What is the initial workup for a patient with elevated liver enzymes?

Initial Workup for Elevated Liver Enzymes

The initial workup for elevated liver enzymes should begin with determining the pattern of liver enzyme elevation (hepatocellular, cholestatic, or mixed), assessing severity, and conducting a targeted laboratory panel with appropriate imaging. 1

Pattern Recognition and Severity Assessment

• Determine the pattern of liver enzyme elevation: hepatocellular (predominant ALT/AST elevation), cholestatic (predominant ALP/GGT elevation), or mixed pattern 1
• Categorize elevation severity: mild to moderate (<3× ULN) or severe (>3× ULN) 1
• Note that an ALT:AST ratio >1 typically suggests non-alcoholic liver diseases, while AST:ALT ratio >1 is more common in alcoholic liver disease 1
• Normal ALT ranges differ by sex, with ranges of 29-33 IU/L for males and 19-25 IU/L for females 2

Comprehensive History and Physical Examination

• Conduct a detailed medication review including prescribed medications, over-the-counter drugs, herbal supplements, and illicit substances 1
• Assess alcohol consumption history (current and past intake, consider AUDIT-C screening) 1
• Evaluate risk factors for viral hepatitis: country of birth, injection drug use, high-risk sexual behavior 1
• Document family history of liver disease or autoimmune conditions 1
• Record travel history and occupational exposures 1
• Calculate body mass index and assess for metabolic syndrome components 2
• Perform abdominal examination for hepatosplenomegaly, ascites, and other signs of chronic liver disease 1
• Look for stigmata of chronic liver disease (spider angiomata, palmar erythema, etc.) 1

Core Laboratory Panel

• Complete blood count with platelets 1
• Comprehensive metabolic panel including:
  • Liver function tests: ALT, AST, alkaline phosphatase, GGT 1
  • Total and direct bilirubin 1
  • Albumin and prothrombin time/INR (to assess synthetic function) 1
• Viral hepatitis screen: Hepatitis B surface antigen, Hepatitis C antibody 1
• Consider additional tests based on pattern of elevation:
  • For hepatocellular pattern: Autoimmune markers (IgG, ANA, anti-smooth muscle antibody), iron studies (serum iron, total iron-binding capacity, ferritin), and consider Hepatitis A and E testing for marked ALT elevations (>1000 U/L) 1
  • For cholestatic pattern: Anti-mitochondrial antibody 1
  • For AST elevation: Consider creatine kinase to rule out muscle disorders 2
  • Thyroid function tests to rule out thyroid disorders as a cause of transaminase elevations 2

Imaging

• Abdominal ultrasound is recommended as the first-line imaging test for evaluating liver enzyme elevations 1, 2
• Ultrasound can identify fatty liver, biliary obstruction, and structural abnormalities 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) 1
• For suspected alcoholic liver disease: Evaluate GGT, AST/ALT ratio >2 1
• For suspected autoimmune hepatitis: Obtain 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
• For medication-related elevations: Consider modification or discontinuation of suspected hepatotoxic medications 1
• For NAFLD: Implement lifestyle modifications (weight loss, exercise) 1
• For alcohol-related: Recommend alcohol cessation 1

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) 1
• Persistent elevation >2× ULN after 3 months despite addressing modifiable factors 1
• Imaging suggesting advanced fibrosis, cirrhosis, or focal lesions 1

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 miss hepatitis B or C infection, which may be asymptomatic but require treatment 1
• Don't overlook the potential relationship between liver function and other factors that could affect liver enzymes 3
• Don't attribute ALT elevation of ≥5× ULN to NAFLD/NASH alone, as this level of elevation warrants evaluation for other causes 2