Through an extensive review of clinical case reports on drug-induced fatty liver disease (DIFLD), we identified distinct drugs associated with specific disease phenotypes that correlated with their physicochemical properties and toxic mechanisms. Based on clinical, biochemical, and histological data, we established the following phenotypic groups: Group 0 (Control): Compounds with no known steatotic effects and no clinical reports indicating DIFLD. Group 1: Drugs with mild pro-steatotic potential, possibly exacerbating pre-existing steatosis. These induce mild metabolic dysfunction or inflammation without hepatocellular injury. Group 2: Agents causing moderate macro/microvesicular steatosis and metabolic disturbances. Liver damage is mild, with occasional enzyme elevation. Group 3: Severe mitochondrial dysfunction with ATP depletion and lactic acidosis due to glycolysis activation. Inflammation is initially absent but may develop later. Group 4: Inflammatory-driven steatohepatitis with significant enzyme elevations (ALT, AST, ALP: 90-700 U/L) and moderate hepatocellular injury, but preserved liver function. Group 5: Severe steatohepatitis marked by high ALT/AST levels (>700 U/L), indicating major hepatocyte damage with inflammation and steatosis. Group 6: Steatohepatitis with cholestasic features, elevated bilirubin (>10 mg/dL), and marked hepatocellular injury. Each group shares characteristic mechanistic and physicochemical profiles. Compared to non-steatotic compounds (Group 0), Groups 1-2 primarily involve β-oxidation and mitochondrial respiratory chain impairment, and display high lipophilicity, low plasma free fraction, and increased solubility. Group 3 features mtDNA depletion, mitochondrial damage and impaired lipid export, while it correlates with high drug exposure, and P-glycoprotein interactions. Groups 4-5 involve both mitochondrial and nuclear receptor interactions, and are also associated with an elevated lipophilicity. Group 6, in addition to mitochondrial stress, β-oxidation inhibition, also displays cholestasis. The molecules are characterized by reduced plasma free fraction and high lipophilicity. Altogether, our findings offer a framework linking initiating events and mechanistic pathways to defined DIFLD phenotypes. These patterns suggest that certain physicochemical properties influence the steatotic potential and the mechanisms of toxicity, so far involved, resulting in characteristic clinical phenotypes.
