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Immunotherapy can inflame the liver, usually without symptoms, so liver blood tests are checked before every dose. If the tests rise, immunotherapy is paused and steroids are given; severe cases mean stopping immunotherapy. Yellow skin or eyes, dark urine or pale stools need a call to your cancer team the same day.
Hepatitis (raised ALT or AST) occurs in about 5% on PD-(L)1 or CTLA-4 inhibitors alone and 19% on combinations (9% grade 3 or more), typically 1 to 15 weeks after starting (SITC 2021); AASLD 2023 gives 1 to 15% across trials and observational studies, mostly asymptomatic in the first 6 to 12 weeks. Only about 30% of demonstrable liver injury in advanced cancer is drug-induced, so metastases, sepsis and other causes are excluded with imaging (AASLD).
SITC 2021: liver tests before every infusion. From grade 2, a workup including clotting, bilirubin, iron studies, an autoimmune hepatitis panel and viral hepatitis serology; imaging for grade 3 or more if there is liver disease or suspected metastases. Recheck weekly for grades 1 to 2, every 1 to 2 days for grade 3 or more. Grade 2: prednisone 0.5 to 1 mg/kg/day; grades 3 to 4: methylprednisolone 1 to 2 mg/kg/day; taper over 4 to 6 weeks once tests are grade 1 or less (LE: 1). No improvement in 10 to 14 days, or relapse on taper: mycophenolate mofetil (LE: 4). Never infliximab (LE: 1).
AASLD 2023 agrees on grade 2 (withhold and consider prednisone 0.5 to 1.0 mg/kg/day), and for grade 3 or more permanently discontinues the checkpoint inhibitor, with intravenous steroids at 1 to 1.5 mg/kg/day and admission for jaundice, keeping liver biopsy for persistent grade 3 injury or jaundice despite steroids. ESMO 2022 could not be read.
Why: Immune hepatitis is usually silent and is found on the blood test.
“Liver biochemical tests (aka liver function tests (LFTs)) should be checked prior to each ICI infusion.”
Why: These separate immune hepatitis from viral hepatitis, other autoimmune liver disease and iron overload.
“Diagnostic workup for grade ≥2 liver toxicity should include ALT, AST, alkaline phosphatase, prothrombin time/international normalized ratio (PT/INR) serum bilirubin, iron studies, autoimmune hepatitis panel (antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), antimitochondrial antibody (AMA), peripheral ANCA (p-ANCA), and antismooth muscle antibody (ASMA)), and viral hepatitis panel.”
Why: In people with advanced cancer, most liver test rises are not caused by the drug.
“Recent studies suggest that bona fide DILI is only responsible for 30% of cases of demonstrable liver injury in patients with advanced cancer, whereas hepatic metastases, sepsis, and other causes of liver disease account for the remainder, emphasizing the importance of contrast‐enhanced CT and MR scanning in evaluation of these patients.”
American Association for the Study of Liver Diseases, Hepatology 2023
Why: Severe hepatitis can progress within days.
“LFTs should be rechecked weekly for patients experiencing grade 1–2 liver toxicities, and should be rechecked every 1–2 days for patients with liver toxicities of grade ≥3.”
Why: Mild rises often settle without stopping; a moderate rise needs a pause.
“For patients with grade 1 liver injury (ALT > 1–3× ULN and/or total bilirubin > 1–1.5× ULN), continued therapy with more frequent laboratory monitoring is advisable.”
American Association for the Study of Liver Diseases, Hepatology 2023
Why: Steroids calm the immune attack on the liver; the dose rises with severity.
“Grade 2 liver toxicity should be treated initially with prednisone 0.5–1 mg/kg/day (or equivalent), and grades 3 and 4 should be treated initially with methylprednisolone 1–2 mg/kg/day (or equivalent).”
Why: A fast taper risks rebound hepatitis.
“Corticosteroids should be tapered over a period of 4–6 weeks after LFTs revert to grade ≤1”
Why: Steroid-refractory hepatitis needs a second immunosuppressant.
“If ALT or AST results do not improve to grade ≤1 within 10–14 days of corticosteroid initiation, or if liver toxicity recurs after steroid taper, mycophenolate mofetil (1–2 g divided two times per day) may be given”
Why: Infliximab can itself damage the liver.
