# Ontogeny of drug-induced fatty liver disease (DIFLD): from key initiating events to disease phenotypes

## TL;DR

This paper classifies drugs based on how they cause fatty liver disease, linking clinical symptoms to drug properties and mechanisms.

## Contribution

A novel classification system for drug-induced fatty liver disease based on clinical, biochemical, and toxicological features.

## Key findings

- Seven distinct clusters of drugs were identified based on their effects on liver steatosis and injury.
- Clusters 1 and 2 are linked to β-oxidation impairment and lipophilicity, while Cluster 3 involves mitochondrial DNA depletion.
- Higher daily doses are associated with more severe liver injury and inflammation in Clusters 4 and 5.

## Abstract

We conducted an expert review of clinical case reports on drug-induced fatty liver disease (DIFLD) to classify drugs according to distinct clinical phenotypes. Seven clusters were identified based on clinical, biochemical, and histological features reflecting drug toxic mechanisms:Cluster 0 (Control): Drugs with no known steatotic effects or clinical evidence of DIFLD.Cluster 1: Drugs with mild pro-steatotic effects, exacerbating existing metabolic steatosis without significant liver enzyme elevation.Cluster 2: Compounds causing moderate steatosis with mild hepatocellular damage, occasional enzyme increases, and delayed onset.Cluster 3: Agents causing severe mitochondrial dysfunction, ATP depletion, and lactic acidosis, initially without inflammation.Cluster 4: Drugs inducing inflammatory steatohepatitis with moderate elevations of liver enzymes (ALT, AST, ALP 90–700 U/L) but preserved liver function.Cluster 5: Drugs causing severe steatohepatitis with marked enzyme elevation (ALT, AST > 700 U/L) indicating significant liver injury and inflammation.Cluster 6: Compounds causing steatohepatitis with additional cholestasis and elevated bilirubin (> 11 mg/dL).

Cluster 0 (Control): Drugs with no known steatotic effects or clinical evidence of DIFLD.

Cluster 1: Drugs with mild pro-steatotic effects, exacerbating existing metabolic steatosis without significant liver enzyme elevation.

Cluster 2: Compounds causing moderate steatosis with mild hepatocellular damage, occasional enzyme increases, and delayed onset.

Cluster 3: Agents causing severe mitochondrial dysfunction, ATP depletion, and lactic acidosis, initially without inflammation.

Cluster 4: Drugs inducing inflammatory steatohepatitis with moderate elevations of liver enzymes (ALT, AST, ALP 90–700 U/L) but preserved liver function.

Cluster 5: Drugs causing severe steatohepatitis with marked enzyme elevation (ALT, AST > 700 U/L) indicating significant liver injury and inflammation.

Cluster 6: Compounds causing steatohepatitis with additional cholestasis and elevated bilirubin (> 11 mg/dL).

Clusters 1 and 2 primarily impair β-oxidation and mitochondrial respiration, linked to high lipophilicity and typically lower daily doses. Cluster 3 involves mitochondrial DNA depletion and impaired lipid export. Clusters 4 and 5 combine mitochondrial and nuclear receptor disruption, often linked to higher daily doses. Cluster 6 combines steatosis-promoting mechanisms with bile acid transport disruption. This classification improves understanding of DIFLD phenotypes by linking clinical manifestations with drug physicochemical properties and toxicological mechanisms, aiding diagnosis and risk assessment of drug-induced steatosis.

The online version contains supplementary material available at 10.1007/s00204-025-04178-x.