What is the initial workup for a patient presenting with elevated liver enzymes?

Initial Workup for Elevated Liver Enzymes

Begin by determining the pattern of enzyme elevation—hepatocellular (predominant ALT/AST), cholestatic (predominant ALP/GGT), or mixed—as this directs the entire diagnostic pathway and determines which etiologies to prioritize. 1

Pattern Recognition and Severity Assessment

Categorize the elevation pattern first:

• Hepatocellular pattern: ALT and AST are predominantly elevated 1, 2
• Cholestatic pattern: ALP and GGT are predominantly elevated 1, 2
• Mixed pattern: Elevation of both hepatocellular and cholestatic enzymes 1, 3

Assess severity of elevation:

• Mild to moderate: <3× upper limit of normal (ULN) 1
• Severe: >3× ULN 1
• Markedly elevated: >1000 U/L suggests acute viral hepatitis or ischemic injury 1

Evaluate the ALT:AST ratio:

• ALT:AST ratio >1 suggests non-alcoholic liver disease 1
• AST:ALT ratio >1 (especially >2) suggests alcoholic liver disease 1, 4

Targeted History Elements

Medication review (this is critical as drug-induced liver injury is common):

• All prescription medications 1
• Over-the-counter medications 1
• Herbal supplements 1
• Illicit drugs 1

Alcohol consumption assessment:

• Current and past intake quantification 1
• Consider AUDIT-C screening tool 1

Viral hepatitis risk factors:

• Country of birth (endemic areas) 1
• Injection drug use history 1
• High-risk sexual behaviors 1

Metabolic risk factors:

• Body mass index calculation 1
• Components of metabolic syndrome 3

Family history specifics:

• Liver disease in relatives 1
• Autoimmune conditions 1

Additional exposures:

• Travel history 1
• Occupational exposures 1

Physical Examination Priorities

Assess for chronic liver disease stigmata:

• Spider angiomata 1
• Palmar erythema 1
• Hepatosplenomegaly 1
• Ascites 1

Calculate BMI to assess for NAFLD risk 1

Core Laboratory Panel (Order Immediately)

Complete blood count with platelets (thrombocytopenia suggests cirrhosis) 1

Comprehensive metabolic panel including creatinine 1

Complete liver function tests:

• Total and direct bilirubin 1
• Albumin 1
• INR (international normalized ratio) 1

Viral hepatitis screening:

• Hepatitis B surface antigen 1
• Hepatitis C antibody 1
• Consider Hepatitis A and E testing if ALT >1000 U/L 1

Autoimmune markers:

• IgG level 1
• Antinuclear antibody (ANA) 1
• Anti-smooth muscle antibody 1
• Anti-mitochondrial antibody (if cholestatic pattern) 1

Iron studies:

• Serum iron 1
• Total iron-binding capacity 1
• Ferritin 1

Initial Imaging

Abdominal ultrasound to evaluate:

• Liver parenchyma 1
• Biliary tract patency 1
• Signs of cirrhosis 1
• Focal lesions 1

Consider MRCP if primary sclerosing cholangitis is suspected (especially with inflammatory bowel disease history and cholestatic pattern) 1, 3

Pattern-Specific Additional Testing

For hepatocellular pattern with negative initial workup:

• Calculate FIB-4 or NAFLD Fibrosis Score if NAFLD suspected 1, 3
• Ceruloplasmin and 24-hour urine copper if age <40 (Wilson disease) 3
• Genetic testing for hemochromatosis if ferritin elevated and transferrin saturation >45% 1

For cholestatic pattern:

• Serum IgG4 levels to exclude IgG4-related cholangiopathy 3
• Serum protein electrophoresis if infiltrative disease suspected 3

For suspected alcoholic liver disease:

• GGT level 4
• Confirm AST/ALT ratio >2 4

Monitoring Strategy Based on Severity

For mild elevations (<3× ULN) without clear cause:

• Repeat testing in 2-5 days to establish trend 1, 4
• Do not assume spontaneous resolution (84% remain abnormal at 1 month) 1, 4

For medication-related elevations:

• Consider modification or discontinuation of suspected hepatotoxic medications 1

For NAFLD:

• Implement lifestyle modifications: 7-10% weight loss through caloric restriction and exercise 3
• Restrict saturated fat to <7% of total calories 3

For alcohol-related disease:

• Recommend complete alcohol cessation 1

Urgent Referral Criteria to Hepatology

Refer immediately if any of the following:

• ALT >8× ULN or >5× baseline in those with elevated baseline 1, 3
• ALT >3× ULN with total bilirubin >2× ULN (Hy's Law criteria—suggests severe drug-induced liver injury) 1, 3
• Evidence of synthetic dysfunction: elevated INR or low albumin 1, 3
• Persistent elevation >2× ULN after 3 months despite addressing modifiable factors 1
• Imaging suggesting advanced fibrosis, cirrhosis, or focal lesions 1

Critical Pitfalls to Avoid

Do not simply repeat the same tests without a diagnostic plan—each repeat should be part of a structured algorithm 1, 4

Do not ignore mild elevations—84% remain abnormal on retesting after 1 month, and 75% at 2 years 1, 3, 4

Do not miss hepatitis B or C infection—these may be completely asymptomatic but require treatment to prevent cirrhosis and hepatocellular carcinoma 1

Do not assume a "hepatocellular pattern" excludes biliary disease—choledocholithiasis can cause markedly elevated transaminases (even >1000 U/L) with severe abdominal pain, and these normalize rapidly after biliary decompression 5

Do not overlook medication review—drug-induced liver injury is extremely common and often reversible if identified early 1