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CHECKPOINT-INHIBITOR TOXICITY

Liver immune-related adverse events

Usually asymptomatic transaminase elevation found on pre-cycle bloods, most often in the first 6-12 weeks. Steroid-responsive, and the alternative causes of liver injury have to be excluded first.

Infliximab is contraindicated here, and is carried on the card as a named prohibition rather than left silent — it is standard second line for colitis, which ASCO manages in the same chapter, so the neighbouring organ's playbook is the foreseeable error. The rungs name their CTCAE grades without the xULN bands that define them; see each entry's omitted rows. Educational reference, not medical advice.

Anchored on the ASCO, ESMO and SITC chapters for this organ. Every source is named beside the position it supports, and labelled with what kind of source it is.

At a glance

ICI-associated hepatitis

Also called: IR-hepatitis · immune-related hepatitis · checkpoint inhibitor hepatitis · ICI hepatotoxicity

Usually asymptomatic transaminase elevation found on pre-cycle bloods, most often in the first 6-12 weeks; steroid-responsive, but infliximab is contraindicated.

commonseriousonset: weeks 6–12

Reported frequency

  • 5%-10% — any-grade hepatitis incidence, ICI monotherapy

    of patients during ICI monotherapy · ESMO IR-hepatotoxicity chapter

    guideline · 36270461

  • 2%-10% — any-grade hepatotoxicity incidence, ICI monotherapy

    of patients treated with ipilimumab, nivolumab, and pembrolizumab monotherapy · ASCO hepatic paragraph — a lower floor than ESMO reports for the same setting

    guideline · 34724392

  • 5% — any-grade hepatitis incidence, PD-(L)1 inhibitors

    of patients treated with PD-(L)1 inhibitors · SITC hepatitis section, which defines hepatitis as ALT/AST elevation. Its sibling row carries SITC's CTLA-4 stratum from the same sentence; both are class-specific, not class-wide

    guideline · 34172516

  • 5% — any-grade hepatitis incidence, CTLA-4 inhibitors

    of patients treated with CTLA-4 inhibitors · SITC hepatitis section

    guideline · 34172516

  • 25%-30% — any-grade hepatitis incidence, combination ICI

    of patients during anti-PD(L)1 plus anti-CTLA-4 combination therapy · ESMO IR-hepatotoxicity chapter; ASCO reports the same range for ipilimumab plus nivolumab

    guideline · 36270461

  • 19% — any-grade hepatitis incidence, combination ICI

    of patients treated with combination ICIs · SITC hepatitis section — materially lower than the ESMO and ASCO figure above

    guideline · 34172516

  • 13.3% in primary liver cancers versus 4.92% in other solid tumors — all-grade ALT elevation, primary liver cancer versus other solid tumours

    of patients in ICI trials pooled by tumour type · 117 pooled ICI trials, 7 of them in primary liver cancer. Carried because the headline pooled rate is a blend of the two and applies cleanly to neither. The only strata the source names are anti-PD-1 and anti-PD-L1, so it carries no CTLA-4 authority

    pooled meta-analysis · 33968750

Severity and class

  • 1%-2% — grade 3 hepatitis incidence, ICI monotherapy

    of patients during ICI monotherapy · ESMO IR-hepatotoxicity chapter. Monotherapy only — the same sentence reports 15% on combination therapy, which is in the incidence list rather than here because one field cannot carry both without silently generalizing one class

    guideline · 36270461

  • 3% — death from hepatitis or its treatment

    of 164 patients with ICI-associated hepatitis · Retrospective multicentre cohort across six international institutions

    cohort · 33628621

  • 6.01% for anti-PD-1 versus 3.60% for anti-PD-L1 — all-grade ALT elevation, anti-PD-1 versus anti-PD-L1

    of patients in ICI trials pooled by agent class · 117 ICI trials pooled in a systematic review and meta-analysis

    pooled meta-analysis · 33968750

Onset

SITC puts the typical window at 1-15 weeks after treatment and notes onset may be delayed by months or years. Median time to onset was 61 days in a multicentre cohort, and ASCO describes onset developing predominantly within the first 6-12 weeks after initiation. Most patients in that cohort presented already at grade 2 (30.5%) or grade 3 (45.7%), so a first abnormal result is often not a mild one.

