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

Diagnostic Workup for Elevated Liver Enzymes

The initial workup for elevated liver enzymes should follow a systematic approach based on pattern recognition, comprehensive history, physical examination, laboratory testing, and imaging to determine the underlying cause and guide appropriate management. 1

Pattern Recognition and Initial Assessment

• Determine the pattern of liver enzyme elevation: hepatocellular (predominant ALT/AST elevation), cholestatic (predominant ALP/GGT elevation), or mixed pattern 1, 2
• Categorize elevation severity: mild to moderate (<3× ULN) or severe (>3× ULN) to guide urgency of workup 1
• Assess ALT:AST ratio - ratio >1 typically suggests non-alcoholic liver diseases, while AST:ALT ratio >1 is more common in alcoholic liver disease 2
• Evaluate for symptoms of liver dysfunction (jaundice, abdominal pain, weight loss, pruritus) 1, 3

Comprehensive History

• Conduct detailed medication review: prescribed medications, over-the-counter drugs, herbal supplements, and illicit substances 1, 2
• Assess alcohol consumption history (current and past intake, consider AUDIT-C screening) 1
• Identify risk factors for viral hepatitis: country of birth, injection drug use, high-risk sexual behavior 2
• Document family history of liver disease or autoimmune conditions 1
• Record travel history and occupational exposures 2

Physical Examination

• Calculate body mass index (BMI) - obesity is associated with non-alcoholic fatty liver disease (NAFLD) 1, 3
• Perform abdominal examination for hepatosplenomegaly, ascites, and other signs of chronic liver disease 2
• Look for stigmata of chronic liver disease (spider angiomata, palmar erythema, etc.) 1

Initial Laboratory Testing

• Complete blood count with platelets 1, 2
• Comprehensive metabolic panel including creatinine 1
• Complete liver function tests: ALT, AST, alkaline phosphatase, GGT, total and direct bilirubin, albumin, INR 2, 3
• Viral hepatitis screen: Hepatitis B surface antigen, Hepatitis C antibody 1, 2
• Consider autoimmune markers if pattern suggests: IgG, ANA, anti-smooth muscle antibody, anti-mitochondrial antibody (if cholestatic pattern) 2
• Iron studies: serum iron, total iron-binding capacity, ferritin 1
• Consider Hepatitis A and E testing for marked ALT elevations (>1000 U/L) 2
• Thyroid function tests to rule out thyroid disorders as a cause of transaminase elevations 3
• Creatine kinase to rule out muscle disorders as a cause of AST elevation 3

Imaging

• Abdominal ultrasound to assess liver parenchyma, biliary tract, and for signs of cirrhosis or focal lesions 1, 2
• Consider MRI/MRCP if primary sclerosing cholangitis is suspected (especially with inflammatory bowel disease history and cholestatic pattern) 1

Management Based on Severity

• For mild elevations (<3× ULN), repeat testing in 2-5 days to establish trend 1
• For moderate elevations (5-10× ULN), repeat ALT, AST, ALP, and bilirubin within 2-5 days 3
• For severe elevations (>10× ULN) or ALT >3× ULN with bilirubin >2× ULN, immediate evaluation with repeat testing within 2-3 days 3
• For immune checkpoint inhibitor-related hepatitis, initiate corticosteroids (1-2 mg/kg/day methylprednisolone or equivalent) for grade 3-4 elevations 4, 1

Additional Testing Based on Initial Results

• For suspected NAFLD: calculate non-invasive fibrosis scores (FIB-4, NAFLD Fibrosis Score) 2
• For suspected alcoholic liver disease: GGT, AST/ALT ratio >2 2
• For suspected autoimmune hepatitis: comprehensive autoimmune panel 2
• For suspected hemochromatosis (elevated ferritin and transferrin saturation >45%): consider genetic testing 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, 2
• Evidence of synthetic dysfunction (elevated INR, low albumin) 2
• 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, 2
• Avoid premature discontinuation of all medications before identifying the likely causative agent 1
• Don't overlook the potential relationship between liver function and other factors that could affect liver enzymes 1
• Don't miss hepatitis B or C infection, which may be asymptomatic but require treatment 2