Evaluation of Hepatic Enzyme Activity, Drug Metabolism and Physiological Alterations in Patients Receiving Long-Term Pharmacotherapy: A Systematic Review

Abstract

Background: Prolonged medication exposure can influence circulating liver-associated enzymes, hepatic biotransformation, transport and physiological functions. These consequences are not equivalent: aminotransferase elevations indicate injury rather than directly measuring CYP activity or clearance. Objective: To evaluate hepatic biochemical, pharmacokinetic and physiological outcomes during long-term pharmacotherapy, with attention to drug-class and host-related variability. Methods: The information-source window was specified from database inception to 30 June 2026. A PRISMA 2020-informed review framework defined medication exposure, hepatic injury, metabolic activity and physiological outcomes. Published clinical cohorts, drug-safety monographs and systematic reviews were examined descriptively; no new pooled meta-analysis was performed. Results: In a prospective DILIN cohort, 899 patients had probable or more certain Drug-Induced Liver Injury (DILI); 10% died or underwent transplantation and 17% experienced chronic injury. A separate published synthesis of 160 antituberculosis studies (116,147 participants) reported 11.50% liver injury (95% CI 10.10–12.97%; I² 98.2%). Liver Tox reports asymptomatic ALT elevations in approximately 5–10% of patients using valproate. Inflammation-mediated alterations in CYP activity have been documented in clinical and mechanistic studies. Conclusion: Assessment of medication-related hepatic effects should distinguish hepatocellular injury from metabolic clearance and systemic physiological function and should integrate medication exposure, clinical context and appropriate laboratory investigation.