What is the appropriate workup and management for elevated liver function tests (LFTs)?

Workup of Elevated Liver Function Tests

Begin with pattern recognition to categorize the elevation as hepatocellular (predominant ALT/AST), cholestatic (predominant alkaline phosphatase/GGT), or mixed, then obtain a core laboratory panel and abdominal ultrasound to identify treatable causes while assessing severity to determine urgency of evaluation. 1

Initial Pattern Recognition and Severity Assessment

Determine the pattern of liver enzyme elevation immediately:

• Hepatocellular pattern: ALT and AST are predominantly elevated, typically with ALT:AST ratio >1 in non-alcoholic liver disease or AST:ALT ratio >1 in alcoholic liver disease 1
• Cholestatic pattern: Alkaline phosphatase and GGT are predominantly elevated, suggesting biliary obstruction or cholestatic liver disease 2, 1
• Mixed pattern: Both hepatocellular and cholestatic markers are elevated 1

Categorize severity to guide urgency:

• Mild to moderate: <3× upper limit of normal (ULN) 1
• Severe: >3× ULN, requiring more urgent evaluation 1
• Critical: ALT ≥3× ULN with total bilirubin ≥2× ULN (Hy's Law criteria), indicating risk of acute liver failure 3

Comprehensive Clinical History

Obtain specific risk factor information that directly impacts differential diagnosis:

• Alcohol consumption: Quantify current and past intake in units per week using AUDIT-C screening tool, as alcohol excess is a leading preventable cause 2, 1
• Medication review: Document all prescribed medications, over-the-counter drugs, herbal supplements, and illicit substances, as drug-induced liver injury is common 2, 1
• Viral hepatitis risk factors: Country of birth (strongest predictor of viral hepatitis), injection drug use, high-risk sexual behavior, and travel history 2, 1
• Metabolic syndrome components: Assess for central obesity, hypertension, diabetes, and dyslipidemia, as NAFLD is the most common cause of elevated LFTs in developed countries 2
• Family history: Autoimmune diseases, hemochromatosis, and other inherited liver conditions 2, 1
• Inflammatory bowel disease: Personal or family history suggests primary sclerosing cholangitis if cholestatic pattern present 2

Physical Examination Findings

Focus on specific signs that indicate chronic liver disease or complications:

• Calculate body mass index to assess for obesity-related NAFLD 2, 1
• Palpate for hepatosplenomegaly and ascites 2, 1
• Examine for stigmata of chronic liver disease including spider angiomata, palmar erythema, jaundice, and muscle wasting 1

Core Laboratory Panel

Order this standardized panel for all patients with elevated LFTs:

• Complete metabolic panel: ALT, AST, alkaline phosphatase, total and direct bilirubin, albumin, and creatinine 2, 1, 3
• Synthetic function markers: INR/prothrombin time to assess liver synthetic capacity 2, 1, 3
• Complete blood count: Including platelet count for fibrosis risk stratification 1
• Viral hepatitis serologies: Hepatitis B surface antigen and hepatitis C antibody (with reflex PCR if positive), as these are treatable causes 2, 1
• Autoimmune markers: Anti-mitochondrial antibody, anti-smooth muscle antibody, antinuclear antibody, and serum immunoglobulins 2, 1
• Iron studies: Simultaneous serum ferritin and transferrin saturation to screen for hemochromatosis (transferrin saturation >45% is significant) 2, 1
• GGT or 5'-nucleotidase: To confirm hepatic origin of isolated alkaline phosphatase elevation 3, 4

For marked ALT elevations (>1000 U/L), add:

• Hepatitis A and E serologies, cytomegalovirus testing 2, 1

First-Line Imaging

Abdominal ultrasound is the initial imaging modality for all patients with persistent LFT abnormalities:

• Sensitivity of 84.8% and specificity of 93.6% for detecting moderate to severe hepatic steatosis 5, 1
• Identifies biliary obstruction, focal liver lesions, hepatosplenomegaly, and signs of cirrhosis 2, 5, 1
• Cost-effective and widely available without radiation exposure 2

Consider MRI/MRCP if:

• Primary sclerosing cholangitis is suspected (cholestatic pattern with inflammatory bowel disease history) 2, 1
• Ultrasound is unrevealing but clinical suspicion remains high 5

Risk Stratification for Advanced Fibrosis

Calculate non-invasive fibrosis scores to determine need for hepatology referral:

