Epidemiology and Risk Factors
Liver injury is a frequent occurrence during systemic therapy for HCC. The incidence varies by drug class and regimen. Tyrosine kinase inhibitors (TKIs) like lenvatinib and sorafenib are associated with ALT/AST elevation rates of 9-25%, while the VEGFR antagonist apatinib demonstrates a higher hepatotoxicity profile. Among ICIs, PD-1 inhibitors cause liver enzyme elevations in 9-26% of cases, with combinations of ICIs (e.g., nivolumab + ipilimumab) or combinations of TKIs with ICIs (e.g., camrelizumab + apatinib) leading to even higher rates, sometimes exceeding 50%. Combination therapies with locoregional treatments like TACE or HAIC further elevate the risk.
Key risk factors for developing liver injury include:
Underlying Liver Disease: Chronic hepatitis B or C infection and impaired liver reserve function (Child-Pugh B status) significantly increase susceptibility. Viral reactivation is a critical concern without proper antiviral prophylaxis.
Genetic Predisposition: Polymorphisms in genes encoding drug-metabolizing enzymes, such as UGT1A1 for sorafenib and UGT1A9 for regorafenib, are linked to an increased risk of hyperbilirubinemia and hepatotoxicity.
Drug-Specific Factors: Apatinib and regimens containing it are consistently associated with higher incidences of liver injury.
Patient Demographics: Younger age and concomitant use of medications like acetaminophen are also identified as risk factors.
Pre-Treatment Assessment and Management
A thorough baseline assessment is paramount before initiating therapy. The consensus strongly recommends that patients should have a Child-Pugh score ≤ 7, ALT/AST ≤ 3x ULN, and TBIL ≤ 1.5x ULN. Key pre-treatment actions include:
Screening for Viral Hepatitis: All patients must be screened for HBsAg, anti-HBc, and anti-HCV. HBsAg-positive patients should initiate antiviral therapy at least one week before starting systemic treatment. HCV RNA-positive patients should receive direct-acting antivirals.
Managing Comorbid Liver Disease: While autoimmune liver diseases require careful monitoring, they are not an absolute contraindication. Active DILI from other drugs should be controlled before commencing anti-cancer therapy.
Pathogenesis and Clinical Presentation
The mechanisms of liver injury differ between drug classes:
Targeted Therapies: Injury is often intrinsic or idiosyncratic, involving direct inhibition of hepatic transporters, mitochondrial dysfunction, oxidative stress, and immune-mediated pathways triggered by reactive metabolites.
ICIs: Injury is immune-mediated (ILICI), resulting from the unchecked activation of T-cells against shared antigens in hepatocytes or bile duct cells. CTLA-4 inhibitors typically cause earlier and more severe hepatitis than PD-1/PD-L1 inhibitors.
Clinically, patients may be asymptomatic or present with non-specific symptoms like fatigue, nausea, and jaundice. Histopathologically, ICI-related injury can manifest as immune-mediated hepatitis (IMH) with lobular inflammation and CD8+ T-cell infiltration, or immune-mediated cholangitis (IMC) with biliary injury.
Diagnosis, Grading, and Differential Diagnosis
Diagnosis relies on a temporal association between drug initiation and liver test abnormalities, improvement upon drug withdrawal, and exclusion of other causes. Liver biopsy is recommended in severe, progressive, or diagnostically uncertain cases.
The consensus provides an optimized severity grading system (Grades 1-4) based on symptoms, liver biochemistry (ALT, AST, ALP, TBIL), and coagulation function (PTA/INR). A critical differential diagnosis must exclude:
Viral hepatitis reactivation.
Progression of HCC (via imaging and tumor markers).
Other drug-induced injuries.
Autoimmune hepatitis.
Myocarditis/Myositis (when AST is disproportionately elevated).
Management Strategies
Management is stratified by severity and drug class, with the foundational principles being prompt anti-inflammatory/hepatoprotective therapy and drug modification based on injury grade.
For Targeted Therapy-Induced Liver Injury:
Grade 1: Continue therapy with hepatoprotective agents (e.g., magnesium isoglycyrrhizinate, bicyclol).
Grade 2: Consider dose reduction alongside intensive hepatoprotection.
Grade 3: Temporarily discontinue therapy; restart at a reduced dose after recovery.
Grade 4: Permanently discontinue the drug and provide aggressive supportive care, including artificial liver support if needed.
For ICI-Induced Liver Injury (ILICI):
Grade 1: Continue ICIs with monitoring.
Grade 2: Temporarily withhold ICIs and administer hepatoprotective therapy.
Grade 3: Discontinue ICIs and initiate glucocorticoids (0.5-1.0 mg/kg/day).
Grade 4: Permanently discontinue ICIs and administer high-dose glucocorticoids (1-2 mg/kg/day). For steroid-refractory cases, second-line immunosuppressants like mycophenolate mofetil or tacrolimus are recommended.
For combination regimens, the primary offending agent should be identified and managed accordingly. After recovery, re-challenging with a different agent may be considered on a case-by-case basis.
Follow-up, Prognosis, and Future Directions
Patients require regular follow-up with liver function tests and imaging every 4-6 weeks after recovery to monitor for relapse and assess tumor status. The prognosis for Grade 1-2 injury is generally good with timely intervention. Most patients with Grade ≥3 ILICI recover with glucocorticoids, though a subset may have a prolonged course.
The consensus concludes by highlighting critical unresolved questions for future research, including the detailed molecular mechanisms of injury, predictive biomarkers for susceptibility, the role of prophylactic hepatoprotection, and the refinement of management strategies for complex combination therapies. This living document will be updated as new evidence emerges, continually striving to safeguard patients undergoing these life-prolonging treatments.
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https://xiahepublishing.com/2310-8819/JCTH-2025-00228
The study was recently published in the Journal of Clinical and Translational Hepatology.
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