What does elevated Lactate Dehydrogenase (LDH), Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) mean?

Elevated LDH, AST, and ALT: Diagnostic Significance and Management

Elevated LDH, AST, and ALT indicate liver injury that requires systematic evaluation to determine the underlying cause, with the pattern and degree of elevation providing important diagnostic clues. 1

Diagnostic Significance of Elevated Enzymes

Pattern Recognition

• AST/ALT ratio > 2: Highly suggestive of alcoholic liver disease (ALD); ratios > 3 are even more specific for ALD 2
• ALT/LDH ratio:
  • Ratio > 1.5: Suggests viral hepatitis (sensitivity 94%, specificity 84%)
  • Ratio < 1.5: Suggests ischemic hepatitis or drug-induced liver injury 3
• Degree of elevation:
  • AST > 500 IU/L or ALT > 200 IU/L: Uncommon in alcoholic hepatitis; suggests another etiology 2
  • ALT/AST > 5× ULN: Requires immediate evaluation 1
  • ALT/AST > 3× ULN with total bilirubin ≥2× ULN (Hy's Law): Indicates severe liver injury with high mortality risk 1

Common Causes

1. Drug-induced liver injury (DILI): Most common cause of severe liver injury in developed countries 1
2. Viral hepatitis: Accounts for approximately 11% of cases with ALT > 500 U/L 4
3. Alcoholic liver disease: Characterized by AST/ALT ratio > 2 2
4. Choledocholithiasis: Most common cause (34%) of notably high ALT (>500 U/L) 4
5. Ischemic hepatitis: Accounts for 18% of cases with ALT > 500 U/L, with high mortality (35%) 4
6. Non-alcoholic fatty liver disease (NAFLD): Common cause of chronic elevation 1
7. Malignancy: Very high isolated LDH is associated with cancer (27%), liver metastases (14%), and hematologic malignancies (5%) 5

Evaluation Approach

Initial Laboratory Tests

• Complete liver panel: ALT, AST, ALP, GGT, total and direct bilirubin 1
• Hepatitis B serology (HBsAg, anti-HBc)
• Hepatitis C antibody with reflex RNA testing if positive
• HIV testing if risk factors present
• Autoimmune markers (ANA, SMA, IgG, IgM, IgA) if autoimmune hepatitis suspected 1

Imaging

• Abdominal ultrasound: First-line imaging to assess:
  • Liver morphology and echogenicity
  • Biliary tract obstruction
  • Presence of masses or metastases
  • Signs of cirrhosis or portal hypertension 1

Medication Review

• Identify and consider discontinuing all non-essential medications that may cause liver injury
• Review all prescription drugs, over-the-counter medications, vitamins, herbs, and supplements 1

Management Based on Severity

Mild Elevation

• Repeat liver enzymes every 3 months
• Implement lifestyle modifications (Mediterranean diet, regular exercise, weight loss if overweight/obese)
• Avoid alcohol consumption 1

Moderate to Severe Elevation

• Monitor liver enzymes every 2-3 days until improving
• Discontinue suspected causative medications immediately if ALT/AST > 5× ULN or ALT/AST > 3× ULN with total bilirubin ≥2× ULN
• Monitor for signs of hepatic decompensation 1

When to Refer to Hepatology

• ALT/AST > 5× ULN
• Persistent elevation > 6 months despite interventions
• Evidence of advanced liver disease on imaging
• Elevated ALT/AST with elevated bilirubin (Hy's Law)
• Suspected autoimmune hepatitis requiring histological confirmation
• Signs of hepatic decompensation 1

Prognostic Significance

• Very high isolated LDH is associated with:
  • Longer hospital stays (9.3 vs. 4.1 days)
  • Higher in-hospital complications
  • Higher mortality rate (26.6% vs. 4.3%) 5
• LDH is an independent predictor of mortality in admitted medical patients 5

Common Pitfalls to Avoid

1. Overlooking non-hepatic causes: AST is present in cardiac and skeletal muscle and erythrocytes; ALT is more specific for liver damage 6
2. Assuming correlation between enzyme levels and liver damage: In chronic viral hepatitis, enzyme elevation may not correlate well with the degree of liver damage 7
3. Premature discontinuation of statins: According to FDA labeling, statins should not be discontinued for mild, asymptomatic elevations in transaminases 1
4. Missing ischemic hepatitis: This condition has high mortality (35%) and requires prompt recognition and management 4
5. Incomplete evaluation: 6% of cases with ALT > 500 U/L have no specific etiology identified despite thorough workup 4