• FIB-4 score: Uses age, ALT, AST, and platelet count; score >2.67 indicates high risk for advanced fibrosis and warrants specialist referral 5, 1
• NAFLD Fibrosis Score: Alternative scoring system for suspected NAFLD 1

Etiology-Specific Management

Based on initial workup results, implement targeted interventions:

For NAFLD (most common cause):

• Target 7-10% weight loss through caloric restriction with low-carbohydrate, low-fructose diet 5, 3
• Prescribe 150-300 minutes of moderate-intensity aerobic exercise weekly 5
• Aggressively manage metabolic comorbidities including diabetes, hypertension, and dyslipidemia 5

For alcoholic liver disease:

• Recommend complete alcohol abstinence, as even moderate consumption impedes recovery 5, 3
• AST:ALT ratio >2 supports this diagnosis 1

For drug-induced liver injury:

• Discontinue suspected hepatotoxic medications immediately 5, 3
• Monitor ALT every 3-7 days until declining, with normalization expected within 2-8 weeks 5, 3

For viral hepatitis (HBsAg or HCV antibody positive):

• Refer to hepatology or infectious disease for antiviral therapy, as these are highly treatable conditions 2, 5

For autoimmune hepatitis (elevated IgG with positive autoantibodies):

• Refer to hepatology for consideration of immunosuppressive therapy 2

For hemochromatosis (ferritin elevated with transferrin saturation >45%):

• Refer to hepatology for genetic testing and therapeutic phlebotomy 2

Monitoring Protocol Based on Severity

For mild elevations (<2× ULN):

• Repeat liver enzymes in 2-4 weeks to establish trend 5, 3
• If normalizing, continue monitoring every 4-8 weeks until stable 5

For moderate elevations (2-3× ULN):

• Repeat testing within 2-5 days and intensify evaluation 5, 1
• Hold potentially hepatotoxic agents immediately 3

For severe elevations (>3× ULN):

• Repeat testing within 2-3 days 5
• Initiate hepatology consultation for persistent or worsening elevations 3

Urgent Hepatology Referral Criteria

Refer immediately if any of the following are present:

• ALT >5× ULN or ALT >3× ULN with total bilirubin >2× ULN (Hy's Law criteria) 1, 3
• Evidence of synthetic dysfunction: INR >1.5, low albumin, or elevated bilirubin 1, 3
• Dilated bile ducts on imaging requiring urgent assessment 2
• Persistent elevation >6 months despite addressing modifiable factors 5, 1
• FIB-4 score >2.67 or imaging suggesting advanced fibrosis or cirrhosis 5, 1

Critical Pitfalls to Avoid

Common errors that delay diagnosis or worsen outcomes:

• Don't assume isolated alkaline phosphatase elevation is hepatic: Always confirm with GGT or alkaline phosphatase isoenzymes, as bone disease is a common alternative cause 3, 4
• Don't ignore mild elevations: 84% of mild elevations remain abnormal on retesting after 1 month, and up to 5% have specific treatable liver disease 2, 1
• Don't miss viral hepatitis: Country of origin is the strongest predictor, and these infections may be asymptomatic but require treatment to prevent progression 2, 1
• Don't continue hepatotoxic drugs while "monitoring" moderate-to-severe elevations: This risks progression to acute liver failure 3
• Don't overlook non-hepatic causes: Intensive exercise, muscle injury, cardiac injury, hemolysis, and thyroid disorders can elevate transaminases, particularly AST 5
• Don't rely solely on aminotransferases in cirrhosis: Monitor bilirubin, INR, and clinical symptoms, as normal ALT does not exclude significant liver disease 3
• Don't delay specialist referral for Hy's Law criteria: ALT ≥3× ULN with bilirubin ≥2× ULN carries 10% mortality risk and requires immediate hepatology consultation 3

Special Considerations

ALT is more liver-specific than AST: ALT is primarily concentrated in liver tissue, while AST can be elevated from cardiac muscle, skeletal muscle, kidney, or red blood cell disorders 5, 6

Normal ALT ranges differ by sex: 29-33 IU/L for males and 19-25 IU/L for females, making elevations more significant in women 5

Isolated elevated ferritin is common in dysmetabolic iron overload syndrome: This occurs with alcohol excess and NAFLD and does not reflect hemochromatosis unless transferrin saturation is also >45% 2

Neonatal cholestasis requires urgent pediatric referral: Conjugated bilirubin >25 μmol/L in infants should be discussed immediately with a pediatrician 2