What is the appropriate workup for elevated liver function tests?

Workup for Elevated Liver Function Tests

Initial Laboratory Panel

Begin with a comprehensive liver panel including ALT, AST, alkaline phosphatase (ALP), GGT, total and direct bilirubin, albumin, and prothrombin time/INR to assess both hepatocellular injury and synthetic function. 1

• Obtain a complete blood count if not performed within the previous 12 months 1
• Measure serum ferritin and transferrin saturation simultaneously to screen for hemochromatosis 1
• Check viral hepatitis serologies: hepatitis B surface antigen (HBsAg), hepatitis B core IgM (anti-HBc IgM), and hepatitis C antibody with reflex PCR if positive 1
• Order autoimmune markers including antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-mitochondrial antibody (AMA), and serum immunoglobulins 1

Pattern Recognition and Severity Classification

Calculate the R-value [(ALT/ULN)/(ALP/ULN)] to determine injury pattern: hepatocellular (R ≥5), mixed (2 < R < 5), or cholestatic (R ≤2). 2

• Classify severity as mild (<5× ULN), moderate (5-10× ULN), or severe (>10× ULN) 3, 2
• Note that ALT is more liver-specific than AST, which can be elevated from cardiac muscle, skeletal muscle, kidney, or red blood cell disorders 3
• Normal ALT ranges differ by sex: 29-33 IU/L for males and 19-25 IU/L for females 3
• An AST:ALT ratio >2 suggests alcoholic liver disease, while a ratio <1 is characteristic of NAFLD or viral hepatitis 3

Clinical History Essentials

Obtain a detailed quantitative alcohol history using validated tools (AUDIT or AUDIT-C), as alcohol intake ≥30 g/day in men or ≥20 g/day in women can produce liver enzyme elevations. 3

• Review all medications, over-the-counter drugs, and herbal supplements against the LiverTox® database, as medication-induced liver injury causes 8-11% of cases with mildly elevated liver enzymes 3
• Assess for metabolic syndrome components: measure waist circumference, blood pressure, fasting glucose or HbA1c, and fasting lipid panel 3
• Evaluate for symptoms of chronic liver disease including fatigue, jaundice, pruritus, right upper quadrant pain, or signs of hepatic decompensation 3

First-Line Imaging

Order abdominal ultrasound as the initial imaging modality, which has 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis. 3

• Ultrasound can identify hepatic steatosis, biliary obstruction or dilation, focal liver lesions, portal hypertension features, and structural abnormalities 1, 3
• Add Doppler ultrasound if vascular abnormalities (portal or hepatic vein thrombosis) are suspected 2
• Consider MRI with MRCP if ultrasound is unrevealing and cholestatic pattern persists, as it is superior for detecting intrahepatic biliary abnormalities and primary sclerosing cholangitis 2

Risk Stratification for Fibrosis

Calculate the FIB-4 score using age, ALT, AST, and platelet count to stratify risk for advanced fibrosis. 1, 3

• FIB-4 <1.3 (or <2.0 if age >65 years) indicates low risk with negative predictive value ≥90% 3
• FIB-4 >2.67 indicates high risk for advanced fibrosis and warrants hepatology referral 3
• Incorporate FIB-4 calculation facilities into primary care computer systems 1

Monitoring and Repeat Testing

For mild elevations (<2× ULN) without identified cause, repeat liver enzymes in 2-4 weeks to establish a trend. 3

• If ALT increases to 2-3× ULN, repeat testing within 2-5 days and intensify evaluation 3
• If ALT increases to >3× ULN or doubles from baseline, escalate monitoring and consider urgent evaluation 3
• For identified causes, monitor response to specific interventions (e.g., lifestyle modifications for NAFLD, alcohol cessation for alcoholic liver disease) 3

Hepatology Referral Criteria

Refer to hepatology if liver enzymes remain elevated for ≥6 months without identified cause, ALT increases to >5× ULN (>235 IU/L for males, >125 IU/L for females), or evidence of synthetic dysfunction develops. 3

• Urgent referral is warranted if ALT ≥3× ULN plus total bilirubin ≥2× ULN (Hy's Law pattern), suggesting potential for acute liver failure 3
• Consider referral if FIB-4 score >2.67 indicating high risk for advanced fibrosis 3
• Refer patients with suspected autoimmune hepatitis, Wilson disease (especially if age <40 years), or unexplained progressive enzyme elevation 3

Common Pitfalls to Avoid

Do not assume mild ALT elevation is benign without proper evaluation, as ALT elevation ≥5× ULN is rare in NAFLD alone and usually indicates viral hepatitis, autoimmune hepatitis, or drug-induced liver injury. 3

• Normal ALT does not exclude significant liver disease—up to 10% of patients with advanced fibrosis may have normal ALT using conventional thresholds 3
• Do not overlook non-hepatic causes of elevated transaminases: intensive exercise, muscle injury (check creatine kinase), cardiac injury, hemolysis, and thyroid disorders can all elevate transaminases, particularly AST 3
• Abnormal liver blood test results should only be interpreted after review of previous results, past medical history, and current medical condition 1
• The extent of liver blood test abnormality is not necessarily a guide to clinical significance—this is determined by the specific analyte which is abnormal and the clinical context 1

Etiology-Specific Considerations

For hepatocellular pattern (R ≥5), prioritize evaluation for NAFLD (most common), viral hepatitis, autoimmune hepatitis, alcohol-related liver disease, drug-induced liver injury, and hemochromatosis. 2

• For cholestatic pattern (R ≤2), evaluate for biliary obstruction, primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis, and infiltrative diseases 2
• In patients with inflammatory bowel disease, obtain high-quality MRCP to evaluate for primary sclerosing cholangitis 2
• Consider Wilson disease in acute liver failure presentations with markedly subnormal ALP and Coombs-negative hemolytic anemia 2