What is the appropriate workup for a patient with persistently elevated liver function tests (LFTs)?

Systematic Approach to Persistently Elevated Liver Function Tests

The initial evaluation of abnormal liver tests should include a detailed history, medication review, physical examination, and pattern recognition of liver enzyme elevations, followed by targeted laboratory and imaging studies to establish the diagnosis. 1, 2

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) 2, 3
• 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, 3
• Evaluate for symptoms of liver dysfunction (jaundice, abdominal pain, weight loss, pruritus) 2

Comprehensive History and Physical Examination

• Conduct detailed medication review: prescribed medications, over-the-counter drugs, herbal supplements, and illicit substances 1, 3
• 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, 3
• Calculate BMI and assess for metabolic syndrome components (waist circumference, hypertension, diabetes, dyslipidemia) 1
• Perform abdominal examination for hepatosplenomegaly, ascites, and other signs of chronic liver disease 2, 3

Initial Laboratory Testing

• Complete blood count with platelets 2, 3
• Comprehensive metabolic panel including liver enzymes (ALT, AST, ALP, GGT), bilirubin (total and direct), albumin, and INR 1, 2
• Viral hepatitis screen: Hepatitis B surface antigen, Hepatitis C antibody 2, 3
• Autoimmune markers: IgG, ANA, anti-smooth muscle antibody, anti-mitochondrial antibody (especially if cholestatic pattern) 2, 3
• Iron studies: serum iron, total iron-binding capacity, ferritin 2, 3
• Consider Hepatitis A and E testing for marked ALT elevations (>1000 U/L) 2

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) 2, 3

Risk Stratification for Common Causes

For suspected NAFLD:

• Calculate non-invasive fibrosis scores (FIB-4, NAFLD Fibrosis Score) 1
• If indeterminate or high risk, proceed to second-line testing with ELF test or Fibroscan/ARFI elastography 1
• Refer patients with evidence of advanced fibrosis or cirrhosis to hepatology 1

For suspected alcoholic liver disease:

• Consider risk stratification with clinical assessment and Fibroscan/ARFI elastography 1
• Refer to secondary care if evidence of advanced liver disease or Fibroscan reading >16 kPa 1
• Consider referral to alcohol services for patients with evidence of alcohol dependency (AUDIT score >19) 1

For suspected drug-induced liver injury:

• Review all medications, including over-the-counter and herbal supplements 1
• Consider temporary discontinuation of suspected hepatotoxic medications 1, 3
• Monitor liver enzymes after medication discontinuation 1, 3

Follow-up and Monitoring

• For mild elevations (<3× ULN) without clear cause: repeat testing in 2-5 days to establish trend 2, 3
• 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 2, 3
• ALT >3× ULN with total bilirubin >2× ULN (meets Hy's Law criteria) 2, 3
• Evidence of synthetic dysfunction (elevated INR, low albumin) 2, 3
• Persistent elevation >2× ULN after 3 months despite addressing modifiable factors 1, 2
• Imaging suggesting advanced fibrosis, cirrhosis, or focal lesions 1, 2
• Adults with abnormal liver blood tests, even with a negative extended liver aetiology screen and no risk factors for NAFLD, should be referred to a gastroenterologist with an interest in liver disease/hepatologist for further evaluation 1

Common Pitfalls to Avoid

• Don't simply repeat the same panel of tests without a diagnostic plan 2, 3
• Don't ignore mild elevations, as 84% remain abnormal on retesting after 1 month 3, 4
• Don't miss hepatitis B or C infection, which may be asymptomatic but require treatment 2, 3
• Be aware that normal liver blood tests do not rule out advanced liver fibrosis and cirrhosis 1
• Remember that in autoimmune liver disease, autoantibodies may be negative and immunoglobulins normal 1