Presentation

  • · Most often asymptomatic — 46.2% of a multicentre cohort — and detected on pre-cycle liver biochemistry rather than by symptoms
  • · Where symptoms occur: fatigue or anorexia, nausea or emesis, abdominal or back pain, arthralgias or myalgias
  • · Fever, malaise, abdominal discomfort and jaundice are the ESMO-listed presentation; ASCO adds dark tea-coloured urine and easy bleeding or bruising
  • · Transaminase elevation is the dominant laboratory signature, with ALT elevation in 5.29% and AST elevation in 5.88% of pooled trial patients

Differential

  • · Alternative causes of liver injury, which ESMO requires be excluded: medication, alcohol, viruses, metabolic disorders, autoimmune disease, vascular disease and tumour involvement
  • · Hepatic metastatic progression rather than toxicity — the reason SITC asks for abdominal imaging at grade 3 or above in patients with pre-existing liver disease or concern for progression
  • · Cholangitis, which ESMO separates from hepatitis: gamma-glutamyltransferase and alkaline phosphatase rise more prominently than transaminases

Work-up

  • Serum transaminases, alkaline phosphatase and bilirubin before every cycle · All patients

    The detection modality for an irAE that is usually asymptomatic. Both ESMO and SITC schedule it per cycle rather than per symptom.

    36270461

  • Prothrombin time / INR · Grade 2+

    Part of SITC's grade 2 or higher diagnostic work-up.

    34172516

  • Factor V · Grade 2+

    ESMO's, not SITC's — a full-text search of the SITC guideline returns no mention of factor V. ESMO states bilirubin, prothrombin time and factor V add prognostic information, without assigning a grade; it is carried at the grade where the chapters first withhold the ICI.

    36270461

  • Autoimmune hepatitis panel (ANA, ANCA, AMA, p-ANCA, ASMA) and viral hepatitis panel · Grade 2+

    SITC's grade 2 or higher exclusion work-up, separating an immune-related hepatitis from the autoimmune and viral causes it mimics.

    34172516

  • Iron studies · Grade 2+

    Part of the same SITC grade 2 or higher panel.

    34172516

  • Abdominal imaging (CT or MRI) · Grade 3+

    Considered at grade 3 or above where there is pre-existing liver disease or concern for disease progression or liver metastases — that is, to answer whether this is toxicity at all.

    34172516

  • Liver biopsy · If refractory

    Considered for persistent or steroid-refractory hepatitis when bloods and imaging are inconclusive, or to identify the cause of steroid failure. ESMO reports the commonest pathological feature as lobular hepatitis with necrosis, either spotty or confluent.

    36270461

Sources differ here

Work-up

  • SITC 2021 (society guideline) — LFTs rechecked weekly for grade 1-2 liver toxicity
  • ESMO 2022 (society guideline) — monitoring of transaminases and bilirubin twice weekly at grade 2

Grade ladder

Grade 1

Continue the ICIOutpatient

Grade 1 — transaminase or bilirubin elevation meeting CTCAE grade 1.

No corticosteroid at this grade

ESMO recommends monitoring liver enzymes every 1-2 weeks with no need to hold ICI therapy at grade 1, and SITC starts corticosteroids only at grade 2 or above. This is a sourced absence of steroids, not an unquoted dose.

  • · Monitor liver enzymes every 1-2 weeks (ESMO); SITC rechecks LFTs weekly for grade 1-2
  • · Begin excluding alternative causes of liver injury — medication, alcohol, viruses, metabolic and vascular disease, tumour involvement

Escalate when: Rise to grade 2, or enzymes that do not settle on scheduled monitoring.

Grade 2

Hold the ICIOutpatient

Grade 2 — CTCAE grade 2 transaminase or bilirubin elevation. Both ESMO and SITC start corticosteroids here.

Corticosteroid 0.5–1 mg/kg/day (oral)

Taper over 4–6 weeks, starting once: LFTs revert to grade 1 or lower.

No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.

  • · Monitor transaminases and bilirubin twice weekly (ESMO); SITC rechecks LFTs weekly at this grade
  • · Complete the exclusion work-up before attributing the event to the ICI

Sources differ here

Corticosteroid dose

  • ESMO 2022 (society guideline) — CS 0.5-1 mg/kg/day should be considered
  • SITC 2021 (society guideline) — prednisone 0.5-1 mg/kg/day (or equivalent)

Escalate when: Progression to grade 3, or ALT/AST not improving to grade 1 or lower within 10-14 days of starting corticosteroids.

