Reframing liver test abnormalities after AAV gene therapy: a mechanistic diagnostic framework

Hepatotoxicity remains one of the most frequent and clinically important safety concerns in adeno-associated virus (AAV) gene therapy. Yet the laboratory patterns observed after vector administration are biologically complex and often difficult to interpret. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations are non-specific, as they may arise from AAV-induced innate and adaptive immune recognition of vector capsid, endoplasmic reticulum stress, mitochondrial strain, cholestasis, or background muscle turnover, especially in neuromuscular disorders where ALT and AST frequently exceed upper limits of normal at baseline. Traditional drug-induced liver injury frameworks, which rely on fixed multiples of population-derived reference ranges, are poorly suited to these settings and risk both overcalling benign changes and overlooking evolving toxicity. This clinical practice review outlines a mechanism-anchored strategy for interpreting hepatic biomarkers in AAV trials. We describe how vector tropism, intracellular capsid burden, and immune kinetics shape post-dose laboratory trajectories across systemic, liver-directed, and neuromuscular programs. The tissue specificity and kinetic behavior of hepatic biomarkers are examined to show why no single analyte is reliable in isolation. A personalized, baseline-anchored interpretive approach is proposed, with quantitative criteria for AAV-associated liver injury and phenotype-based classifications tailored to pediatric, neuromuscular, and liver disease populations. Finally, we translate these biological principles into a practical clinical framework emphasizing enzyme trajectory, corroboration with hepatic markers such as gamma glutamyl transferase (GGT), recognition of delayed adaptive immune responses, and early attention to bilirubin or international normalized ratio (INR) drift. Together, these concepts provide a structured and biologically grounded approach, proposed here, for interpreting liver tests after AAV gene therapy, strengthening safety monitoring while preserving transgene expression and trial integrity.