“Infliximab should not be used in patients with liver toxicity, given the risk for hepatotoxicity”
Why: Biopsy rarely changes early management but helps when steroids are failing.
“Liver biopsy typically demonstrates lobular or periportal hepatitis and is generally not recommended unless patients have persistent grade 3 hepatotoxicity or jaundice despite corticosteroids.”
American Association for the Study of Liver Diseases, Hepatology 2023
Why: Hepatitis can rebound after steroids stop.
“After tapering of immunosuppression, the liver tests should continue to be monitored every 2–4 weeks because of the risk of rebound hepatitis.”
American Association for the Study of Liver Diseases, Hepatology 2023
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
SITC 2021 and AASLD 2023 agree on the frame: liver tests before every dose, exclusion of metastases, infection and viral hepatitis, prednisone 0.5 to 1 mg/kg/day for grade 2, and mycophenolate mofetil when steroids fail. They differ for grade 3 or more: SITC gives methylprednisolone 1 to 2 mg/kg/day and does not state discontinuation in its hepatitis section; AASLD permanently discontinues the checkpoint inhibitor and considers intravenous steroids at 1 to 1.5 mg/kg/day with admission for jaundice. SITC grades the 4 to 6 week taper LE: 1 and the warning against infliximab LE: 1; AASLD's guidance is expert consensus. ASCO 2021 permanently stops checkpoint inhibitors after most grade 4 toxicities; its hepatitis table and ESMO 2022 were not read.
SITC, Journal for ImmunoTherapy of Cancer 2021 · American Association for the Study of Liver Diseases, Hepatology 2023 · ASCO, Journal of Clinical Oncology 2021 · ESMO, Annals of Oncology 2022
Where it differs: For ALT 5 to 20 times the upper limit and/or bilirubin 3 to 10 times, or symptomatic liver dysfunction, permanently discontinues the checkpoint inhibitor and considers intravenous steroids at 1 to 1.5 mg/kg/day with hospital admission for jaundice; names azathioprine as well as mycophenolate for steroid-refractory disease.
Evidence: Expert-panel practice guidance commissioned instead of a guideline because randomised trials are lacking.
American Association for the Study of Liver Diseases, Hepatology 2023
Where it differs: Lists tacrolimus and antithymocyte globulin as other agents to consider, and a liver biopsy if mycophenolate fails to bring tests to grade 1 within 10 to 14 days.
Evidence: Not graded (expert consensus), based on use in autoimmune hepatitis.
| Recommendation | Grade, as printed | Source |
|---|---|---|
| Steroid taper over 4 to 6 weeks after liver tests return to grade 1 or less | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Mycophenolate mofetil for steroid-refractory or recurrent hepatitis | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| No infliximab in liver toxicity | LE: 1 | SITC, Journal for ImmunoTherapy of Cancer 2021 |
| Grade 3 or more: permanently discontinue the checkpoint inhibitor “For patients with grade 3 or higher hepatotoxicity (ALT 5–20× ULN and/or bilirubin 3–10× ULN or symptomatic liver dysfunction), the ICI should be permanently discontinued, and i.v. steroids at a dose of 1–1.5 mg/kg per day along with hospitalization for patients with jaundice should be considered.” | expert opinion (practice guidance) | American Association for the Study of Liver Diseases, Hepatology 2023 |
| General rule: permanent discontinuation after grade 4 | expert consensus | ASCO, Journal of Clinical Oncology 2021 |
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Shares Methylprednisolone, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab and the tags protocol, irae, acute-oncology.
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Shares Methylprednisolone, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab and the tags protocol, irae, acute-oncology.
Shares ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab, Tremelimumab and the tags protocol, irae.
Shares Immune-related diarrhoea and colitis from checkpoint inhibitors, by grade, Society for Immunotherapy of Cancer, Avelumab, Tremelimumab and the tags protocol, irae.
Shares Methylprednisolone, ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab and the tags protocol, irae.
Shares ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors, Society for Immunotherapy of Cancer, Avelumab, Tremelimumab and the tags protocol, irae.