What is the recommended stepwise approach to evaluating elevated liver function tests in an adult patient?

Stepwise Approach to Evaluating Elevated Liver Function Tests

Begin with urgent triage: patients with marked enzyme elevations (>5× upper limit of normal), synthetic dysfunction (prolonged INR, low albumin), or clinical signs of decompensation (jaundice, ascites, encephalopathy) require immediate hepatology referral. 1

Initial Clinical Assessment

Obtain a detailed medication history including all prescription drugs, over-the-counter medications, herbal supplements, and vitamins, as drug-induced liver injury is a common reversible cause. 1

• Document alcohol consumption using validated tools like the AUDIT questionnaire, as alcohol-related liver disease accounts for the majority of liver-related mortality in Western populations. 1
• Assess metabolic risk factors: body mass index >25, type 2 diabetes, hypertension, and dyslipidemia, which suggest non-alcoholic fatty liver disease (NAFLD). 1
• Note that there is synergy between alcohol and obesity—when BMI >35, the risk of liver disease doubles for any given alcohol intake. 1

Pattern Recognition Based on Enzyme Elevation

Determine whether the pattern is hepatocellular (transaminase-predominant) or cholestatic (alkaline phosphatase-predominant) to guide subsequent testing. 1, 2

Hepatocellular Pattern (ALT/AST >5× normal, ALP <3× normal):

• Order a standard liver etiology panel including: hepatitis B surface antigen, hepatitis C antibody with reflex PCR, ferritin with transferrin saturation, anti-mitochondrial antibody, anti-smooth muscle antibody, antinuclear antibody, and serum immunoglobulins. 1
• Add alpha-1-antitrypsin level, thyroid function tests, and ceruloplasmin (if age <40 years). 1

Cholestatic Pattern (ALP >3× normal, transaminases mildly elevated):

• Confirm hepatic origin by checking gamma-glutamyltransferase (GGT). 1, 3
• Obtain abdominal ultrasound to distinguish extrahepatic biliary obstruction from intrahepatic cholestasis. 1, 2
• If biliary dilatation is present, proceed to endoscopic retrograde cholangiopancreatography. 2

Management of Mild Transaminase Elevations (<5× normal)

If initial serologic testing is unremarkable, the decision between observation versus additional testing depends on chronicity and clinical context. 1

• For transient elevations that normalize within 2 days, particularly in patients with vascular disease, no further workup is needed as these likely reflect decreased hepatic perfusion. 4
• Persistent elevations ≥6 months warrant comprehensive evaluation including imaging and consideration of liver biopsy, as entirely treatable conditions like seronegative autoimmune hepatitis may be overlooked. 1

Risk Stratification for NAFLD and Alcohol-Related Liver Disease

For patients with metabolic risk factors or harmful alcohol use (≥35 units/week women, ≥50 units/week men), fibrosis assessment is the critical next step. 1

First-Line Fibrosis Testing:

• Calculate FIB-4 score (using age, AST, ALT, platelet count) or NAFLD Fibrosis Score. 1
• Low-risk thresholds: FIB-4 <1.3 or NFS ≤-1.455 (use <2.0 and <0.12 for age >65). 1
• High-risk thresholds: FIB-4 >3.25 or NFS >0.675 warrant immediate specialist referral. 1

Second-Line Fibrosis Testing:

• For intermediate scores, obtain quantitative assessment with Enhanced Liver Fibrosis (ELF) test or transient elastography (FibroScan/ARFI). 1
• Refer to hepatology if ELF >9.5 or FibroScan >7.8 kPa (>16 kPa for alcohol-related disease). 1

Indications for Hepatology Referral

Refer patients with any of the following: 1

• Evidence of advanced fibrosis on non-invasive testing (elevated FIB-4, high elastography values)
• Features of cirrhosis or portal hypertension (thrombocytopenia, splenomegaly, varices)
• Persistently abnormal liver tests with negative extended workup and no NAFLD risk factors
• Synthetic dysfunction (prolonged PT/INR not corrected by vitamin K, low albumin)
• AUDIT score >19 indicating alcohol dependency requiring specialized alcohol services 1

Common Pitfalls to Avoid

Do not dismiss mildly elevated GGT, as isolated GGT elevation is associated with increased liver-related and all-cause mortality, particularly when significantly elevated (>100 U/L). 1

• Avoid extensive testing when pre-test probability suggests a specific diagnosis—focused testing based on clinical clues is more cost-effective and generates fewer false positives. 5
• Do not assume normal liver enzymes exclude significant liver disease, as NAFLD and alcohol-related liver disease can progress to cirrhosis with normal or minimally elevated enzymes. 1
• In NAFLD patients with cholestatic enzyme pattern (elevated ALP/GGT), there is higher prevalence of advanced fibrosis (31.3% vs 4.5% in mixed pattern) and metabolic comorbidities. 6
• Repeat testing only makes sense if values are <2× normal and normalize within 2 days; otherwise proceed with full evaluation rather than serial monitoring. 4