Workup for Elevated Liver Enzymes
The appropriate workup for elevated liver enzymes should begin with a thorough clinical history, targeted physical examination, and pattern recognition of enzyme elevation, followed by a systematic diagnostic approach to determine the underlying cause rather than simply repeating the same panel of tests. 1
Initial Assessment and Pattern Recognition
- Determine the pattern of liver enzyme elevation: hepatocellular (predominant ALT/AST elevation), cholestatic (predominant ALP/GGT elevation), or mixed pattern 1, 2
- An ALT:AST ratio >1 typically suggests non-alcoholic liver diseases, while AST:ALT ratio >1 is more common in alcoholic liver disease 2
- Categorize elevation severity: mild to moderate (<3× ULN) or severe (>3× ULN) 2
- Assess for symptoms of liver dysfunction (jaundice, abdominal pain, weight loss, pruritus) 1
Comprehensive History
- Medication review: prescribed, over-the-counter, herbal supplements, and illicit drugs 1
- Alcohol consumption history (current and past intake, consider AUDIT-C screening) 1, 2
- Risk factors for viral hepatitis: country of birth, injection drug use, high-risk sexual behavior 1
- Metabolic syndrome components: obesity, hypertension, diabetes, dyslipidemia 2, 3
- Family history of liver disease or autoimmune conditions 1
- Travel history and occupational exposures 1
Physical Examination
- Body mass index calculation 1
- Abdominal examination for hepatosplenomegaly, ascites, and other signs of chronic liver disease 1
- Assessment for stigmata of chronic liver disease (spider angiomata, palmar erythema, etc.) 2
Core Laboratory Panel
- Complete blood count with platelets 2
- Comprehensive metabolic panel including creatinine 2
- Additional liver function tests: total and direct bilirubin, albumin, INR 1, 2
- Viral hepatitis screen: Hepatitis B surface antigen, Hepatitis C antibody 1, 2
- Autoimmune markers: IgG, ANA, anti-smooth muscle antibody, anti-mitochondrial antibody (if cholestatic pattern) 1
- Iron studies: serum iron, total iron-binding capacity, ferritin 2, 3
- Consider Hepatitis A and E testing for marked ALT elevations (>1000 U/L) 1
Imaging
- Abdominal ultrasound to assess liver parenchyma, biliary tract, and for signs of cirrhosis or focal lesions 2
- Consider MRI/MRCP if primary sclerosing cholangitis is suspected (especially with inflammatory bowel disease history and cholestatic pattern) 1
Additional Testing Based on Initial Results
- For suspected NAFLD: calculate non-invasive fibrosis scores (FIB-4, NAFLD Fibrosis Score) 2, 3
- For suspected alcoholic liver disease: GGT, AST/ALT ratio >2 2
- For suspected autoimmune hepatitis: comprehensive autoimmune panel 1
- For suspected hemochromatosis (elevated ferritin and transferrin saturation >45%): consider genetic testing 1
Monitoring and Follow-up
- For mild elevations (<3× ULN) without clear cause: repeat testing in 2-5 days to establish trend 1, 2
- For medication-related elevations: consider modification or discontinuation of suspected hepatotoxic medications 2
- For NAFLD: implement lifestyle modifications (weight loss, exercise) 2
- For alcohol-related: recommend alcohol cessation 2
Referral Criteria
- ALT >8× ULN or >5× baseline in those with elevated baseline 1
- ALT >3× ULN with total bilirubin >2× ULN (meets Hy's Law criteria) 1
- Evidence of synthetic dysfunction (elevated INR, low albumin) 2
- Persistent elevation >2× ULN after 3 months despite addressing modifiable factors 2
- Imaging suggesting advanced fibrosis, cirrhosis, or focal lesions 2
Common Pitfalls to Avoid
- Don't simply repeat the same panel of tests without a diagnostic plan 1
- Don't ignore mild elevations, as 84% remain abnormal on retesting after 1 month 1
- Don't overlook extrahepatic causes of enzyme elevation (thyroid disorders, celiac disease, muscle disorders) 3
- Don't forget to assess for metabolic syndrome, which is associated with NAFLD, the most common cause of elevated transaminases 3
- Don't miss hepatitis B or C infection, which may be asymptomatic but require treatment 1, 2