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Causality: well established
Causality assessment · Causality: well established
Valproate and Hepatotoxicity: is the FAERS signal real?
A written Bradford Hill assessment of one drug–event pair. The grade is a judgement about the signal, not a statement that this drug causes this event in any one person; FAERS counts are reports, not rates.
Valproate ↔ Hepatotoxicity
n=175 co-reports · PRR 5.3 · ROR 5.3
Valproate carries a boxed warning for fatal hepatotoxicity, a rare but catastrophic reaction that is most feared in very young children, in people with inherited metabolic disorders, and in those taking multiple antiepileptic drugs. The injury is thought to arise from the drug's mitochondrial effects, and it is the reason liver function and, where relevant, metabolic screening are part of valproate monitoring. The 175 co-reports (PRR 5.3) reflect a rare but severe and regulatorily-prominent effect.
Regulatory basis: valproate prescribing information (boxed warning for hepatotoxicity). Established valproate-hepatotoxicity literature.
| Bradford Hill viewpoint | Status | Note |
|---|---|---|
| Temporality (necessary) | met | Liver injury develops during therapy and can be fatal, especially in young children |
| Strength | partial | PRR 5 on a moderate co-report count |
| Consistency | met | Reproduced across decades of valproate case reports |
| Specificity | partial | A recognised idiosyncratic hepatotoxicity, but also largely metabolic/mitochondrial |
| Biological gradient | partial | Higher risk in young children, polytherapy, and metabolic disease |
| Plausibility | met | Mitochondrial toxicity and metabolic disruption of liver cells are proposed |
| Coherence | met | Coheres with the boxed warning and liver-function monitoring |
| Experiment | partial | Dechallenge (withdrawal) is essential and can be life-saving; no randomized trial |
| Analogy | met | Analogous to other mitochondrial-hepatotoxic drugs |
This page's own qualitative read, not an automated/citation-gated assessment.
✗ No ClinicalTrials.gov results-posting trial in the top search hits for valproate captured hepatotoxicity; the reaction is idiosyncratic and rare, and is identified through case reports and regulatory review rather than a trial AE table.