Initial Evaluation for Liver Function
The initial investigation for potential liver disease should include bilirubin, albumin, ALT, ALP, and GGT, together with a full blood count if not already performed within the previous 12 months. 1, 2
Standard Liver Aetiology Screen
After identifying abnormal liver function tests, a comprehensive liver aetiology screen should be performed to determine the underlying cause. This includes:
For Adults:
- Abdominal ultrasound scan
- Hepatitis B surface antigen
- Hepatitis C antibody (with follow-on PCR if positive)
- Autoantibody panel:
- Anti-mitochondrial antibody
- Anti-smooth muscle antibody
- Antinuclear antibody
- Serum immunoglobulins
- Simultaneous serum ferritin and transferrin saturation 1, 2
For Children:
- Abdominal ultrasound
- Viral hepatitis panel
- Autoantibody panel (including anti-liver kidney microsomal antibody)
- Coeliac antibodies
- Alpha-1-antitrypsin level
- Caeruloplasmin (age >3 years) 1
Interpretation of Abnormal Results
The pattern of liver test abnormalities can help determine the category of liver disease:
Hepatocellular Pattern (ALT/AST predominant elevation):
- Consider viral hepatitis, NAFLD, ARLD, autoimmune hepatitis, drug-induced liver injury
- For marked elevations in ALT (>1000 U/L), prioritize evaluation for acute viral hepatitis, autoimmune hepatitis, and drug toxicity 2, 3
Cholestatic Pattern (ALP/GGT predominant elevation):
- Consider primary biliary cholangitis, primary sclerosing cholangitis, biliary obstruction
- Urgent referral needed if biliary obstruction is suspected 2, 3
Mixed Pattern:
- Consider overlap syndromes, drug-induced liver injury, infiltrative diseases
Risk Stratification for Fibrosis
For patients with NAFLD or liver disease of unknown etiology:
Calculate FIB-4 or NAFLD Fibrosis Score (NFS)
- Low risk: FIB-4 <1.3 or NFS ≤1.455 (use higher cutoffs for patients >65 years: <2.0 and <0.12)
- Intermediate/high risk: FIB-4 >1.3 or NFS >1.455
For intermediate/high risk, proceed to second-line testing:
Consider referral to hepatology if:
- Evidence of advanced fibrosis (FibroScan >7.8 kPa)
- Invalid scan or high-risk scores 1
Important Clinical Considerations
The extent of liver test abnormality is not necessarily a guide to clinical significance; interpretation depends on the specific abnormal analyte and clinical context 1, 2
Both AST and ALT can be normal even in the setting of cirrhosis, and the AST:ALT ratio >1 suggests advanced fibrosis/cirrhosis 1, 2
GGT is the most sensitive test for detecting liver disease with the fewest false negatives 4, but its addition to a liver panel increases the likelihood of an abnormal result from 15% to 30% 1
Less than 5% of people with abnormal liver blood tests have a specific liver disease, and only 1.3% have a condition requiring immediate treatment 2
Indications for Urgent Referral to Secondary Care
- Marked derangement of liver blood tests
- Evidence of synthetic failure (low albumin, prolonged INR)
- Suspicious clinical symptoms/signs
- Dilated bile ducts on imaging
- Evidence of advanced liver disease (features of cirrhosis or portal hypertension) 1, 2
Common Pitfalls to Avoid
- Relying solely on the magnitude of enzyme elevation to determine clinical significance
- Failing to calculate fibrosis scores for patients with NAFLD
- Missing advanced liver disease due to normal or minimally elevated transaminases
- Overlooking the need for hepatitis viral load testing in patients who test positive for HBsAg, HBcAb IgG, or HCV antibodies 1
- Repeating a complete panel in response to an abnormal reading rather than focusing on specific abnormal analytes 5
By following this structured approach to liver function evaluation, clinicians can effectively identify patients with liver disease requiring immediate attention while avoiding unnecessary testing in those with benign or self-limiting conditions.