DILI Threshold Based on ALT/AST Levels
For patients with normal baseline ALT, suspect DILI when ALT reaches ≥5× ULN in asymptomatic patients without elevated bilirubin, or ≥3× ULN when combined with total bilirubin ≥2× ULN or hepatic symptoms. 1
Thresholds for Normal Baseline ALT (<1.5× ULN)
Initiate Close Observation
- ALT ≥5× ULN without hepatic symptoms (severe fatigue, nausea, vomiting, right upper quadrant pain) and normal total bilirubin warrants accelerated monitoring and repeat testing within 2-5 days 1
- This threshold is specifically designed to exclude clinically insignificant self-limited events while capturing true DILI signals 1
Interrupt Study Drug/Suspect DILI
- ALT ≥3× ULN plus total bilirubin ≥2× ULN (Hy's Law criteria) - this combination signals potential serious DILI 1
- ALT ≥3× ULN plus hepatic symptoms (severe fatigue, nausea, vomiting, right upper quadrant pain) 1
- ALT ≥8× ULN even with normal bilirubin and no symptoms 1
- ALT ≥5× ULN with liver-related symptoms or immunologic reaction (rash, >5% eosinophilia) 1
Thresholds for Elevated Baseline ALT (≥1.5× ULN)
Initiate Close Observation
- ALT ≥3× baseline OR ≥300 U/L (whichever occurs first) without hepatic symptoms or elevated bilirubin requires repeat testing within 2-5 days 1
- This approach uses multiples of baseline rather than ULN because patients with pre-existing liver disease may already exceed 3× ULN at enrollment 1
Interrupt Study Drug/Suspect DILI
- ALT ≥2× baseline OR ≥300 U/L (whichever occurs first) plus total bilirubin ≥2× baseline 1
- ALT ≥2× baseline OR ≥300 U/L (whichever occurs first) plus hepatic symptoms 1
- ALT ≥5× baseline OR ≥500 U/L (whichever occurs first) regardless of symptoms or bilirubin 1
Critical Context and Pitfalls
The 5× ULN threshold for normal baseline patients represents a consensus shift from the older 3× ULN FDA guidance, as the higher threshold better excludes benign fluctuations while maintaining sensitivity for serious DILI 1. The rationale is that raising the threshold to 5× ULN reduces false positives from clinically insignificant events 1.
For patients with elevated baseline ALT, using absolute multiples of baseline is essential because their baseline may already exceed standard ULN thresholds 1. The dual criteria (multiples of baseline OR absolute values like 300 U/L) ensures that patients with very high baselines don't escape detection 1.
Bilirubin elevation is the critical modifier - when ALT ≥3× ULN combines with bilirubin ≥2× ULN (Hy's Law), mortality risk approaches 10% 1. This combination mandates immediate drug interruption and close monitoring 1.
Hepatic symptoms lower the ALT threshold significantly - the presence of severe fatigue, nausea, vomiting, or right upper quadrant pain reduces the concerning ALT threshold from 5× to 3× ULN in normal baseline patients 1.
Establish true baseline carefully - in patients with fluctuating ALT, average two consecutive tests at least 2 weeks apart before enrollment 1. If values differ by >50%, perform a third test to determine the direction of change 1.
Don't attribute ALT >5× ULN to underlying NASH or fatty liver disease alone - such elevations are rare in the natural history of these conditions and warrant investigation for alternative causes including DILI 1, 2.