What causes elevated Alanine Transaminase (ALT) levels?

Causes of Elevated ALT Levels

Elevated ALT (alanine aminotransferase) is most commonly caused by hepatocellular injury from various etiologies including nonalcoholic fatty liver disease (NAFLD), viral hepatitis, alcohol-related liver disease, and medication-induced liver injury. 1

Common Causes of ALT Elevation

Hepatic Causes

• Nonalcoholic Fatty Liver Disease (NAFLD)

  • Most common cause in Western countries (17-46% of adults) 1
  • Associated with metabolic syndrome components: obesity, hypertension, diabetes/insulin resistance, dyslipidemia

• Viral Hepatitis

  • Hepatitis A, B, C, D, E
  • Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Herpes simplex virus (HSV) 2
  • Acute viral hepatitis can cause marked ALT elevation (>1000 U/L) 1

• Alcohol-Related Liver Disease

  • Even moderate alcohol consumption can interact with metabolic factors 1
  • Typically shows AST:ALT ratio >2, often >3 2
  • AST usually 2-6 times upper limit of normal; ALT rarely >200 IU/L 2

• Drug-Induced Liver Injury (DILI)

  • Prescription medications (statins, antibiotics, antiepileptics)
  • Over-the-counter medications (acetaminophen)
  • Herbal supplements and dietary supplements 2

• Autoimmune Liver Diseases

  • Autoimmune hepatitis
  • Primary biliary cholangitis
  • Primary sclerosing cholangitis 1

• Hemochromatosis and Other Metabolic Disorders

  • Iron overload disorders
  • Alpha-1 antitrypsin deficiency
  • Wilson's disease 1

Non-Hepatic Causes

• Muscle Injury/Rhabdomyolysis

  • Intensive exercise (especially weight lifting)
  • Muscle trauma
  • Can be confirmed by elevated creatine kinase (CK) 2

• Cardiac Conditions

  • Acute myocardial infarction
  • Congestive heart failure causing hepatic congestion 3

• Endocrine Disorders

  • Hypothyroidism
  • Celiac disease 3

• Occupational Chemical Exposure

  • Various industrial solvents and chemicals 1

Diagnostic Approach to Elevated ALT

Initial Assessment

1. Confirm persistence of elevation

   • 84% of abnormal tests remain abnormal after 1 month 1
   • Transient elevations may occur with exercise or minor illnesses

2. Assess pattern and degree of elevation

   • Mild elevation (<5x ULN): Often NAFLD, chronic viral hepatitis, medication-related 2
   • Moderate elevation (5-10x ULN): Consider acute viral hepatitis, alcohol-related injury
   • Severe elevation (>10x ULN): Acute viral hepatitis, ischemic injury, toxin exposure 2

3. Evaluate for risk factors

   • Obesity (30.2%) and alcoholism (28.6%) are most frequently associated with ALT elevation 4
   • Even light alcohol intake increases mortality in those with elevated ALT 5

Laboratory Evaluation

1. First-line testing 2

   • Hepatitis serology (HAV-IgM, HBsAg, HBc-IgM, HCV antibody)
   • Complete blood count with platelets
   • Liver function panel (AST, ALT, alkaline phosphatase, bilirubin, albumin)
   • Prothrombin time
   • Creatine kinase (to rule out muscle origin)

2. Second-line testing 2, 1

   • Autoimmune markers (ANA, ASMA)
   • Iron studies (ferritin, transferrin saturation)
   • Ceruloplasmin (Wilson's disease)
   • Alpha-1 antitrypsin levels
   • HEV, EBV, CMV serology

Imaging

• Abdominal ultrasound: First-line imaging to assess for fatty liver, biliary obstruction, masses 2
• CT or MRI: For further characterization of liver lesions if needed 2

Special Considerations

ALT/LD Ratio

• ALT/LD (lactate dehydrogenase) ratio can help differentiate causes:
  • Viral hepatitis: mean ratio 4.65
  • Ischemic hepatitis: mean ratio 0.87
  • Acetaminophen injury: mean ratio 1.46 6
• An ALT/LD ratio >1.5 suggests viral hepatitis (sensitivity 94%, specificity 84%) 6

NASH vs. Other Causes

• ALT elevation ≥5× ULN is rare in NASH and should prompt investigation for other causes 2
• New or worsening symptoms (abdominal pain, severe fatigue, nausea, vomiting) suggest diagnoses other than NASH 2

Common Pitfalls

• Attributing elevation solely to NAFLD without excluding other causes 1
• Not evaluating alcohol use, even when another cause is identified 1
• Ignoring mild elevations, which may be the first sign of significant disease 1
• Overlooking non-hepatic causes like muscle injury or thyroid disease 3

Management Approach

1. For mild, asymptomatic elevation:

   • Repeat testing to confirm persistence
   • Address modifiable risk factors (weight loss, alcohol cessation)
   • Monitor every 8 weeks initially 4

2. For persistent unexplained elevation:

   • Consider liver biopsy, especially if age >40 with borderline or mildly elevated ALT 1
   • Complete abstinence from alcohol should be advised for those with elevated ALT 5

3. For severe elevation or symptoms:

   • Expedite diagnostic evaluation
   • Consider referral to hepatologist 3

ALT elevation is a common finding that requires systematic evaluation to identify the underlying cause. While many cases represent benign or reversible conditions, some indicate serious liver disease requiring prompt intervention.