From the Guidelines
Elevated ALT workup should begin with a thorough history and physical examination, focusing on risk factors for liver disease, and initial laboratory testing should include a comprehensive metabolic panel, complete blood count, and coagulation studies, as recommended by the most recent study 1. The workup is crucial because elevated ALT indicates hepatocellular injury, which can result from various conditions including viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune hepatitis, and medication-induced liver injury. Key aspects of the workup include:
- Thorough history of symptoms, co-existing medical conditions, concomitant medications, dietary and nutritional supplements, excessive exercise or muscle injury, alcohol consumption, and illicit substances, as outlined in the study 1.
- First-line testing should include serum creatine kinase, hepatitis A testing, hepatitis B testing, hepatitis C testing, hepatitis E testing, autoantibody and immunoglobulin testing, and hepatobiliary imaging, as recommended by the study 1.
- Second-line testing may include serological tests for EBV, CMV, HSV, and additional tests such as liver biopsy, alcohol testing, and serum acetaminophen level, as suggested by the study 2. The goal of the workup is to identify the underlying cause of the elevated ALT and prevent progression to cirrhosis and liver failure, as emphasized by the study 3. It is essential to consider the patient's history, severity of liver injury, underlying disease, and geography when determining the extent and type of workup, as noted in the study 1. A liver biopsy may be necessary to confirm a diagnosis of autoimmune hepatitis or to determine the pattern and severity of drug-induced liver injury, as recommended by the study 1.
From the Research
Elevated ALT Workup
Elevated serum levels of transaminases (AST and ALT) usually indicate hepatocellular damage, with ALT elevations also possibly being of extrahepatic origin (muscle) 4. The following are potential causes and steps for evaluation:
- Hepatocellular injury: defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels 5
- Cholestatic injury: defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels 5
- Viral hepatitis A, B, and C
- Nonalcoholic fatty liver disease
- Alcoholic liver disease
- Hereditary hemochromatosis
- Autoimmune hepatitis
- Wilson's disease
- Alpha-1 antitrypsin deficiency
- Prescribed and over-the-counter medicines
Evaluation Steps
The evaluation of hepatocellular injury includes:
- Testing for viral hepatitis A, B, and C
- Assessment for nonalcoholic fatty liver disease and alcoholic liver disease
- Screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency
- History of prescribed and over-the-counter medicines 5 For the evaluation of an alkaline phosphatase elevation determined to be of hepatic origin, testing for primary biliary cholangitis and primary sclerosing cholangitis should be undertaken 5.
Diagnostic Considerations
A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible 5. The presence of an elevated ALT has been associated with increased liver-related mortality, and a true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females 5. Elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions, and an elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings 5.
Autoantibodies and Autoimmune Hepatitis
Autoantibodies may exist in serum of patients with nonalcoholic fatty liver disease (NAFLD), although their prevalence and clinical significance is uncertain 6. The presence of autoantibodies is associated with higher fibrosis stage, higher inflammatory grade, and higher levels of gammaglobulin 6. Liver biopsy is required to rule out autoimmune hepatitis (AIH) in most NAFLD patients with positive autoantibodies 6. Markedly elevated transaminases with minimal elevation of ALP and positive ANA in a young woman should have pointed toward AIH at an earlier stage 7.
ALT as a Biomarker
Assay of the serum activity of the enzyme alanine aminotransferase (ALT) has become the primary screening tool for detecting acute liver injury, but it is not a test of liver function, and it does not necessarily predict worse effects to come (in a given person) 8. ALT is a very useful biomarker if understood and used properly, and it is important to consider how and why these erroneous concepts came to have such wide acceptance, and how elevations of ALT activity for evaluating patients and subjects under study might be interpreted better 8.