Grade 3

Hold — consider permanent discontinuationConsider admission

Grade 3 — CTCAE grade 3 transaminase or bilirubin elevation. ESMO and SITC both manage grade 3 and 4 under one dosing recommendation, so this rung and the one below share a dose and diverge on the ICI decision.

Corticosteroid 1–2 mg/kg/day (intravenous)

Taper over 4–6 weeks, starting once: LFTs revert to grade 1 or lower.

No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.

Second line

  • Infliximab — do not use — Never for this indication; listed because it is standard second-line for ICI colitis.Should not be used in patients with liver toxicity given the risk of hepatotoxicity (SITC, evidence level 1); ASCO likewise does not recommend it, citing concern for liver toxicity.
  • Mycophenolate mofetil — 1000 mg twice daily (ESMO); 1-2 g divided twice daily (SITC) — No response to corticosteroids within 2-3 days (ESMO), or ALT/AST not improved to grade 1 or lower within 10-14 days of starting corticosteroids, or recurrence after the taper (SITC).
  • Tocilizumab 8 mg/kg — No response to corticosteroids within 2-3 days.
  • Tacrolimus — No response to corticosteroids within 2-3 days; also listed by SITC among agents to consider.
  • Azathioprine — No response to corticosteroids within 2-3 days.
  • Ciclosporin — No response to corticosteroids within 2-3 days.
  • Anti-thymocyte globulin — No response to corticosteroids within 2-3 days; also listed by SITC among agents to consider.
  • · Recheck LFTs every 1-2 days
  • · Consider hospitalisation
  • · Second-line immunosuppression was required in 22.6% of a multicentre hepatitis cohort, so plan for it rather than treating it as exceptional

Escalate when: No response to corticosteroids within 2-3 days, or progression to grade 4 — either one moves to second-line immunosuppression.

Grade 4

Discontinue permanentlyConsider admission

Grade 4 — life-threatening liver injury or hepatic decompensation.

Corticosteroid 1–2 mg/kg/day (intravenous)

Taper over 4–6 weeks, starting once: LFTs revert to grade 1 or lower.

No step size or interval is carried: the source guideline states a total window and a response marker, and does not specify a cadence.

Second line

  • Infliximab — do not use — Never for this indication; listed because it is standard second-line for ICI colitis.Should not be used in patients with liver toxicity given the risk of hepatotoxicity (SITC, evidence level 1); ASCO likewise does not recommend it, citing concern for liver toxicity.
  • Mycophenolate mofetil — 1000 mg twice daily (ESMO); 1-2 g divided twice daily (SITC) — No response to corticosteroids within 2-3 days, or ALT/AST not improved to grade 1 or lower within 10-14 days.
  • Tacrolimus or anti-thymocyte globulin — No response to corticosteroids within 2-3 days. Both societies name these two.
  • Tocilizumab 8 mg/kg, azathioprine or ciclosporin — No response to corticosteroids within 2-3 days. ESMO's list only — SITC's hepatitis section does not name these three, and its mentions of them elsewhere belong to other organs.
  • · Admit; recheck LFTs every 1-2 days
  • · Hepatology involvement
  • · ASCO recommends permanent discontinuation for grade 4 toxicities in general — this is its cross-toxicity rule, not a statement specific to the liver

Escalate when: Already the top rung. Death attributed to hepatitis or its treatment occurred in 3% of a multicentre cohort, which is the weight this rung carries.

Rechallenge

individualized

About a quarter of rechallenged patients in the multicentre cohort had recurrent hepatitis, and a pharmacovigilance analysis cited by ASCO puts hepatitis among the irAEs with a raised recurrence rate on rechallenge (ROR 3.38, 95% CI 1.31 to 8.74). Neither finding forecloses rechallenge; both argue against doing it without a reason and a monitoring plan.

