What are the causes of transaminitis (elevated liver enzymes)?

Causes of Transaminitis (Elevated Liver Enzymes)

Transaminitis is most commonly caused by non-alcoholic fatty liver disease (NAFLD) and alcohol-induced liver disease, with other important causes including viral hepatitis, drug-induced liver injury, autoimmune hepatitis, and metabolic disorders. 1

Common Causes

Metabolic and Lifestyle-Related Causes

• Non-alcoholic fatty liver disease (NAFLD): The most common cause of transaminitis in developed countries, affecting 20-30% of the general population, increasing to 70% in obesity and 90% in diabetes 1
• Alcohol-induced liver disease: Characterized by an AST:ALT ratio typically >2 (compared to <1 in metabolic-related fatty liver) 1
• Obesity: A significant independent risk factor for transaminitis (OR 3.23) 2
• Type 2 diabetes: Associated with increased risk of persistent transaminitis (OR 3.52) 2
• Hypercholesterolemia: Independent risk factor for transaminitis (OR 2.56) 2
• Hyperuricemia: Associated with increased risk of transaminitis (OR 3.52) 2

Infectious Causes

• Viral hepatitis: Including hepatitis A, B, C, and E infections 1, 3
• Cytomegalovirus and Epstein-Barr virus: Can trigger transaminitis and occasionally precipitate autoimmune hepatitis 1

Drug-Induced Causes

• Medications: Common culprits include:
  • Statins: Can cause dose-dependent transaminase elevations in 0.5-2.0% of patients 1
  • Methotrexate: Associated with transaminitis, particularly in patients with underlying NAFLD risk factors 2
  • Acetaminophen (Paracetamol): Can cause severe hepatitis even at therapeutic doses in alcoholic patients 4
  • Minocycline and nitrofurantoin: Associated with drug-induced autoimmune hepatitis 1
  • Biologics: Infliximab and other immune checkpoint inhibitors can cause immune-related hepatitis 1

Autoimmune and Genetic Causes

• Autoimmune hepatitis: Accounts for approximately 1.3% of cases of unexplained transaminitis 5
• Primary biliary cirrhosis: Found in about 1.3% of patients with unexplained transaminitis 5
• Hemochromatosis: Uncommon cause of elevated liver enzymes 1
• Wilson's disease: Rare cause of transaminitis 1
• Alpha-1-antitrypsin deficiency: Rare genetic cause (0.7% of unexplained cases) 5

Other Causes

• Celiac disease: Associated with transaminitis in 40% of adults and 54% of children at diagnosis 1
• Ischemic hepatitis: Due to reduced blood flow to the liver 1
• Budd-Chiari syndrome: Hepatic venous outflow obstruction 1
• Cryptogenic hepatitis: Chronic hepatitis with no obvious etiology accounts for approximately 24% of cases with persistent transaminitis 5
• Non-hepatic causes: Particularly for AST elevations, including muscle disorders, thyroid disease, and strenuous exercise 1

Diagnostic Approach

Initial Assessment

• Severity classification of transaminitis: 1
  • Mild: <5 times the upper reference limit
  • Moderate: 5-10 times the upper reference limit
  • Severe: >10 times the upper reference limit

Key Diagnostic Tests

• Ultrasound: First-line investigation for mild transaminase elevations, with 84.8% sensitivity and 93.6% specificity for moderate to severe hepatic fat deposition 1
• Viral hepatitis serology: Test for hepatitis A, B, C, and E 3
• Autoimmune markers: Including ANA, ASMA, and ANCA if suspicion for autoimmune hepatitis is high 1
• Metabolic assessment: Evaluate for insulin resistance, which is strongly associated with NAFLD 1
• Alcohol history: Critical to differentiate alcoholic from non-alcoholic liver disease 1

Special Considerations

HIV Patients

• HIV-infected individuals have multiple risk factors for transaminitis including coinfection with hepatitis viruses, medication toxicity, alcohol use, and metabolic comorbidities 3

Immune Checkpoint Inhibitor Therapy

• Patients on immune checkpoint inhibitors require close monitoring of liver enzymes due to risk of immune-related hepatitis 1
• Infliximab is contraindicated for immune-related hepatitis 1

Celiac Disease

• Patients with celiac disease and NAFLD should follow a gluten-free diet to improve liver enzymes and histology 1

Methotrexate Users

• Patients on methotrexate with NAFLD risk factors require careful monitoring for liver injury 2

Pitfalls to Avoid

• Relying solely on transaminase levels: Normal levels do not rule out significant liver disease, as 30% of patients with normal ALT may have significant inflammation 1
• Overlooking non-hepatic causes: Particularly for AST elevations, which can originate from cardiac and skeletal muscle, kidney, and brain 6
• Ignoring mild elevations: Even mild transaminase elevations can indicate significant underlying liver disease, including cirrhosis in some cases 5
• Missing drug-induced causes: Always review all medications and supplements, as many can cause hepatotoxicity 1

By systematically evaluating these potential causes and following appropriate diagnostic pathways, clinicians can effectively identify and manage the underlying etiology of transaminitis.