: 29434164]
    (42 year old man with metastatic melanoma developed ALT elevations after 17 cycles [1 year] of nivolumab therapy [ALT initially 380 rising to 693 U/L, Alk P 373 U/L, bilirubin 0.6 mg/dL, ANA negative], with slow response to corticosteroid therapy, ALT falling to near normal by 4 months but remaining mildly elevated after stopping).
  • 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 16-151 [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 to 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).
  • 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).
  • Kashima J, Okuma Y, Shimizuguchi R, Chiba K. Bile duct obstruction in a patient treated with nivolumab as second-line chemotherapy for advanced non-small-cell lung cancer: a case report. Cancer Immunol Immunother. 2018;67:61–65. [PubMed: 28913619]
    (63 year old Japanese man with refractory lung adenocarcinoma was found to have a dilated gallbladder without gallstones on routine CT scan of the chest after 4 cycles of nivolumab, subsequently he developed abdominal discomfort and imaging suggesting obstruction of lower end of common bile duct but none found of endoscopic imaging [ALT 92 U/L, Alk P 1543 U/L], improving temporarily with stenting and then more completely with high dose prednisone).
  • Kuraoka N, Hara K, Terai S, Yatabe Y, Horio Y. Peroral cholangioscopy of nivolumab-related (induced) ulcerative cholangitis in a patient with non-small cell lung cancer. Endoscopy. 2018;50:E259–E261. [PubMed: 29969801]
    (69 year old man with advanced, refractory adenocarcinoma of the lung, developed rash after 3rd course of nivolumab with elevations in ALT and Alk P not responsive to prednisolone, imaging showing hypertrophy and dilatation of extrahepatic bile ducts without obstruction, endoscopy demonstrating yellow plaques and inflammation of biliary duct epithelium resulting in progressive cholestasis and death 3 months later).
  • 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 pathology of checkpoint inhibitor induced immune adverse events with acute hepatitis and acute cholangitic patterns found on liver biopsy).
  • Pandey A, Ezemenari S, Liaukovich M, Richard I, Boris A. A rare case of pembrolizumab-induced reactivation of hepatitis B. Case Rep Oncol Med. 2018;2018:5985131. [PMC free article: PMC6207901] [PubMed: 30416833]
    (51 year old man with metastatic lung cancer developed liver injury after 1st dose of pembrolizumab and was found to have reactivation of HBV [bilirubin normal, ALT 528 rising to 994 U/L, Alk P normal, HBsAg positive, HBeAg negative, HBV DNA > 170 million IU/mL], responding to tenofovir therapy, and later restarted on checkpoint inhibitor therapy).
  • Zhang X, Zhou Y, Chen C, Fang W, Cai X, Zhang X, Zhao M, et al. Hepatitis B virus reactivation in cancer patients with positive Hepatitis B surface antigen undergoing PD-1 inhibition. J Immunother Cancer. 2019;7:322. [PMC free article: PMC6873745] [PubMed: 31753012]
    (Among 114 HBsAg-positive Chinese patients undergoing checkpoint inhibitor therapy for advanced malignancies, 6 developed HBV reactivation [1 of 85 on prophylaxis vs 5 of 29 not] after 3-35 [median=18] weeks of therapy with peak ALT 28 to 465 U/L, HBV DNA 1,800 to 60 million IU/mL [all were undetectable at baseline], none with jaundice, 5 treated with rapid improvement, all 6 recovered).
  • 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).
  • Fouchard M, Jantzem H, Quere G, Descourt R, Robinet G, Poureau PG. Three cases of immune cholangitis related to anti-programmed cell death and programmed cell death ligand agents for the treatment of non-small cell lung cancer. Eur J Cancer. 2019;115:107–110. [PubMed: 31132740]
    (3 patients with metastatic lung cancer developed cholangitis 2, 4 and 9 months after starting checkpoint inhibitor therapy [nivolumab, durvalumab/tremelimumab, pembrolizumab] presenting with abdominal pain and fever, modest ALT but marked Alk P elevations and minimal jaundice; imaging showing biliary dilation and thickening of the gallbladder wall, biopsies showing inflammation with CD8+ lymphocytes, and slow clinical response to corticosteroids but long-term remission in cancer).
  • Oda H, Ishihara M, Miyahara Y, Nakamura J, Kozuka Y, Iwasa M, Tsunoda A, et al. First case of cytokine release syndrome after nivolumab for gastric cancer. Case Rep Oncol. 2019;12:147–156. [PMC free article: PMC6477485] [PubMed: 31043953]
    (43 year old man with advanced, refractory gastric cancer developed high fever, fatigue and jaundice 8 days after starting nivolumab [ALT 31 rising to ~160 U/L, Alk P 598 rising to 1400 U/L, bilirubin 3.7 rising to 8 mg/dL], with concurrent elevations in serum levels of interferon gamma, TNF alpha and ferritin, responding minimally to corticosteroid therapy and dying before recovery of progressive cancer).