  • 25.8% — recurrent hepatitis after ICI rechallenge

    of 66 rechallenged patients (40 initially grade 1/2, 26 grade 3/4) · Retrospective multicentre cohort of patients with ICI-associated hepatitis

    cohort · 33628621

  • · Liver biochemistry recovered to grade 1 or lower — this is SITC's response marker for the liver; ASCO's resumption rule is a permissive cross-toxicity statement, not a hepatitis-chapter threshold
  • · Alternative causes of liver injury excluded and still excluded
  • · A monitoring schedule agreed before the next dose, given that most recurrences are found on bloods rather than by symptoms

Deliberately not carried

  • ladder[].steroid.taper step cadence — SITC gives the total window and the start trigger — tapered over 4-6 weeks after LFTs revert to grade 1 or lower — and no step size or interval. No anchor guideline states a cadence for any organ, so it is null here as it is on the renal entry, rather than borrowed from the beta taper planner's illustrative figure.
  • onset.medianWeeks — The cohort reports a median of 61 days; converting it into a weeks figure would print a number no source did, so the median is stated in `note` in the unit its source used. The range bounds are NOT omitted — they carry SITC's 1-15 week window. An earlier version of this row also claimed no source gave a range, which was false: SITC states one and is the second-most-cited source on this entry.
  • guidelinePmids — Left empty although all three anchors are rows in guidelines.ts. Their stored keyRecommendation strings are renal-scoped, so linking them here would surface kidney advice on a liver card — the precise substitution assertion 19.5 exists to block. The hepatic chapters are carried in `citations` with their own quotes instead.
  • ladder.g1.steroid dose — Not an unsourced gap: ESMO holds neither the ICI nor a steroid at grade 1 and SITC starts corticosteroids at grade 2 or above, so the rung carries kind: none with those citations rather than kind: unsourced.
  • pulse — No anchor chapter describes pulse methylprednisolone for IR-hepatitis. SITC's switch from prednisone to methylprednisolone at grade 3 is a change of agent at the same 1-2 mg/kg/day, not a pulse, and is not recorded as one.
  • ladder[].steroid.route — The grade 3 and 4 rungs render an intravenous route, and no anchor chapter states one. It is an inference from SITC's switch from prednisone to methylprednisolone — an agent change at the same dose, from which a route does not follow. The rungs keep the route because methylprednisolone is not orally given at these doses in practice, but it is an inference and is recorded here as one.
  • ladder[].gradeDefinition — the xULN bands — Every rung names its CTCAE grade without the transaminase and bilirubin multiples that define it, which makes grades 1-3 circular on their face. CTCAE v5.0 carries those bands, but it has no PubMed record and no anchor chapter reprints them, so entering them would be an uncited number on the field that decides which rung a patient lands on. They are omitted rather than approximated.

Sources

  • Haanen J, et al. (2022) Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-upCited for: Class-stratified incidence of IR-hepatitis, the pre-cycle laboratory schedule, exclusion of alternative causes, and the grade-indexed ICI action, corticosteroid dose and second-line list from the IR-hepatotoxicity chapter.Supporting text: the full text
  • Schneider BJ, et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateCited for: Monotherapy and combination incidence, the 6-12-week onset window, presenting symptoms, the biopsy indication, the infliximab caution, the recurrence-risk signal after rechallenge, and the general grade-4 discontinuation rule. HEPATIC SCOPE, except the last item which ASCO states across toxicities and which is cited as such.Supporting text: the full text + the PubMed abstract (checkable at the link above)
  • Brahmer JR, et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsCited for: Class-stratified incidence, the grade-indexed laboratory work-up and monitoring cadence, the imaging indication, the corticosteroid dose and route by grade, the taper window and its LFT-based start trigger, the mycophenolate trigger, and the infliximab contraindication.Supporting text: the full text
  • Patrinely JR, et al. (2021) A multicenter characterization of hepatitis associated with immune checkpoint inhibitors.Cited for: Median time to onset, the grade distribution at presentation, time to improvement and resolution, second-line requirement, hepatitis-attributed mortality, and the recurrence rate after rechallenge.Supporting text: the PubMed abstract (checkable at the link above)
  • Fu J, Li WZ, McGrath NA, Lai CW, Brar G, Xiang YQ, Xie C (2021) Immune Checkpoint Inhibitor Associated Hepatotoxicity in Primary Liver Cancer Versus Other Cancers: A Systematic Review and Meta-Analysis.Cited for: Pooled transaminase-elevation incidence across ICI trials, the anti-PD-1 versus anti-PD-L1 difference, and the primary-liver-cancer versus other-solid-tumour difference.Supporting text: the PubMed abstract (checkable at the link above)

Educational use only. Educational synthesis of the published literature — not a treatment protocol, dosing guide, or medical advice. Regimens and agents shown are illustrative of what the literature describes; verify against current guidelines (ASON / KDIGO / ASCO / NCCN) and individualize to the patient. Using this site creates no clinician–patient relationship.

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