Management of Elevated Liver Enzymes

Initial Assessment and Grading

This presentation represents Grade 3 transaminitis with ALT >5× ULN and AST >3× ULN but with normal bilirubin levels, according to the American Gastroenterological Association 1
These values do not meet criteria for Hy's Law (ALT >3× ULN with total bilirubin >2× ULN), which would indicate more severe hepatocellular injury, as stated by the European Association for the Study of the Liver 2, 3

Interrupt any potentially hepatotoxic medications that may be contributing to liver injury, as recommended by the American Gastroenterological Association 1, 3
Initiate close monitoring with repeat liver function tests (ALT, AST, ALP, total and direct bilirubin) within 2-5 days, according to the European Association for the Study of the Liver 3
Begin comprehensive evaluation for competing etiologies of liver injury, including evaluation for metabolic causes (NAFLD/NASH), as suggested by the American Association for the Study of Liver Diseases 1
Assessment for autoimmune hepatitis should be performed, as recommended by the European Association for the Study of the Liver 4

For Grade 3 transaminitis (ALT >5× ULN to 20× ULN), urgent hepatology consultation is recommended by the American College of Gastroenterology 1
Consider starting methylprednisolone 1-2 mg/kg/day if no improvement after workup or if autoimmune etiology is suspected, as suggested by the American College of Gastroenterology 1
Monitor liver function tests every 1-2 days until stable or improving, according to the Society for Immunotherapy of Cancer 5

If drug-induced liver injury (DILI) is suspected, permanently discontinue the offending agent if ALT ≥8× ULN, as recommended by the European Association for the Study of the Liver 3
For immune checkpoint inhibitor-related hepatitis, permanently discontinue the ICI and start corticosteroids, according to the Society for Immunotherapy of Cancer 5
If non-alcoholic steatohepatitis (NASH) is diagnosed, focus on metabolic syndrome treatment, as suggested by the American Association for the Study of Liver Diseases 1
Use multiples of baseline rather than ULN for monitoring in patients with NASH, as recommended by the European Association for the Study of the Liver 2, 3

Continue monitoring liver function tests every 1-2 days until improvement is noted, according to the European Association for the Study of the Liver 6, 1
Once improvement begins, can decrease frequency to weekly until normalization, as suggested by the American College of Gastroenterology 1
For drug rechallenge (if appropriate), wait for complete normalization of liver enzymes and reintroduce at lower doses with careful monitoring, as recommended by the American College of Gastroenterology 1

If ALT increases to ≥8× ULN, immediate action is required, as stated by the European Association for the Study of the Liver 3
If total bilirubin increases to ≥2× ULN, immediate action is required, according to the European Association for the Study of the Liver 2, 3
If INR increases to >1.5, immediate action is required, as recommended by the European Association for the Study of the Liver 3
If hepatic symptoms develop, immediate action is required, according to the European Association for the Study of the Liver 6, 3
Any of these findings should trigger immediate drug discontinuation and hospitalization, as recommended by the American College of Gastroenterology 3, 1

For patients on methotrexate with elevated liver enzymes, consider stopping if ALT/AST is >3× ULN, as suggested by the European League Against Rheumatism 7
For patients with underlying chronic liver disease, use multiples of baseline rather than ULN for monitoring, as recommended by the European Association for the Study of the Liver 2, 4