What are the next steps for a patient with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels three times the upper limit of normal (3x ULN) on a comprehensive metabolic panel (CMP)?

From the Guidelines

For elevated AST and ALT levels that are 3 times the upper limit of normal (ULN) on a comprehensive metabolic panel (CMP), the study drug should be withheld, and a comprehensive medical evaluation should be triggered, as recommended by the most recent guidelines 1.

Next Steps

The following steps should be taken:

• Repeat the liver function tests within 1-2 weeks to confirm the abnormality
• Obtain a complete history focusing on alcohol use, medications (including over-the-counter and supplements), and risk factors for viral hepatitis
• Order further testing including:
  • Hepatitis serologies (HAV, HBV, HCV)
  • Autoimmune markers (ANA, ASMA, AMA)
  • Iron studies
  • Ceruloplasmin (if patient is young)
  • Ultrasound of the liver to evaluate for fatty liver disease or structural abnormalities
• Advise the patient to abstain from alcohol, discontinue potentially hepatotoxic medications if possible, and maintain adequate hydration
• If symptoms such as jaundice, severe abdominal pain, or mental status changes develop, immediate medical attention is warranted

Evaluation of DILI

As recommended by the guidelines 1, a tiered approach towards investigating liver test abnormalities is recommended, and should evaluate the most likely alternative causes of liver injury first, before moving onto investigations for rarer causes of liver injury.

Management

The management of the patient should be based on the grade of ALT elevation, as recommended by the guidelines 1.

• For grade 1 ALT elevation (ALT > ULN-3x ULN), closer monitoring and a detailed medical history should be obtained
• For grade 2 serum ALT elevation (ALT > 3-5x ULN), ICI treatment should be withheld, and close monitoring and evaluation for alternative causes of liver injury should be initiated
• For grade 3 or 4 serum ALT elevation (> 5x ULN), ICI therapy should be withheld, and corticosteroid therapy should be initiated.

From the Research

Next Steps for AST and ALT 3x ULN on CMP

• Evaluate the patient's clinical presentation and medical history to determine the potential cause of elevated liver enzymes 2
• Consider the pattern of injury, such as hepatocellular or cholestatic, to guide further evaluation 3
• Initial investigations may include:
  • Viral hepatitis serologies
  • Autoantibody tests (e.g. ANA, anti-smooth muscle antibody)
  • Imaging studies (e.g. ultrasound, CT scan)
  • Liver biopsy to assess for histopathologic changes and liver fibrosis 4, 5
• If drug-induced liver injury is suspected, consider discontinuing the offending medication and monitoring for resolution of liver enzyme elevations 6
• If autoimmune hepatitis is suspected, consider referral to a gastroenterologist or hepatologist for further evaluation and management 4, 6