Diagnostic Approach for Elevated Liver Function Tests
For patients with elevated liver function tests (LFTs), a systematic diagnostic workup should begin with determining the pattern of elevation, followed by comprehensive laboratory testing including viral hepatitis screening, autoimmune markers, and appropriate imaging studies. 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
- Categorize elevation severity: mild to moderate (<3× upper limit of normal [ULN]) or severe (>3× ULN) 1
- Calculate ALT:AST ratio - ratio >1 typically suggests non-alcoholic liver diseases, while AST:ALT ratio >1 is more common in alcoholic liver disease 1, 2
- Assess for symptoms of liver dysfunction (jaundice, abdominal pain, weight loss, pruritus) 1
Core Laboratory Panel
- Complete blood count with platelets to assess for cytopenias that may suggest portal hypertension 1, 3
- Comprehensive metabolic panel including electrolytes, creatinine, BUN, and glucose 3, 1
- Additional liver function tests: total and direct bilirubin, albumin, INR/prothrombin time to assess synthetic function 1, 2
- Viral hepatitis screen: Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody 3, 1
- Autoimmune markers: IgG, ANA, anti-smooth muscle antibody, anti-mitochondrial antibody (particularly if cholestatic pattern) 1
- Iron studies: serum iron, total iron-binding capacity, ferritin to evaluate for hemochromatosis 1
- Consider thyroid-stimulating hormone (TSH) to rule out thyroid dysfunction 3
- Consider Hepatitis A and E testing for marked ALT elevations (>1000 U/L) 1
Comprehensive History and Risk Assessment
- Medication review: prescribed medications, over-the-counter drugs, herbal supplements, and illicit substances 1, 3
- Alcohol consumption history (current and past intake, consider AUDIT-C screening) 1, 3
- Risk factors for viral hepatitis: country of birth, injection drug use, high-risk sexual behavior 1
- Family history of liver disease or autoimmune conditions 1
- Travel history and occupational exposures 1
Imaging Studies
- Abdominal ultrasound should be performed to assess liver parenchyma, biliary tract, and for signs of cirrhosis or focal lesions 3, 1
- 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) 3, 1
- For suspected alcoholic liver disease: check GGT, AST/ALT ratio >2 1, 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, 4
- For medication-related elevations: consider modification or discontinuation of suspected hepatotoxic medications 1
- For NAFLD: implement lifestyle modifications (weight loss, exercise) 3
- For alcohol-related: recommend alcohol cessation 1
Referral Criteria for Specialty Care
- 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 most remain abnormal on retesting after 1 month 1, 4
- Don't miss hepatitis B or C infection, which may be asymptomatic but require treatment 3, 1
- Don't overlook medication-induced liver injury, which is a common cause of abnormal LFTs 3, 1