What tests should be done for a patient with elevated liver function, considering their age, sex, medical history, and risk factors for liver disease?

Evaluation of Elevated Liver Function Tests

All patients with elevated liver function tests should undergo a standard liver aetiology screen including complete blood count, comprehensive metabolic panel, hepatitis B surface antigen, hepatitis C antibody, anti-mitochondrial antibody, anti-smooth muscle antibody, antinuclear antibody, serum immunoglobulins, ferritin, and transferrin saturation, along with abdominal ultrasound. 1

Initial Laboratory Panel

The foundation of evaluating elevated liver enzymes requires a comprehensive approach to identify the underlying etiology and assess disease severity.

Core biochemical tests should include:

• Bilirubin, albumin, ALT, alkaline phosphatase (ALP), and GGT as the minimum panel 1
• Complete blood count if not performed within the previous 12 months 1
• Comprehensive metabolic panel to assess synthetic function including prothrombin time/INR 1
• Fasting lipid panel to evaluate for metabolic syndrome components 2

Viral hepatitis screening is essential:

• Hepatitis B surface antigen (HBsAg) 1
• Hepatitis C antibody with reflex PCR if positive 1
• Consider hepatitis B core antibody depending on risk factors 1

Autoimmune markers should be obtained:

• Anti-mitochondrial antibody (AMA) for primary biliary cholangitis 1
• Anti-smooth muscle antibody (ASMA) for autoimmune hepatitis 1
• Antinuclear antibody (ANA) 1
• Serum immunoglobulins 1

Metabolic screening includes:

• Simultaneous serum ferritin and transferrin saturation for hemochromatosis 1
• Alpha-1-antitrypsin level (especially in children or young adults) 1
• Ceruloplasmin if age >3 years in children or if Wilson's disease suspected 1

Alcohol and Medication Assessment

Screen all patients for alcohol use using the Alcohol Use Disorders Identification Test (AUDIT) 1. Harmful drinking is defined as:

• >14 units/week for women or >21 units/week for men 1
• AUDIT score >19 indicates alcohol dependency requiring referral to alcohol services 1

Complete medication review is critical:

• Document all prescription medications, over-the-counter drugs, vitamins, herbs, and supplements 1
• Check medications against the LiverTox® database for hepatotoxic potential 2, 3
• Medication-induced liver injury accounts for 8-11% of cases with elevated liver enzymes 3, 4

Imaging Evaluation

Abdominal ultrasound is the first-line imaging modality:

• Sensitivity of 84.8% and specificity of 93.6% for detecting moderate to severe hepatic steatosis 3, 4
• Identifies biliary obstruction, focal liver lesions, and signs of portal hypertension 1, 4
• Should be performed as part of the standard liver aetiology screen 1

Risk Stratification for Fibrosis

For patients with suspected NAFLD or persistent elevations, non-invasive fibrosis assessment is essential:

Calculate FIB-4 score as the primary screening tool:

• FIB-4 <1.3 indicates low risk (use <2.0 as cutoff if age >65 years) 1
• FIB-4 1.3-2.67 indicates indeterminate risk requiring further evaluation 1
• FIB-4 >2.67 indicates high risk requiring hepatology referral 1

NAFLD Fibrosis Score (NFS) is an alternative first-line test 1, 2

Liver stiffness measurement via transient elastography (FibroScan) for indeterminate risk patients:

• <8 kPa indicates low risk 1
• 8-12 kPa indicates indeterminate risk 1
• >12 kPa indicates high risk requiring hepatology referral 1

High-Risk Groups Requiring Screening

Three groups warrant proactive screening for NAFLD-related fibrosis:

1. All patients with type 2 diabetes - up to 20% have clinically significant fibrosis 1
2. Patients with ≥2 metabolic risk factors including central obesity, hypertriglyceridemia (≥150 mg/dL), low HDL cholesterol (<40 mg/dL men, <50 mg/dL women), hypertension (≥130/85 mm Hg), or prediabetes (fasting glucose 100-125 mg/dL) 1
3. Incidental hepatic steatosis on imaging with elevated aminotransferases - 11% have advanced fibrosis 1

Pattern Recognition and Interpretation

Hepatocellular pattern (disproportionate ALT/AST elevation):

• AST:ALT ratio <1 suggests NAFLD, viral hepatitis, or medication-induced injury 3
• AST:ALT ratio ≥2 is highly suggestive of alcoholic liver disease 3
• ALT is more liver-specific than AST, which can be elevated from cardiac, skeletal muscle, kidney, or red blood cell disorders 3, 5

Cholestatic pattern (disproportionate ALP elevation):

• Confirm hepatic origin with elevated GGT 5
• Ultrasound distinguishes extrahepatic (biliary obstruction) from intrahepatic cholestasis 5

Severity-Based Management

Mild elevations (<5× upper limit of normal):

• Repeat testing in 2-4 weeks to establish trend 3, 4
• Continue standard workup as outlined above 1

Moderate elevations (5-10× ULN):

• More urgent evaluation within 2-5 days 3
• Complete full aetiology screen immediately 1

Severe elevations (>10× ULN):

• Consider urgent referral to secondary care 1
• Evaluate for acute hepatitis, ischemic hepatitis, or drug-induced liver injury 3

Referral Criteria to Hepatology

Urgent referral is warranted for:

• ALT >8× ULN or >5× baseline 2
• Evidence of synthetic dysfunction (elevated INR, low albumin, elevated bilirubin) 2
• Dilated bile ducts on imaging 2
• Features of cirrhosis or portal hypertension 1
• FibroScan reading >16 kPa in alcohol-related liver disease 1

Routine referral is indicated for:

• Persistent elevation >2× ULN after 3 months despite addressing modifiable factors 2
• Abnormal liver tests with negative extended aetiology screen and no NAFLD risk factors 1
• FIB-4 score >2.67 or liver stiffness >12 kPa 1
• Persistent elevation ≥6 months without identified cause 3, 4

Common Pitfalls to Avoid

Do not assume normal ALT excludes liver disease - up to 10% of patients with advanced fibrosis have normal ALT using conventional thresholds 3. True healthy normal ALT ranges are 29-33 IU/L for males and 19-25 IU/L for females, significantly lower than commercial laboratory cutoffs 3, 6.

Do not overlook non-hepatic causes - intensive exercise, muscle injury, cardiac injury, hemolysis, and thyroid disorders can elevate transaminases, particularly AST 3. Check creatine kinase if muscle injury suspected 3, 4.

Do not delay imaging - approximately 20% of patients with abnormal liver tests have a co-existing etiology beyond the obvious cause 4. Early ultrasound establishes baseline and may identify conditions requiring urgent intervention 3.

Do not attribute ALT ≥5× ULN to NAFLD alone - this level of elevation is rare in NAFLD and warrants investigation for viral hepatitis, autoimmune hepatitis, or drug-induced liver injury 3.