Analysis of 386 alternative medicinal products implicated in liver injury reveal clinically relevant associations with potentially hepatotoxic botanicals, pharmaceutical adulteration, heavy metal contamination, and undisclosed animal content

Background: Complementary and alternative medicine (CAM)-related hepatotoxicity is a growing global concern. We utilized multi-modal analysis to characterize CAM product safety and identify predictors of severe liver injury. Methods: This retrospective study analyzed 386 CAM products from 91 consecutive patients (mean 4.2 products/patient) presenting with CAM-related adverse events at a tertiary center in South India (2021-2023). Product-level analyses characterize the CAM supply chain while patient-level analyses inform clinical outcome associations. Investigations included ingredient documentation, heavy metal quantification, and GC-MS compound profiling. Results: The mean patient age was 48.2 years (75.8% male). ACLF occurred in 39.6% of all patients (36/91) and 41.9% of those with hepatic adverse events (36/86), with associated mortality of 38.9% (14/36) compared to 10.9% (6/55) in non-ACLF presentations (OR 5.20, P = 0.004). Heavy metals exceeded WHO limits in many products: mercury (34%), cadmium (25%), arsenic (21%), and lead (14%). Cadmium exposure exceeding WHO limits showed a strong association with ACLF (75.9% vs 22.6%, P<0.001, FDR q<0.001). The association with mortality did not reach statistical significance after correction for multiple comparisons (34.5% vs 16.1%, uncorrected P = 0.061, FDR q=0.24). Undeclared pharmaceutical adulteration (at least one adulterant found in 27.7% of products; exposure to at least one adulterated product in 46.2% of patients) and animal-derived content (31.3%) were prevalent. Notably, unlabeled product consumption significantly predicted mortality (P = 0.025). Conclusion: CAM-associated liver injury frequently manifests as ACLF with high mortality, driven by pervasive heavy metal contamination and adulteration. Unlabeled product exposure is a strong mortality predictor, highlighting the urgent need for mandatory product surveillance.