What is the initial workup and management for a patient with elevated Liver Function Tests (LFTs)?

Workup and Management of Elevated Liver Function Tests

Begin by measuring a complete hepatic panel (ALT, AST, ALP, GGT, total/direct bilirubin, albumin, PT/INR) to classify the pattern as hepatocellular, cholestatic, or mixed, then proceed with pattern-specific investigations and severity-based monitoring. 1, 2

Initial Laboratory Assessment

Obtain the following tests to characterize the liver injury pattern:

• Aminotransferases (ALT, AST) and cholestatic markers (ALP, GGT, bilirubin) to determine whether injury is hepatocellular, cholestatic, or mixed 3, 2
• Serum creatine kinase (CK) to exclude muscle injury as a cause of elevated AST 1, 2
• Albumin and PT/INR to assess synthetic liver function 2, 4
• Review all previous LFT results before ordering additional investigations, as this is frequently overlooked 2

Critical History Elements

Focus your clinical assessment on these specific factors:

• Medication exposure: All prescription drugs, over-the-counter medications, herbal supplements, and illicit drug use 3, 4
• Alcohol consumption: Quantify using AUDIT-C tool; specifically ask about >50 units/week (men) or >35 units/week (women) 3, 2, 4
• Metabolic risk factors: Central obesity, hypertension, diabetes, dyslipidemia (for NAFLD assessment) 3, 4
• Viral hepatitis risk: Country of birth (strongest predictor), ethnicity, travel history, occupational exposure 3
• Autoimmune features: Personal or family history of autoimmune disease, inflammatory bowel disease (for PSC consideration) 3

Pattern-Based Investigation

Hepatocellular Pattern (Elevated ALT/AST)

Order this core panel for all patients 3:

• Viral hepatitis markers: Anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HCV (with PCR if positive) 3, 2, 4
• Autoimmune markers: ANA, anti-smooth muscle antibody, anti-mitochondrial antibody, serum immunoglobulins 3, 4
• Iron studies: Simultaneous serum ferritin and transferrin saturation (>45% suggests hemochromatosis) 3
• Abdominal ultrasound: To evaluate liver parenchyma, assess for steatosis, exclude masses 3, 1

For patients with NAFLD risk factors (obesity, diabetes, dyslipidemia, hypertension), calculate FIB-4 or NAFLD Fibrosis Score for risk stratification 2, 4

Cholestatic Pattern (Elevated ALP/GGT)

• Confirm hepatic origin by checking GGT if ALP is elevated alone 2, 4
• Abdominal ultrasound immediately to evaluate for biliary obstruction and assess the biliary system 3, 2, 4
• Consider anti-mitochondrial antibody for primary biliary cholangitis 3
• Consider MRI if PSC is suspected (cholestatic pattern + inflammatory bowel disease history) 3

Severity Classification and Monitoring

Classify aminotransferase elevations as follows 1, 4:

Mild Elevations (<5× ULN)

• Monitor liver enzymes weekly until normalization 1, 2, 4
• Discontinue all potentially hepatotoxic medications and alcohol 2, 4
• If initial workup is unrevealing and LFTs remain mildly elevated, observe for 3-6 months with repeat testing before considering liver biopsy 1

Moderate Elevations (5-10× ULN)

• Monitor liver enzymes every 2-3 days until stable or improving 1, 2, 4
• For patients on immune checkpoint inhibitors with Grade 2 hepatotoxicity (ALT >3× ULN), hold treatment and consider steroids (0.5-1 mg/kg/day prednisone) if no improvement after 3-5 days 2, 4

Severe Elevations (>10× ULN)

• Monitor liver enzymes every 1-2 days 2, 4
• For patients on immune checkpoint inhibitors with Grade 3 hepatotoxicity (ALT 5-20× ULN), permanently discontinue treatment and immediately start steroids (1-2 mg/kg methylprednisolone) 2, 4

Life-Threatening Elevations (>20× ULN)

• Immediate hospitalization for intensive monitoring and supportive care 1, 4
• For patients on immune checkpoint inhibitors with Grade 4 hepatotoxicity, permanently discontinue treatment 4

Medication-Specific Management

For patients on methotrexate 3:

• Minor elevations are common
• If elevation exceeds 2× normal: Check more frequently
• If elevation exceeds 3× normal: Consider dose reduction
• If elevation exceeds 5× normal: Discontinue methotrexate

For all other medications, stop potentially hepatotoxic drugs if ALT/AST exceeds 5× ULN, or if any elevation occurs with jaundice or elevated bilirubin 2

Special Population: Harmful Alcohol Drinkers

For patients consuming >50 units/week (men) or >35 units/week (women) 2, 4:

• Perform FibroScan/ARFI elastography for risk stratification 2, 4
• Refer to hepatology if ARFI >7.8 kPa 2
• Refer to alcohol services if AUDIT score >19 (alcohol dependency) 4

Mandatory Hepatology Referral Criteria

Refer immediately for 2, 4:

• Hepatitis B (HBsAg positive) or hepatitis C (antibody and PCR positive)
• Autoimmune hepatitis (raised IgG ± positive autoantibodies)
• Primary biliary cholangitis (cholestatic enzymes + positive anti-mitochondrial antibody)
• PSC (cholestatic enzymes ± inflammatory bowel disease history)
• Hemochromatosis (raised ferritin and transferrin saturation >45%)
• Persistent unexplained elevations after initial workup
• Evidence of advanced fibrosis on non-invasive testing
• ALT >5× ULN

Common Pitfalls to Avoid

• Isolated elevated ferritin does not reflect hemochromatosis; it commonly occurs in dysmetabolic iron overload syndrome with alcohol excess or NAFLD 3
• Transient LFT abnormalities in patients with vascular disease may be due to decreased liver perfusion and typically normalize within 2 days 5
• In the BALLETS study, <5% of adults with abnormal LFTs had a specific liver disease, and only 1.3% required immediate treatment 3
• Country of origin (not ethnic group) is the strongest predictor of viral hepatitis 3
• Infliximab is contraindicated in patients on immune checkpoint inhibitors with hepatitis 4