What is the appropriate workup for a patient with elevated Liver Function Tests (LFTs)?

Diagnostic Approach for Elevated Liver Function Tests

The appropriate workup for a patient with elevated liver function tests (LFTs) should follow a systematic approach that includes pattern recognition, comprehensive history, targeted physical examination, laboratory testing, and imaging studies to identify the underlying cause.

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
• Categorize severity of elevation: mild (<5× ULN), moderate (5-10× ULN), or severe (>10× ULN) 1
• For mild elevations, do not simply repeat testing without a diagnostic plan, as 84% remain abnormal after 1 month and 75% after 2 years 1

Comprehensive History

• Medication review: prescribed, over-the-counter, herbal supplements, and illicit drugs 1, 2
• Alcohol consumption history using AUDIT-C screening tool 1
• Risk factors for viral hepatitis: country of birth/ethnicity, injection drug use, high-risk sexual behavior 1
• Travel history, occupational exposures, and tick bites 1
• Family history of liver disease or autoimmune conditions 1, 2
• Features of metabolic syndrome (obesity, hypertension, diabetes, dyslipidemia) 1

Physical Examination

• Body mass index calculation 1, 2
• Abdominal examination for hepatosplenomegaly, ascites, and other signs of chronic liver disease 1
• Assessment for stigmata of chronic liver disease (spider angiomata, palmar erythema) 2

Core Laboratory Panel

• Complete liver panel: ALT, AST, ALP, GGT, total and direct bilirubin, albumin, INR 1
• Viral hepatitis screen: Hepatitis B surface antigen, Hepatitis C antibody (with PCR if positive) 1
• Autoimmune markers: IgG, anti-nuclear antibody, anti-smooth muscle antibody, anti-mitochondrial antibody 1
• Iron studies: serum ferritin and transferrin saturation 1
• For marked ALT elevations (>1000 U/L), consider hepatitis A, hepatitis E, and cytomegalovirus 1
• For isolated elevation of transaminases, consider checking creatine kinase 1
• If cholestatic pattern with elevated ALP, confirm hepatic origin by checking GGT 3

Imaging Studies

• Abdominal ultrasound to assess liver parenchyma, biliary tract, and for signs of cirrhosis or focal lesions 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) 1
• For suspected alcoholic liver disease: note AST/ALT ratio >2 1, 2
• For suspected hemochromatosis (elevated ferritin and transferrin saturation >45%): consider genetic testing 1
• For suspected autoimmune hepatitis: comprehensive autoimmune panel 1
• Liver biopsy should be considered if the patient is steroid-refractory or if there is concern for other differential diagnoses that would alter medical management 1

Specific Scenarios

• For patients on immune checkpoint inhibitors with elevated LFTs: monitor ALT, AST, and bilirubin before each infusion and consider weekly monitoring if Grade 1 LFT elevations are present 1
• For patients with cholestatic pattern: distinguish between extrahepatic (biliary obstruction) and intrahepatic (PBC, PSC, drugs) causes 3
• For patients with both elevated transaminases and cholestatic enzymes: consider conditions affecting both hepatocytes and bile ducts 1

Referral Criteria

• ALT >5× ULN or bilirubin >3× ULN 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 1
• Positive tests for viral hepatitis, autoimmune hepatitis, primary biliary cholangitis, or hemochromatosis 1

Common Pitfalls to Avoid

• Don't ignore mild elevations, as they may indicate underlying liver disease 1, 4
• Don't miss hepatitis B or C infection, which may be asymptomatic but require treatment 1, 2
• Don't attribute elevated LFTs to known liver disease without excluding other causes 1
• Don't overlook medication-induced liver injury, which requires prompt identification 1, 5
• Don't forget to assess for alcohol consumption, which is a common cause of liver enzyme elevation 1