Drug-Induced Liver Injury (DILI)
Definition
DILI is hepatocellular damage caused by drugs or their reactive metabolites, either through direct toxicity (predictable, dose-dependent) or idiosyncratic reactions (unpredictable, immune-mediated). It is a leading cause of acute liver failure and drug withdrawal from the market.
Pathophysiology
- Reactive metabolite formation — CYP450-mediated oxidation of drugs → electrophilic intermediates
- Protein adduct formation — reactive metabolites bind covalently to proteins, including HSA (via Cys34) → neoantigens
- Mitochondrial dysfunction — impaired oxidative phosphorylation → hepatocyte energy failure
- Oxidative stress — increased ROS → protein oxidation, lipid peroxidation → PTM changes on plasma proteins
- Immune activation — drug-protein adducts trigger adaptive immune response → immune-mediated DILI
Current diagnostic markers
| Marker | Type | Threshold | Limitation |
|---|---|---|---|
| ALT | Enzyme | >3× ULN | Non-specific, late |
| AST | Enzyme | >2× ULN | Non-specific |
| ALP | Enzyme | >2× ULN | Cholestatic pattern |
| Total bilirubin | Metabolite | >2× ULN | Late marker |
| Hy’s Law | Combined | ALT>3× + Bili>2× | Still non-specific |
| GLDH | Mitochondrial enzyme | Emerging | Better specificity |
Key problem: current markers are not specific to DILI (vs. other liver diseases), appear late (after significant damage), and don’t predict severity.
PTM-based biomarker candidates
| Protein | PTM | Method | Status | Notes |
|---|---|---|---|---|
| HSA | Drug adducts (Cys34) | LC-MS | Discovery | Drug-specific adducts = mechanistic proof |
| HSA | Oxidation (Cys34) | Top-down MS | Discovery | Reflects oxidative stress |
| HSA | Carbonylation | Bottom-up MS | ⚠️ Early | General oxidative damage marker |
| Transferrin | N-glycosylation changes | LC-MS | ⚠️ Early |
Open questions for our research
- Can CQFD-PTM pipeline detect DILI-specific PTM signatures in plasma?
- Is there a PTM fingerprint that distinguishes hepatocellular from cholestatic DILI?
- Does the HSA cysteinylation/oxidation ratio correlate with DILI severity scores (RUCAM)?
- Can PTM-based markers appear earlier than ALT/AST elevation?
EASL 2019 Clinical Practice Guidelines context
- No specific DILI biomarker exists in clinical practice — diagnosis is exclusion-based (RUCAM causality assessment)
- ALT/AST: sensitive but non-specific; appear only after hepatocyte necrosis (late markers)
- Hy’s Law: drug-induced jaundice + hepatocellular injury → ~10% mortality/transplantation rate — underscores why early detection matters
- HDS (herbal/dietary supplements): 16–20% of DILI cases, increasing; hardest to attribute causally
- See easl-dili-2019 for full guideline
Key studies in this vault
- el-balkhi-2024-seb — SEB test detects liver injury at Day 3 in rat model vs ALT/AST at Day 7; proof-of-concept for early HSA-based DILI detection
- easl-dili-2019 — EASL Clinical Practice Guidelines on DILI; current diagnostic standard and biomarker gap
Connections
- Liver fibrosis — DILI can progress to fibrosis in severe/chronic cases
- Oxidative stress — central mechanism
- HSA — primary plasma protein affected by drug adducts and oxidative PTMs
- ALBOM study — our biomarker study including DILI context
- DILI-Fibrose analysis — our statistical analysis