The expanding use of immune checkpoint inhibitors (ICIs) has increased immune‑related hepatotoxicity (ChILI). Despite major guidelines, no standardized treatment consensus exists. Key controversies include immunosuppression thresholds, biopsy indications, second‑line therapies, and rechallenge criteria. Corticosteroids remain first‑line, but 20–30% are steroid‑refractory. Ursodeoxycholic acid (UDCA) shows promise in cholestatic ChILI. Rechallenge is increasingly considered, with recurrence rates of 22–31%, mostly mild. In HCC patients with cirrhosis, hepatotoxicity is hard to distinguish from tumor progression, emphasizing biopsy and multidisciplinary evaluation. Future studies must clarify algorithms and rechallenge safety.
Introduction
ICIs (anti‑PD‑1/PD‑L1/CTLA‑4) are widely used, including in HCC, leading to more ChILI. Diagnostic criteria exist, but grading, treatment thresholds, and rechallenge recommendations vary across ASCO, ESMO, SITC, AGA, and NCCN guidelines. Real‑world data differ from trials, and differentiating ChILI from tumor progression or drug interactions remains challenging, especially in underlying liver disease.
Divergent Guideline Recommendations
Corticosteroids: ASCO/SITC start early at grade 2 without improvement; ESMO/NCCN are more conservative.
Biopsy: ASCO/ESMO optional; SITC/AGA strongly encourage for atypical/prolonged cases or cirrhosis.
Second‑line: Mycophenolate mofetil (MMF) is common but data limited. Infliximab is generally contraindicated, though one study reported response without hepatotoxicity.
Rechallenge: ASCO/SITC permit after resolution of grade 2; ESMO cautious; AGA discourages after grade ≥3 or second‑line immunosuppression; NCCN only discontinues for grade 4.
Steroid‑Refractory ChILI
While guidelines cite 70–80% response, real‑world shows significant steroid‑refractory cases. Mechanisms include severe T‑cell damage, cholangitic patterns (small‑duct ductopenia), delayed recognition, underlying liver disease, and alternative immune pathways.
Second‑Line and Alternative Therapies
MMF most used but unproven.
UDCA: A retrospective study (27 patients, cholestatic ChILI) showed 81.5% biochemical improvement with UDCA alone, but macroscopic bile duct injury (37%) had 75% recurrence. UDCA plus corticosteroids appears safer than monotherapy.
ChILI in HCC and Cirrhosis
Incidence 5–20%, higher with combination ICI regimens. In cirrhotic patients, distinguishing hepatotoxicity from tumor progression or viral flare is difficult, delaying immunosuppression. Steroid non‑response 15–30%.
Rechallenge Evidence
Patrinely et al. (2021) (n=145 initial, 66 rechallenged): recurrence 25.8%, similar severity.
Hountondji et al. (2024) (51 rechallenged): recurrence 23%, mostly mild; cholestatic injury associated.
Peeraphatdit et al. (2020) (14 rechallenged): recurrence 28%.
Simonaggio et al. (2019) (22 hepatitis patients): recurrence 17%.
Riveiro‑Barciela et al. (2023) (prospective) (23 with prior grade 3–4): recurrence 35%, manageable, no fatalities; elevated ANA and autoimmune disease predicted recurrence; recurrent patients had better oncologic outcomes.
Overall recurrence 20–35%, mostly mild, no fatal recurrences reported.
Conclusions
Guideline discrepancies reflect limited high‑level evidence. In HCC with cirrhosis, ICIs offer benefit but hepatotoxicity risk requires careful assessment. Rechallenge after ChILI is feasible in selected patients, with low recurrence and mild relapses. Decisions must individualize risk versus potential survival benefit. Future studies need standardized algorithms, biopsy roles, and rechallenge safety criteria.
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The study was recently published in the Journal of Clinical and Translational Hepatology .
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