From the Guidelines
Significantly elevated AST and ALT levels in the context of normal bilirubin and a negative hepatitis panel are most likely caused by non-alcoholic fatty liver disease (NAFLD) or alcohol-induced liver disease.
Key Causes
- NAFLD: a spectrum of fat deposition and hepatic inflammation followed by fibrosis due to metabolic insults, with a prevalence of 20% to 30% in the general population, increasing to 70% with obesity and 90% with diabetes mellitus 1.
- Alcohol-induced liver disease: caused by excess alcohol consumption, with an AST:ALT ratio generally >2 1.
Other Considerations
- Medications/toxins: can cause hepatocyte injury, leading to elevated ALT and AST levels 1.
- Autoimmune hepatitis: can cause hepatocellular injury, but is less common and typically associated with other clinical features such as hypergammaglobulinemia 1.
- Muscle injury: can cause elevated AST and ALT levels, especially in patients who engage in intensive exercising or take statins, and can be confirmed by testing for blood levels of creatine phosphokinase (CK) or other muscle-related enzymes 1.
Diagnostic Approach
- Liver biopsy: may be helpful in ruling out idiopathic autoimmune hepatitis or other causes of liver injury, especially in patients with pre-existing NAFLD or an experimental agent in early development 1.
- Exclusion of other causes: of liver injury, such as viral hepatitis, biliary obstruction, or hepatic metastases, is essential for causality assessment 1.
From the Research
Elevated AST and ALT Levels
- Significantly elevated AST and ALT levels in the context of normal bilirubin and a negative hepatitis panel can be caused by various factors, including hepatocellular injury, nonalcoholic fatty liver disease, alcoholic liver disease, and other liver conditions 2.
- The degree of elevation of ALT and AST can help guide the evaluation, and a history of prescribed and over-the-counter medicines should be sought 2.
- Elevated AST levels have been associated with increased liver-related mortality and all-cause mortality, and may be a better predictor of mortality than ALT levels 3.
Potential Causes
- Alcoholic liver disease, viral hepatitis, and non-alcoholic steatosis are common diagnoses in asymptomatic patients with accidentally detected transaminase elevations 4.
- Drug-induced liver disease and other liver conditions should also be considered in the evaluation of elevated AST and ALT levels 2, 4.
- Elevated GGT levels have been shown to be a marker for metabolic syndrome, cardiovascular diseases, and mortality, and should be considered in the evaluation of liver function tests 5.
Evaluation and Diagnosis
- The evaluation of hepatocellular injury includes testing for viral hepatitis, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, and screening for hereditary hemochromatosis, autoimmune hepatitis, and other liver conditions 2.
- A liver biopsy may be considered when serologic testing and imaging fail to elucidate a diagnosis, or when multiple diagnoses are possible 2.
- The ratio of AST to ALT and the mitochondrial isoenzyme of AST can help differentiate between alcoholic and non-alcoholic liver disease 4.