How to Grade the Severity of Suspected DILI in a Clinical Trial

by DILI expert Melissa Palmer, MD. Dr. Palmer is a DILI consultant to the biotech and pharmaceutical industries. Contact Dr. Palmer at drpalmer@liverdisease.com

When evaluating an adverse event (AE) related to liver safety in clinical trials, two important grading systems should be utilized: the CTCAE (Common Terminology Criteria for Adverse Events) which is virtually always used, and the NIH DILIN (Drug-Induced Liver Injury Network) severity scale, which is used in combination with the CTCAE by DILI expert consultants.

While they look at the same laboratory values, they serve different purposes. CTCAE grades the degree of liver test elevation. The DILIN  classification is a clinical diagnosis and prognosis tool that grades the severity of liver injury.

The Key Differences

1. CTCAE (Common Terminology Criteria for Adverse Events) version 6.0

The CTCAE is a universal framework used across clinical trials to grade the severity of any adverse event from Grade 1 (mild) to Grade 5 (death).

• How it works: It grades each lab value in isolation based on fixed multiples of the Upper Limit of Normal (ULN) if the baseline value was ≤ ULN and on multiples of the baseline if the baseline was >ULN.  Version 6.0 has corrected for patients who have baseline values >ULN
• The criteria for ALT  and AST:

If Baseline ≤ Normal                                      If Baseline > normal

• Grade 1: >1.0 to 3.0 × ULN          1-1.5 x baseline
  • Grade 2: >3.0 to 5.0 × ULN          >1.5-2.0 x baseline
  • Grade 3: >5.0 to 20.0 × ULN        >2-4x baseline up to 5xULN
  • Grade 4: >20.0 × ULN                  >4.0 x baseline

• Limitation: A patient can have, for example,  a Grade 3 ALT elevation (>5 × ULN) due to transient, benign enzyme leakage (transaminitis) without any actual loss of liver function (increased INR or TBL).  The CTCAE does not determine the severity of  liver injury.

2. The Nation Institutes of Health DILIN (Drug-Induced Liver Injury Network) Severity Scale

The DILIN scale was specifically designed by hepatologists with expertise in DILI to grade the actual clinical severity of liver injury due to a drug, herb or dietary supplement

• How it works: It integrates multiple data points simultaneously, combining aminotransferase (ALT and AST) spikes with functional biomarkers (TBL and INR) and clinical outcomes (hospitalization, organ failure).
• The criteria:
  • Grade 1 (Mild): Elevated ALT/AST or ALP, but TBL remains <2.5 mg/dL and INR is normal (<1.5).
  • Grade 2 (Moderate): Elevated ALT/AST/ALP and TBL ≥2.5 mg/dL, OR an INR ≥1.5 without TBL elevation.
  • Grade 3 (Moderate-Severe): Meets Mild or Moderate criteria and results in hospitalization (or prolongs an existing one).
  • Grade 4 (Severe): Liver injury accompanied by hepatic or extrahepatic organ failure (e.g., encephalopathy, ascites, or renal failure).
  • Grade 5 (Fatal/Transplant): Death or liver transplantation due to DILI

Why This Distinction is Crucial

The distinction between these two systems matters profoundly for trial safety, drug development decisions, and avoiding false alarms.

Hy's Law and Functional Impairment

The most critical reason to separate these grading criteria is Hy's Law, a powerful prognostic principle stating that pure aminotransferase elevation is rarely fatal, but when combined with a functional clearing defect (TBL elevation), the mortality rate jumps to 10–50%.

• CTCAE blindsides true DILI risk: If a subject has an ALT of 6 × ULN and a TBL of 3 × ULN, CTCAE merely logs two separate events: a Grade 3 ALT elevation and a Grade 2 Bilirubin elevation. It treats them as isolated laboratory anomalies.
• DILIN captures the synergy: DILIN instantly flags this combination as a true clinical event (Grade 2 Moderate DILI or higher), recognizing that the liver's functional capacity is actively failing.

Preventing Premature Discontinuation

Many novel therapies (such as immunotherapies or gene therapies) cause transient, asymptomatic "flares" in liver enzymes that do not represent true structural injury.

• Relying strictly on high CTCAE grades can trigger automatic, protocol-mandated drug discontinuation or trial holds for a drug that might otherwise be safe and highly effective.
• Utilizing a DILIN-style assessment allows investigators to differentiate between benign adaptation (isolated enzyme leaks) and true toxicity (functional liver failure).

Contact DILI consultant Melissa Palmer, MD at drpalmer@liverdisease.com to discuss how she can help you with your DILI needs.

Copyright Melissa Palmer, MD 7/19/26