What are the causes of elevated Liver Function Tests (LFTs)?

Common Causes of Elevated Liver Function Tests (LFTs)

Elevated liver function tests (LFTs) are most commonly caused by non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, and chronic viral hepatitis, with the pattern of elevation often providing important diagnostic clues to the underlying etiology. 1

Hepatocellular Pattern (Predominant ALT/AST Elevation)

Common Causes

• Non-alcoholic fatty liver disease (NAFLD) - Most common cause in developed countries, affecting 20-30% of general population, up to 70% in obesity and 90% in diabetes 1
• Alcohol-related liver disease - Typically shows AST:ALT ratio >2 (often >3) 2
• Viral hepatitis - Acute or chronic (hepatitis A, B, C, D, E, EBV, CMV, HSV) 2
• Drug-induced liver injury (DILI) - Prescription medications, OTC drugs, herbal supplements 2

Less Common Causes

• Autoimmune hepatitis
• Hemochromatosis - Genetic disorder with iron overload 2
• Wilson's disease - Genetic disorder with copper accumulation 2
• Alpha-1 antitrypsin deficiency
• Ischemic hepatitis (shock liver)
• Muscle disorders - Can cause AST elevation (check creatine kinase) 2

Cholestatic Pattern (Predominant ALP Elevation)

Common Causes

• Biliary obstruction - Gallstones, strictures, tumors
• Primary biliary cholangitis
• Primary sclerosing cholangitis
• Drug-induced cholestasis

Less Common Causes

• Infiltrative diseases - Sarcoidosis, amyloidosis
• Malignancy - 57% of isolated ALP elevations of unclear etiology are associated with underlying malignancy 2
• Sepsis
• Bone disorders - Can cause non-hepatic ALP elevation 2

Mixed Pattern (Both Hepatocellular and Cholestatic)

• Drug-induced liver injury
• Alcoholic hepatitis
• Infiltrative liver diseases
• Advanced liver disease/cirrhosis

Clinical Approach to Elevated LFTs

Step 1: Assess Pattern and Severity

• Hepatocellular pattern: ALT/AST elevated more than ALP
  • Mild: <5× upper limit of normal
  • Moderate: 5-10× upper limit of normal
  • Severe: >10× upper limit of normal 1
• Cholestatic pattern: ALP elevated more than ALT/AST
• Mixed pattern: Both elevated proportionally

Step 2: First-Line Investigations

• Repeat LFTs to confirm abnormality
• Complete blood count with platelets
• Hepatitis serology (HBsAg, HCV antibody)
• Liver function panel (bilirubin, albumin, INR)
• GGT to confirm hepatic source of ALP elevation
• Creatine kinase if muscle origin suspected 2

Step 3: Risk Assessment and Additional Testing

• Lifestyle factors: Alcohol intake, obesity, diabetes
• Medication review: Prescription drugs, OTC medications, supplements
• Abdominal ultrasound: First-line imaging for fatty liver, biliary obstruction, masses 2
• Second-line testing based on clinical suspicion:
  • Autoimmune markers (ANA, ASMA, AMA)
  • Iron studies (ferritin, transferrin saturation)
  • Ceruloplasmin (Wilson's disease)
  • Alpha-1 antitrypsin levels
  • Additional viral serology (HEV, EBV, CMV) 2

Important Clinical Considerations

AST:ALT Ratio

• >2: Suggests alcohol-related liver disease
• <1: Consider NAFLD, viral hepatitis, or Wilson's disease 2

Pitfalls to Avoid

1. Attributing elevation solely to NAFLD without excluding other causes 2
2. Ignoring mild elevations - May indicate significant underlying disease, particularly in cholestatic processes 2
3. Not evaluating alcohol use - Even when another cause is identified 1
4. Assuming normal LFTs exclude liver disease - LFTs can be normal despite significant fibrosis or cirrhosis 3

Monitoring Recommendations

• Lifestyle modifications: Repeat LFTs in 4-8 weeks 2
• Medication-related: Check LFTs at 4 weeks, then every 3-6 months 2
• Persistent unexplained elevation: Consider referral for further evaluation, including possible liver biopsy 1

Special Considerations

Drug-Induced Liver Injury

• Common medications: Statins, antibiotics, NSAIDs, antiepileptics
• Pioglitazone: Rare cases of hepatotoxicity reported; monitor LFTs before initiation and periodically thereafter 4

Fibrosis Assessment

• Non-invasive tests: FIB-4 score, NAFLD fibrosis score, elastography
• Consider referral if evidence of advanced fibrosis on non-invasive testing 1, 2

Remember that LFTs alone have poor predictive value for significant liver disease, with only 3.9% of patients with abnormal values being diagnosed with significant liver disease within 5 years 1. A systematic approach based on pattern recognition and targeted investigations is essential for accurate diagnosis and management.