Browse All / Modules / Drug-Induced Liver Injury Module

Drug-Induced Liver Injury Module

Module drug_induced_liver_injury 1 disorder Pathograph 5
A conserved treatment-toxicity module representing the final common pathway by which hepatotoxic drugs injure and kill hepatocytes. The culprit agent and the proximal trigger vary — dose-dependent reactive-metabolite formation (the acetaminophen/NAPQI archetype), bile salt export pump (BSEP) inhibition and cholestatic stress, or idiosyncratic immune-mediated injury — but the downstream sequence repeatedly converges on mitochondrial dysfunction and oxidative stress, hepatocyte cell death (necrosis and apoptosis), sterile/immune inflammatory amplification, and clinically apparent liver injury that can progress to acute liver failure. This is a "side effect as mechanism" module: it captures the adverse-drug-reaction pathophysiology shared across many hepatotoxic drugs, so a drug-toxicity entry can declare conformance rather than re-deriving the chain.
⚙

Pathophysiology Nodes

5
5 shared nodes are defined in this module.
◉

Cell Types

3
hepatocyte CL:0000182 Kupffer cell CL:0000091 neutrophil CL:0000775
⇄

Biological Processes

5
xenobiotic metabolic process GO:0006805 INCREASED response to oxidative stress GO:0006979 INCREASED cell death GO:0008219 INCREASED apoptotic process GO:0006915 INCREASED inflammatory response GO:0006954 INCREASED
i

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "drug_induced_liver_injury#Hepatocyte Cell Death"). Conforming nodes should substitute the disorder-specific hepatotoxic driver (the particular drug and its proximal mechanism — reactive metabolite, BSEP inhibition, or immune-mediated idiosyncratic injury) while preserving the conserved metabolite/stress → mitochondrial dysfunction → hepatocyte death → inflammation → liver injury chain. The key conformance / central-effector target is "drug_induced_liver_injury#Hepatocyte Cell Death".
↗

Used By Disorder Entries

1
Acetaminophen Hepatotoxicity via NAPQI reactive metabolite formation and glutathione depletion → Reactive Drug Metabolite Formation and Hepatocellular Stress , Mitochondrial oxidative stress and dysfunction → Mitochondrial Dysfunction and Oxidative Stress , Centrilobular hepatocyte necrosis → Hepatocyte Cell Death , Sterile inflammatory amplification → Sterile and Immune-Mediated Inflammatory Amplification , Acute liver failure → Liver Injury and Acute Liver Failure
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.
Pathograph: causal mechanism network for Drug-Induced Liver Injury Module Interactive directed graph showing how this shared module's pathophysiology nodes connect.
⚙

Pathophysiology

5
Reactive Drug Metabolite Formation and Hepatocellular Stress
trigger
The conserved initiating lesion is hepatic handling of the drug producing a proximal toxic stimulus: bioactivation to a reactive metabolite (the acetaminophen → NAPQI archetype), inhibition of the bile salt export pump with cholestatic accumulation, or covalent/oxidative stress on hepatocyte macromolecules. Hepatocytes, the principal site of xenobiotic metabolism, bear the brunt of this stress regardless of the specific drug.
hepatocyte CL:0000182
xenobiotic metabolic process GO:0006805 INCREASED
Used by disorders
Acetaminophen Hepatotoxicity as NAPQI reactive metabolite formation and glutathione depletion
Downstream
  • Mitochondrial Dysfunction and Oxidative Stress Reactive metabolites and cholestatic stress converge on mitochondrial injury and oxidant production.
Mitochondrial Dysfunction and Oxidative Stress
amplifier
Reactive metabolites and accumulated bile acids damage mitochondria, the organelle most central to hepatocyte bioenergetics, producing oxidative stress, impaired ATP synthesis, and mitochondrial permeability transition. This is the major amplifying event linking the proximal drug stress to hepatocyte death across hepatotoxic agents.
hepatocyte CL:0000182
response to oxidative stress GO:0006979 INCREASED
mitochondrion GO:0005739
Used by disorders
Acetaminophen Hepatotoxicity as Mitochondrial oxidative stress and dysfunction
Downstream
  • Hepatocyte Cell Death Mitochondrial failure and oxidative stress precipitate hepatocyte necrosis and apoptosis.
Hepatocyte Cell Death
central effector
Mitochondrial failure and oxidative stress precipitate hepatocyte death by necrosis and apoptosis. This is the central effector step and the most common manifestation of DILI; conforming disorder nodes substitute the drug-specific upstream driver but converge here. It is the key conformance target of the module.
hepatocyte CL:0000182
cell death GO:0008219 INCREASED apoptotic process GO:0006915 INCREASED
Used by disorders
Acetaminophen Hepatotoxicity as Centrilobular hepatocyte necrosis
Downstream
  • Sterile and Immune-Mediated Inflammatory Amplification Hepatocyte death releases damage-associated signals that recruit and activate inflammatory cells.
  • Liver Injury and Acute Liver Failure Loss of hepatocyte mass produces clinically apparent liver injury.
Sterile and Immune-Mediated Inflammatory Amplification
amplifier
Dying hepatocytes release damage-associated molecular patterns that drive a sterile inflammatory response; in idiosyncratic DILI, innate and adaptive immune activation (death-ligand signaling, HLA-restricted responses) further propagates injury. Inflammation amplifies and extends the hepatocellular death initiated upstream.
hepatocyte CL:0000182 Kupffer cell CL:0000091 neutrophil CL:0000775
inflammatory response GO:0006954 INCREASED
Used by disorders
Acetaminophen Hepatotoxicity as Sterile inflammatory amplification
Downstream
  • Liver Injury and Acute Liver Failure Sustained inflammatory injury extends hepatocyte loss toward clinical liver failure.
Liver Injury and Acute Liver Failure
consequence
Accumulated hepatocyte loss and inflammation produce clinically apparent liver injury, manifesting as a hepatocellular, cholestatic, or mixed biochemical pattern, and in severe cases progressing to acute liver failure — the most feared consequence of DILI and a leading cause of drug attrition.
hepatocyte CL:0000182
cell death GO:0008219 INCREASED
Used by disorders
Acetaminophen Hepatotoxicity as Acute liver failure