  • 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).
  • Kopecký J, Kubecek O, Geryk T, Podhola M, Ziaran M, Priester P, Hanisova M, et al. Hepatic injury induced by a single dose of nivolumab - a case report and literature review. Klin Onkol. 2019 ;32(:133-138. [PubMed: 30995854]
    (38 year old female with metastatic melanoma developed liver injury 14 days after an initial infusion of nivolumab [bilirubin 6.1 rising to 21 mg/dL, ALT 720 rising to 3012 U/L, GGT >2000 U/L], with only a partial response to corticosteroids and mycophenolate and death from progressive disease 2 months later).
  • Sawada K, Shonaka T, Nishikawa Y, Hasegawa K, Hayashi H, Hasebe T, Nakajima S, et al. Successful treatment of nivolumab-related cholangitis with prednisolone: a case report and review of the literature. Intern Med. 2019;58:1747–1752. [PMC free article: PMC6630117] [PubMed: 30799364]
    (76 year old man with advanced gastric cancer developed marked Alk P elevations after 4 cycles of nivolumab [bilirubin 0.8 mg/dL, ALT 68 U/L, Alk P 2427 U/L], biopsy showing eosinophilic cholangitis and prednisolone therapy followed by a rapid improvement).
  • 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 21-94 [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).
  • Onoyama T, Takeda Y, Yamashita T, Hamamoto W, Sakamoto Y, Koda H, Kawata S, et al. Programmed cell death-1 inhibitor-related sclerosing cholangitis: a systematic review. World J Gastroenterol. 2020;26:353–365. [PMC free article: PMC6969883] [PubMed: 31988594]
    (Review of literature on secondary sclerosing cholangitis due to anti-PD-1/PD-L1 therapy identified 31 cases with male:female ratio of 2:1, median age 67 [range 43-89] years, arising after a median of 5.5 [range 1-27] cycles of nivolumab [19], pembrolizumab [10], avelumab [1], or durvalumab [1], with median bilirubin 0.8 [0.3-15.9] mg/dL, ALT 125 [31-1536] U/L, AST 129 [49-961] U/L, Alk P 1543 [237-5066] U/L, GGT 452 [114-2094] U/L, cholangiography demonstrating biliary dilation without obstruction [77%], hypertrophy of the extrahepatic biliary tree [90%], and biliary strictures [30%] and biopsy demonstrating CD8+ infiltrates around bile ducts, and adequate response to corticosteroids in only 11%).
  • 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).
  • 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 PD-1 and PD-L1 blockers, the abnormalities arising after a median 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).
  • Mathew Thomas V, Bindal P, Ann Alexander S, McDonald K. Nivolumab-induced hepatitis: A rare side effect of an immune checkpoint inhibitor. J Oncol Pharm Pract. 2020;26:459–461. [PubMed: 30909794]
    (74 year old woman with recurrent, metastatic renal cell carcinoma developed jaundice 2 weeks after starting nivolumab [bilirubin 2 mg/dL, ALT 112 U/L, Alk P not given] and was treated with high doses of corticosteroids which led to improvement, but she died shortly thereafter of gastrointestinal bleeding and multiorgan failure ).
  • Nordness MF, Hamel S, Godfrey CM, Shi C, Johnson DB, Goff LW, O'Dell H, et al. Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: Are checkpoint inhibitors safe for the pretransplant patient? Am J Transplant. 2020;20:879–883. [PMC free article: PMC10176099] [PubMed: 31550417]
    (65 year old man with cirrhosis due to successfully treated chronic hepatitis C and hepatocellular carcinoma on long term nivolumab therapy underwent liver transplantation but developed severe hepatic necrosis starting on post-transplant day 5 [AST 6,000 rising to 19,000 U/L, bilirubin 2.0 rising to 17.0 mg/dL and INR to 10], leading to multiorgan failure and death).
  • Sawada K, Hayashi H, Nakajima S, Hasebe T, Fujiya M, Okumura T. Non-alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor. J Gastroenterol Hepatol. 2020 Jun;35(6):1042–1048. [PubMed: 31752049]
    (Among 135 patients with cancer treated with nivolumab or pembrolizumab, 8 developed immune mediated hepatitis of whom 3 [37.5%] had preexisting chronic liver disease versus 14 of the total [10.3%]).
