From the Guidelines
The next step for a patient with elevated liver enzymes, negative hepatitis screen, and normal liver ultrasound would be to refer them to a gastroenterologist with an interest in liver disease/hepatologist for further evaluation, as recommended by the most recent guidelines 1. This approach is based on the understanding that liver enzyme elevations can have numerous potential causes beyond viral hepatitis and structural abnormalities, including metabolic, autoimmune, genetic, and drug-induced liver injury, which require systematic evaluation to identify and appropriately manage.
Key Considerations
- A detailed history and physical examination should be conducted to identify potential causes, including assessment of alcohol consumption, medication review, and evaluation for metabolic conditions.
- Additional targeted testing may include a complete metabolic panel, complete blood count, iron studies, ceruloplasmin level, antimitochondrial antibodies, anti-smooth muscle antibodies, and immunoglobulin levels to evaluate for autoimmune hepatitis, hemochromatosis, Wilson's disease, and primary biliary cholangitis.
- Non-alcoholic fatty liver disease (NAFLD) should be considered even with normal ultrasound, particularly in patients with metabolic risk factors.
- If clinical suspicion warrants, consider testing for alpha-1 antitrypsin deficiency and celiac disease.
Rationale
The American Gastroenterological Association medical position statement on the evaluation of liver chemistry tests emphasizes the importance of interpreting abnormal liver chemistries in the clinical context of a given patient 1. However, the most recent guidelines from 2018 recommend referral to a specialist for further evaluation, even with a negative extended liver aetiology screen and no risk factors for NAFLD 1. This approach prioritizes the identification and management of potential underlying causes of liver enzyme elevations, ultimately aiming to improve patient outcomes in terms of morbidity, mortality, and quality of life.
From the Research
Next Steps for Patients with Elevated Liver Enzymes
The next steps for a patient with elevated liver enzymes, a negative hepatitis screen, and a normal liver ultrasound are:
- Repeat the liver enzyme test to confirm the result 2
- Differentiate between a predominant "necrotic pattern" of liver chemistry, as indicated by an elevation of ALT- or AST-activity, or a predominant "cholestatic pattern", as indicated by elevated activities of g-GT and alkaline phosphatase 2
- Consider non-invasive serologic tests to exclude hepatic diseases, such as chronic hepatitis B and C, autoimmunhepatitis, non-alcoholic steatohepatitis, hemochromatosis, Wilson-disease, and celiac sprue 2
- If non-invasive serologic studies remain inconclusive, consider further diagnostic tests such as ultrasound, mini-laparoscopy, and liver biopsy 2
- Evaluate the patient's clinical presentation and the pattern of injury to guide the diagnostic work-up and management 3
- Consider the possibility of extrahepatic diseases that may cause similarly increased serum activities, and evaluate the patient accordingly 4
Common Causes of Elevated Liver Enzymes
Some common causes of elevated liver enzymes include:
- Viral hepatitis 4
- Genetic liver diseases, such as Wilson's disease or hemochromatosis 4
- Drug-induced liver diseases 4
- Alcoholic or non-alcoholic fatty liver disease 4
- Infiltrating liver diseases 4
- Chronic hepatitis B and C 5
- Autoimmunhepatitis 2
- Non-alcoholic steatohepatitis 2
- Hemochromatosis 2
- Wilson-disease 2
- Celiac sprue 2
Diagnostic Approach
The diagnostic approach to elevated liver enzymes should be guided by both the clinical presentation and the pattern of injury 3. A step-wise algorithm can be used to interpret abnormal elevation of liver enzymes in asymptomatic patients 6. The algorithm should classify enzyme alterations on the basis of pattern (hepatocellular, cholestatic, and isolated hyperbilirubinemia) and review the most common causes of enzyme alteration, and suggest initial investigations 6.