What is the appropriate workup for an adult patient with elevated Liver Function Tests (LFTs) and no prior history of liver disease?

Workup for Elevated Liver Function Tests

Begin with pattern recognition of the enzyme elevation (hepatocellular vs. cholestatic vs. mixed), followed by a comprehensive etiologic screen including viral hepatitis, autoimmune markers, iron studies, and abdominal ultrasound, as 84% of abnormal liver tests remain abnormal at 1 month and require systematic evaluation. 1, 2

Determine the Pattern of Elevation

• Hepatocellular pattern: Predominant ALT/AST elevation suggests conditions like viral hepatitis, NAFLD, alcoholic liver disease, or drug-induced liver injury 1, 2
• Cholestatic pattern: Predominant alkaline phosphatase (ALP) or GGT elevation suggests biliary obstruction, primary biliary cholangitis, or infiltrative disease 1, 2
• Mixed pattern: Proportional elevation of both hepatocellular and cholestatic enzymes 1
• Check GGT with isolated ALP elevation to confirm hepatic origin versus bone source 1
• Check creatine kinase (CK) if isolated transaminase elevation is present to exclude muscle source, particularly in patients who exercise regularly 1, 3

Essential Clinical History Elements

• Alcohol quantification: Use AUDIT-C screening; exclude consumption >21 drinks/week in men or >14 drinks/week in women 4, 2
• Complete medication review: Include prescribed drugs, over-the-counter medications, herbal supplements, and illicit drugs as potential hepatotoxins 1, 2
• Viral hepatitis risk factors: Country of birth, injection drug use, high-risk sexual behavior, tattoos 1, 2
• Metabolic syndrome features: Central obesity, hypertension, diabetes/insulin resistance, dyslipidemia (suggests NAFLD) 2
• Family history: Liver disease, autoimmune conditions, hemochromatosis 1
• Sexual history: High-risk behavior may indicate syphilitic hepatitis, which presents with elevated LFTs 5

Core Laboratory Panel (Order Immediately)

• Viral hepatitis screen: Hepatitis B surface antigen, Hepatitis C antibody 4, 1, 2
• Autoimmune markers: IgG, antinuclear antibody (ANA), anti-smooth muscle antibody; add anti-mitochondrial antibody if cholestatic pattern 4, 1
• Iron studies: Serum iron, total iron-binding capacity, ferritin, transferrin saturation (hemochromatosis screening) 4, 1, 2
• Liver synthetic function: Total and direct bilirubin, albumin, INR, platelet count 4, 1
• Complete blood count: Including platelets to assess for portal hypertension 4
• Comprehensive metabolic panel: Including creatinine 1
• Alpha-1 antitrypsin level: Consider based on clinical context 4
• Ceruloplasmin: Consider in younger patients (<40 years) to exclude Wilson disease 4

Imaging

• Abdominal ultrasound: Assess liver parenchyma for steatosis, biliary tract patency, signs of cirrhosis (nodular contour, splenomegaly), and focal lesions 4, 1
• MRI/MRCP: Consider if primary sclerosing cholangitis suspected, especially with inflammatory bowel disease history and cholestatic pattern 1

Pattern-Specific AST/ALT Ratio Interpretation

• AST:ALT ratio >2: Suggests alcoholic liver disease, particularly when GGT is also elevated 4, 2
• ALT:AST ratio >1: Typically indicates non-alcoholic liver diseases including NAFLD 4, 1
• Very high transaminases (>1000 U/L): Consider acute viral hepatitis (A or E), ischemic hepatitis, or drug-induced liver injury 1

Risk Stratification for NAFLD (Most Common Cause)

• NAFLD accounts for approximately 40% of abnormal liver tests in developed countries 2
• Calculate FIB-4 or NAFLD Fibrosis Score to assess for advanced fibrosis risk in patients with suspected NAFLD 1, 2
• Diagnosis requires fatty liver on ultrasound with alcohol consumption <7 drinks/week for women, <14 for men 2

Monitoring Strategy Based on Severity

• Mild elevations (<3× ULN): Repeat testing in 2-5 days to establish trend; address modifiable factors (discontinue hepatotoxic medications, alcohol cessation, weight loss) 4, 1, 2
• Moderate elevations (3-8× ULN): More frequent monitoring and expedited workup 4, 1
• Severe elevations (>8× ULN or >5× baseline): Daily monitoring of liver enzymes, bilirubin, and INR until trend established 4, 1, 2

Immediate Referral to Hepatology

• ALT >8× ULN or >5× baseline in patients with elevated baseline 4, 1, 2
• ALT >3× ULN with total bilirubin >2× ULN (meets Hy's Law criteria for severe drug-induced liver injury) 4, 1
• Evidence of synthetic dysfunction: Elevated INR (>1.2), low albumin, or thrombocytopenia 4, 1, 2
• Imaging suggesting cirrhosis or focal lesions 1

Routine Referral to Hepatology

• Persistent elevation >2× ULN after 3 months despite addressing modifiable factors 1
• Inconclusive etiology after comprehensive workup 4
• Suspected advanced fibrosis based on non-invasive scoring 1, 2

Critical Pitfalls to Avoid

• Do not simply repeat the same tests without a diagnostic plan; each recheck should be purposeful 1
• Do not dismiss mild elevations; 84% remain abnormal on retesting after 1 month 1, 2
• Do not miss asymptomatic hepatitis B or C, which require treatment to prevent progression to cirrhosis and hepatocellular carcinoma 1, 2
• Do not overlook exercise-induced elevations; consider checking CK and asking about recent strenuous physical activity 1, 3
• Do not forget sexual history; syphilitic hepatitis is rare but treatable and can present with isolated LFT elevation 5
• Do not exclude hemochromatosis screening; check ferritin and transferrin saturation simultaneously as part of initial workup 4, 1, 2