  • Anugwom C, Leventhal T. Nivolumab-induced autoimmune-like cholestatic hepatitis in a liver transplant recipient. ACG Case Rep J. 2020;7:e00416. [PMC free article: PMC7363460] [PubMed: 32766358]
    (62 year old man with alcohol and HCV related cirrhosis and HCC underwent liver transplantation but had recurrence of HCC and de novo metastatic NSCLC after transplant, which was refractory to conventional chemotherapy and who developed severe cholestatic hepatitis within 2 months of starting nivolumab [bilirubin 8.3 rising to 24 mg/dL, ALT 1265 U/L, Alk P 813 U/L], with subsequent infection, multiorgan failure and gastrointestinal bleeding and death within two weeks of presentation).
  • 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 developed high grade liver injury but 19 were considered mild, 7 moderate, 1 severe and 1 fatal).
  • Vitale G, Lamberti G, Comito F, Di Nunno V, Massari F, Morelli MC, Ardizzoni A, et al. Anti-programmed cell death-1 and anti-programmed cell death ligand-1 immune-related liver diseases: from clinical pivotal studies to real-life experience. Expert Opin Biol Ther. 2020;20:1047–1059. [PubMed: 32425081]
    (Review of the hepatic complications of anti-PD-1 and anti-PD-L1 checkpoint inhibitors that includes immune mediated hepatitis [typically panlobular inflammation and injury], small and large duct cholangitis [similar to primary biliary and sclerosing cholangitis], immune mediated cholecystitis, nodular regenerative hyperplasia and vanishing bile duct syndrome).
  • 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).
  • 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]).
  • Lee PC, Chao Y, Chen MH, Lan KH, Lee IC, Hou MC, Huang YH. Risk of HBV reactivation in patients with immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. J Immunother Cancer. 2020;8:e001072. [PMC free article: PMC7462159] [PubMed: 32863270]
    (Among 62 Taiwanese patients with HBsAg or anti-HBc without HBsAg treated with checkpoint inhibitors for advanced HCC, reactivation of HBV rose in none of 56 given prophylaxis vs 1 of 6 not given antiviral prophylaxis: the one case in an HBsAg positive patient with HBV DNA 8960 IU/mL at baseline rising to 168,000 IU/mL, peak ALT 174U/L, bilirubin 5.2 mg/dL, resolving with tenofovir 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).
  • 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%]).
  • 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).
  • Yoshikawa Y, Imamura M, Yamaoka K, Kosaka Y, Murakami E, Morio K, Fujino H, et al. A case with life-threatening secondary sclerosing cholangitis caused by nivolumab. Clin J Gastroenterol. 2021;14:283–287. [PubMed: 33200345]
    (75 year old man with metastatic NSCLC developed marked liver abnormalities after 3 cycles of nivolumab [bilirubin 0.6 mg/dL, ALT 162 U/L, Alk P 1721 U/L, ANA negative] with biliary imaging showing diffuse dilation of the common bile duct and multifocal stenosis, with progressive cholestatic liver injury and death from liver failure despite therapy with corticosteroids and ursodiol).
  • 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 prednisone 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 VigiBase™ 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).
  • Aya F, González-Navarro EA, Martínez C, Carcelero E, Arance A. Safe anti-programmed cell death-1 rechallenge with antibody switching after immune-related adverse events: brief communication. Immunotherapy. 2021;13:745–752. [PubMed: 33906373]
    (68 year old woman with metastatic melanoma developed ALT elevations [215 U/L] after an initial dose of nivolumab, which resolved rapidly with prednisone therapy and she was later tolerated pembrolizumab without recurrent hepatic injury).
  • da Silva JA, Falcão D, Cardoso C, Pires AL, Araújo A, Castro-Poças F. Hepatic immune-mediated adverse effects of immune checkpoint inhibitors: analysis of real-life experience. Ann Hepatol. 2021;26:100561. [PubMed: 34653687]
    (Among 151 patients treated with checkpoint inhibitors, 8 [5%] developed liver injury, 5 due to metastases and 3 from immune mediated hepatitis, 2 from nivolumab and 1 pembrolizumab, with latency of 84 days, all three cholestatic and responding to immunosuppression).
  • Arai K, Matsuda M, Nakayasu H, Meguro S, Kurokami T, Kubota A, Iwasaki T, et al. Nivolumab-induced liver injury with a steroid-refractory increase in biliary enzymes, in a patient with malignant mesothelioma: an autopsy case report. Clin Case Rep. 2021;9:e05174. [PMC free article: PMC8697699] [PubMed: 34987810]
    (75 year old man with refractory, advanced mesothelioma, developed liver injury during a second cycle of nivolumab [ALT 397 U/L, Alk P 272 U/L, bilirubin 0.4 to 0.7 mg/dL] who had progressive liver injury despite immunosuppression).
  • 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).