Targeted drugs and immune checkpoint inhibitors have dramatically improved survival in advanced hepatocellular carcinoma (HCC), yet they frequently cause liver injury – in some combination regimens in more than 50 % of patients. To standardize care and prevent unnecessary treatment interruptions or life-threatening complications, the Chinese Society of Hepatology has published the “Consensus on the Management of Liver Injury Associated with Targeted Drugs and Immune Checkpoint Inhibitors for Hepatocellular Carcinoma (Version 2024)”.
The document, developed by a multidisciplinary panel of China’s leading liver oncologists and hepatologists, is the country’s first evidence-based guideline dedicated exclusively to this increasingly common clinical problem.
Key incidence figures from the consensus:
- Sorafenib and lenvatinib: 9–25 % of patients develop elevated ALT/AST
- Apatinib-containing regimens: markedly higher hepatotoxicity
- PD-1/PD-L1 inhibitors alone: 9–26 % liver enzyme elevation
- TKI + ICI combinations (e.g., camrelizumab + apatinib, lenvatinib + pembrolizumab): Grade ?3 liver injury in 15–50 % of cases
- Adding locoregional therapy (TACE/HAIC): further increases risk
Major risk factors identified:
- Chronic hepatitis B (especially without antiviral prophylaxis) – risk of HBV reactivation
- Child-Pugh B liver function
- Genetic polymorphisms (e.g., UGT1A1*28 for sorafenib, UGT1A9 for regorafenib)
- Younger age and concomitant hepatotoxic drugs
Pre-treatment requirements (strongly recommended):
- Child-Pugh ?7, ALT/AST ?3× ULN, total bilirubin ?1.5× ULN
- Mandatory screening for HBsAg, anti-HBc, HBV-DNA, and HCV-RNA
- Antiviral prophylaxis started ?1 week before systemic therapy in all HBsAg-positive patients
Diagnosis and grading
Liver injury is diagnosed by temporal relationship, exclusion of tumor progression, viral reactivation, or other causes, and (in unclear cases) liver biopsy. A practical four-grade system combines biochemistry, symptoms, and coagulation parameters.
Management highlights
Targeted therapy-induced injury
- Grade 1–2: Continue or reduce dose + hepatoprotectants (e.g., magnesium isoglycyrrhizinate, bicyclol)
- Grade 3: Temporary suspension, restart at lower dose after recovery
- Grade 4: Permanent discontinuation
Immune checkpoint inhibitor-induced liver injury (ILICI)
- Grade 1: Continue ICI with close monitoring
- Grade 2: Hold ICI, start hepatoprotectants
- Grade 3: Permanently discontinue ICI + prednisone/prednisolone 0.5–1.0 mg/kg/day
- Grade 4 or steroid-refractory: 1–2 mg/kg/day methylprednisolone; add mycophenolate mofetil or tacrolimus if no response within 48–72 h
The consensus emphasizes early, aggressive immunosuppression in ICI-related hepatitis and cautions against premature steroid use in pure TKI-induced injury.
The full open-access document (published 12 September 2025 in Journal of Clinical and Translational Hepatology) serves as a living guideline and will be updated as new data emerge, particularly from ongoing TKI+ICI+locoregional therapy trials.
DOI: 10.14218/JCTH.2025.00228
Full text: https://xiahepublishing.com/2310-8819/JCTH-2025-00228
With China treating the world’s largest HCC population and leading global recruitment in many pivotal TKI+ICI studies, these national recommendations are expected to influence clinical practice far beyond Asia.
