From the Guidelines
Elevated liver enzymes should be worked up and managed based on the severity of the elevation, with mild elevations (<5 times the upper reference limit) often requiring only **close monitoring**, while **moderate to severe elevations** (5-10 times or >10 times the upper reference limit) may necessitate further diagnostic evaluation and potentially treatment interruption or initiation of corticosteroid therapy 1.
Initial Evaluation
The initial evaluation of abnormal liver tests includes a detailed history, inventory of medications, and a physical examination to assess the patient's risk factors for liver disease, medications, alcohol consumption, comorbid conditions, and signs and symptoms of hepatic disease 1.
Classification of Abnormal Aminotransferase
The severity of abnormal aminotransferase can be classified as:
- Mild: <5 times the upper reference limit
- Moderate: 5 to 10 times the upper reference limit
- Severe: >10 times the upper reference limit 1
Management of Elevated Liver Enzymes
- Grade 1 ALT elevation (ALT > ULN-3x ULN): close monitoring for signs and symptoms of liver injury and hepatic biochemical tests 1
- Grade 2 serum ALT elevation (ALT > 3-5x ULN): withholding ICI treatment and initiating close monitoring for signs and symptoms of liver injury and hepatic biochemical tests, with potential initiation of oral corticosteroid therapy 1
- Grade 3 or 4 serum ALT elevation (> 5x ULN): withholding ICI therapy and initiating corticosteroid therapy 1
Additional Considerations
- Elevated ALP levels may occur in cholestatic liver disease, and further evaluation is necessary to determine the etiology 1
- Hyperbilirubinemia due to either hepatocellular, cholestatic, or metabolic disease requires further evaluation and potentially treatment 1
From the Research
Workup for Elevated Liver Enzymes
The workup for elevated liver enzymes typically involves a stepwise evaluation based on the prevalence of diseases that cause mild elevations in transaminase levels 2. The initial testing should include:
- A fasting lipid profile
- Measurement of glucose, serum iron, and ferritin
- Total iron-binding capacity
- Hepatitis B surface antigen and hepatitis C virus antibody testing
Common Causes of Elevated Liver Enzymes
The most common causes of elevated liver enzymes are:
- Nonalcoholic fatty liver disease (NAFLD) 2, 3
- Alcoholic liver disease 2, 3
- Medication-associated liver injury 2
- Viral hepatitis (hepatitis B and C) 2, 3
- Hemochromatosis 2
Less Common Causes of Elevated Liver Enzymes
Less common causes of elevated liver enzymes include:
- α(1)-antitrypsin deficiency 2, 3
- Autoimmune hepatitis 2
- Wilson disease 2
- Extrahepatic conditions (e.g., thyroid disorders, celiac disease, hemolysis, muscle disorders) 2, 4
Management of Elevated Liver Enzymes
The management of elevated liver enzymes typically involves:
- A trial of lifestyle modification with observation or further testing for less common causes if initial test results are normal 2
- Referral for further evaluation and possible liver biopsy if transaminase levels remain elevated for six months or more 2
- A single-act office visit with a hepatologist, which has been shown to be efficient in reaching a diagnosis in most patients 3
Special Considerations
In patients treated with immune checkpoint inhibitors, liver enzyme elevation is common, but often has a cause other than immunotoxicity 5. A biochemical signature with higher ALT and ALT/AST ratio, a history of prior ICI exposure, and other organ immunotoxicities may help to identify patients at a higher likelihood of immunotoxicity 5. Liver biopsy can be safely deferred in most patients 5.