What is ALT (Alanine Transaminase) and what's its significance?

Alanine Aminotransferase (ALT): Definition and Clinical Significance

ALT is a liver-specific enzyme that serves as a primary biomarker for hepatocellular injury, with normal levels defined as <30 U/L for men and <19 U/L for women, and elevations indicating potential liver damage requiring further evaluation. 1

What is ALT?

ALT (Alanine Aminotransferase) is an enzyme primarily found in liver cells (hepatocytes) that catalyzes the transfer of an amino group from alanine to α-ketoglutarate. While ALT is predominantly expressed in the liver, it's also present in smaller amounts in other tissues:

• Liver specificity: ALT is more liver-specific than AST (Aspartate Aminotransferase), making it a more reliable marker for liver damage 2
• Isoforms: Two isoforms exist - ALT1 and ALT2 - with different tissue distribution patterns:
  • ALT1 is predominantly expressed in the liver
  • ALT2 is more abundant in muscle tissue 3

Clinical Significance of ALT

1. Diagnostic Value

ALT elevations are typically classified by severity:

• Mild: <5× upper limit of normal (ULN)
• Moderate: 5-10× ULN
• Severe: >10× ULN 4

The pattern of elevation provides diagnostic clues:

• Hepatocellular pattern: Predominant ALT elevation (ALT > AST)
• AST:ALT ratio >2: Suggestive of alcoholic liver disease 4
• ALT isoform analysis: Can distinguish hepatic from extrahepatic injury (ALT1 predominates in liver injury while ALT2 increases more in muscle injury) 3

2. Screening Applications

ALT is used for screening in several contexts:

• Non-alcoholic fatty liver disease (NAFLD): Recommended screening tool in obesity guidelines 5
• Viral hepatitis: Part of core laboratory panel for hepatitis evaluation 4
• Medication monitoring: Used to detect drug-induced liver injury 4

3. Prognostic Value

ALT has important prognostic implications:

• Cardiovascular risk: Elevated ALT predicts coronary heart disease events independent of traditional risk factors 6
• Treatment response: Normal on-treatment ALT during antiviral therapy for hepatitis B is associated with a lower risk of hepatic events 7
• Fibrosis progression: Persistently elevated ALT may indicate ongoing liver damage and fibrosis progression 4

Updated Reference Ranges

Traditional ALT reference ranges have been revised downward based on studies of healthy populations:

• Men: <30 U/L (previously 40 U/L)
• Women: <19 U/L (previously 30 U/L) 1

These updated ranges improve sensitivity for detecting liver disease, particularly in patients with early-stage liver conditions 1.

Evaluation of Elevated ALT

When ALT is elevated, a systematic approach is recommended:

1. Initial assessment:

   • Review medication history (prescription, OTC, supplements)
   • Assess alcohol consumption
   • Evaluate metabolic risk factors (obesity, diabetes, dyslipidemia)
   • Check for symptoms of liver disease 4

2. First-line testing:

   • Complete liver panel (AST, alkaline phosphatase, GGT, bilirubin, albumin, PT/INR)
   • Viral hepatitis serology (HAV-IgM, HBsAg, HBcIgM, HCV antibody)
   • Metabolic panel and lipid profile
   • Abdominal ultrasound 4

3. Second-line testing (based on clinical suspicion):

   • Autoimmune markers (ANA, ASMA, ANCA)
   • Iron studies
   • Ceruloplasmin (in younger patients) 4

Management Considerations

Management depends on the underlying cause:

• NAFLD: Weight loss, regular exercise, Mediterranean diet 4
• Medication-induced: Consider discontinuation of suspected hepatotoxic medications 4
• Viral hepatitis: Referral to hepatology for specific antiviral treatment 4
• Alcoholic liver disease: Complete alcohol abstinence, nutritional support 4

Monitoring Recommendations

• Mild elevations: Monitor every 1-2 weeks until improvement
• Persistent elevation: Refer to gastroenterology/hepatology if ALT remains elevated after 12 weeks despite addressing modifiable factors
• Advanced fibrosis risk: Calculate FIB-4 score; consider non-invasive fibrosis assessment 4

Common Pitfalls

• Relying on outdated reference ranges: Using traditional cutoffs may miss early liver disease
• Ignoring normal ALT in liver disease: Some patients with significant liver disease may have normal ALT levels
• Overlooking extrahepatic sources: Muscle injury can also cause ALT elevation, though ALT2 isoform predominates 3
• Focusing solely on ALT: Comprehensive evaluation requires assessment of other liver enzymes and function tests

By understanding the significance of ALT and following a systematic approach to evaluation, clinicians can effectively identify and manage underlying liver conditions to improve patient outcomes.