What to Order When Requesting Bilirubin to Rule Out Liver Problems
When ordering tests to rule out liver disease, you should request a comprehensive liver panel including bilirubin (total and direct), albumin, ALT, ALP, and GGT, along with a complete blood count if not done in the past 12 months. 1
Initial Liver Panel Components
The 2018 Gut guidelines provide clear direction on the initial workup:
- Bilirubin (total and direct/conjugated): Essential for determining whether hyperbilirubinemia is conjugated or unconjugated, which narrows the differential diagnosis 1, 2
- Albumin: Measures hepatic synthetic function and helps differentiate acute from chronic liver disease 1
- ALT (alanine aminotransferase): Primary marker of hepatocellular injury 1
- ALP (alkaline phosphatase): Indicates cholestatic liver disease or bile duct obstruction 1
- GGT (gamma-glutamyl transferase): Confirms hepatic origin of elevated ALP and increases sensitivity for detecting NAFLD and alcohol-related liver disease, which account for 90% of liver mortality 1
- Complete blood count: If not performed within the previous 12 months 1
Why This Specific Panel Matters
The combination of these tests allows you to identify the pattern of liver injury—hepatocellular, cholestatic, or mixed—which guides further workup. 2
- GGT addition increases detection of abnormal liver tests from 15% to 30%, and elevated GGT is associated with increased liver-related and all-cause mortality 1
- While AST is not recommended routinely in the initial panel, it should be added reflexively if ALT or GGT is abnormal to calculate the AST:ALT ratio, which helps assess fibrosis risk 1
- An AST:ALT ratio >1 indicates advanced fibrosis or cirrhosis, even when both values are within normal range 1
Critical Next Step: Bilirubin Fractionation
Always fractionate total bilirubin into direct (conjugated) and indirect (unconjugated) components when elevated. 1, 3
- Direct bilirubin >35% of total suggests hepatobiliary disease or drug-induced liver injury 3
- Unconjugated bilirubin <20-30% of total without hemolysis confirms Gilbert's syndrome, a benign condition requiring only reassurance 2, 3
- This fractionation is essential because the pattern determines whether you're dealing with hemolysis, impaired conjugation (Gilbert's), biliary obstruction, or parenchymal liver disease 3
Common Pitfalls to Avoid
- Don't order bilirubin alone: A single test lacks sensitivity and specificity for liver disease 4
- Don't confuse "direct" with "conjugated": Direct bilirubin includes both conjugated bilirubin and delta bilirubin (half-life 21 days), which can cause prolonged hyperbilirubinemia even after resolution of acute injury 3
- Don't ignore normal transaminases in suspected cirrhosis: Both AST and ALT can be normal even with established cirrhosis, making the AST:ALT ratio valuable even when both are within reference range 1
- Don't add AST routinely to every initial panel: The BALLETS study showed this doesn't improve detection of specific disease, but it should be added reflexively when ALT or GGT is abnormal 1
Additional Considerations Based on Clinical Context
If specific risk factors are present, consider simultaneous second-line testing 1:
- High-risk groups (injection drug users, migrants from high-prevalence areas, prisoners): Add hepatitis B and C serology upfront 1
- Suspected autoimmune disease: Add autoantibodies (ANA, ASMA, anti-LKM) and immunoglobulins 1
- Suspected metabolic disease: Add alpha-1-antitrypsin, thyroid function, ceruloplasmin (ages 3-40) 1
Monitoring Strategy
- Mild elevations (<5× ULN) without symptoms: Monitor periodically while investigating the underlying cause 2
- Moderate-severe elevations or symptomatic patients: Monitor every 3-7 days 2
This algorithmic approach based on the 2018 Gut guidelines ensures you capture the 90% of liver mortality from NAFLD and alcohol-related disease while avoiding the false positives and patient anxiety that come from overly broad initial testing. 1