What causes elevated liver enzymes?

Causes of Elevated Liver Enzymes

The most common causes of elevated liver enzymes include nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease, drug-induced liver injury, viral hepatitis, and occupational chemical exposures, with NAFLD being the predominant cause in first world countries. 1

Pattern Recognition in Liver Enzyme Elevations

Different patterns of liver enzyme elevation can help identify the underlying cause:

• Hepatocellular pattern (ALT > AST)

  • Nonalcoholic fatty liver disease (NAFLD)
  • Viral hepatitis (HBV, HCV)
  • Drug-induced liver injury
  • Genetic liver diseases (Wilson's disease, hemochromatosis)

• Alcoholic pattern (AST > ALT, ratio >2:1)

  • Alcohol-induced liver disease
  • Can also indicate non-hepatic causes (hemolysis, myopathy, thyroid disease)

• Cholestatic pattern (elevated ALP and GGT)

  • Primary biliary cholangitis
  • Primary sclerosing cholangitis (PSC)
  • Biliary obstruction (stones, tumors)
  • Drug-induced cholestasis

• Isolated GGT elevation

  • Alcoholic liver disease
  • Non-alcoholic fatty liver disease
  • Infiltrative liver diseases 2

Specific Etiologies

1. Metabolic Causes

• Nonalcoholic fatty liver disease (NAFLD): Most common cause in Western countries (17-46% of adults) 3
• Metabolic syndrome components: Central obesity, hypertension, diabetes/insulin resistance, dyslipidemia 3

2. Toxic/Drug-Related Causes

• Alcohol consumption: Even moderate amounts can interact with metabolic factors 3
• Medications: Antimalarials, antibiotics, statins, NSAIDs, antiepileptics 1
• Herbal supplements: Account for up to 25% of fulminant hepatic failure 4

3. Infectious Causes

• Viral hepatitis: HBV, HCV, HAV, HEV, CMV 3
• COVID-19: 15% of hospitalized patients experience elevated LFTs 1

4. Autoimmune/Inflammatory Causes

• Autoimmune hepatitis: Positive autoantibodies, elevated IgG 3
• Primary biliary cholangitis: Positive anti-mitochondrial antibody 3
• Primary sclerosing cholangitis: Often associated with inflammatory bowel disease 3

5. Genetic/Metabolic Disorders

• Hemochromatosis: Elevated ferritin and transferrin saturation >45% 3
• Wilson's disease: Especially in younger patients 2

6. Other Causes

• Endocrine disorders: Addison's disease can cause chronically elevated liver enzymes 5
• Occupational exposures: Chemical toxins 1
• Ischemic injury: Hypotension, heart failure 1
• Malignancy: Primary or metastatic liver tumors 1

Diagnostic Approach

1. Confirm persistence of elevation

   • 84% of abnormal tests remain abnormal after 1 month, 75% remain abnormal at 2 years 3
   • Don't simply repeat the same panel; determine the cause unless there's high suspicion of a transient finding 3

2. Obtain thorough history

   • Age, ethnicity/country of birth (risk for viral hepatitis)
   • Symptoms (jaundice, abdominal pain, weight loss, pruritus)
   • Medication history (prescribed, OTC, herbal supplements)
   • Alcohol intake (current and past)
   • Travel history, occupational exposures
   • Family history of liver disease 3

3. Physical examination

   • BMI, abdominal examination for hepatosplenomegaly, ascites, signs of chronic liver disease 3

4. Initial laboratory testing (core panel)

   • Hepatitis B surface antigen
   • Hepatitis C antibody (with PCR if positive)
   • Anti-mitochondrial antibody
   • Anti-smooth muscle antibody
   • Antinuclear antibody
   • Serum immunoglobulins
   • Ferritin and transferrin saturation 3

5. Imaging

   • Abdominal ultrasound to assess for fatty liver, biliary obstruction, masses 3
   • Consider MRI/MRCP for suspected PSC or biliary pathology 3

Special Considerations

• For marked ALT elevation (>1000 U/L): Consider acute viral hepatitis (HAV, HEV, CMV) 3

• For cholestatic pattern: Confirm hepatic origin with GGT or ALP isoenzymes 3

• For HIV patients: Higher risk of drug-induced liver injury, especially with HCV coinfection (2-10 fold increased risk) 6

• For persistent unexplained elevation: Consider liver biopsy, especially if age >40 with borderline or mildly elevated ALT 3

• For isolated ALP elevation: Thorough investigation warranted as 57% of cases may be associated with underlying malignancy 1

Common Pitfalls to Avoid

1. Ignoring mild elevations: Even mild elevations can indicate significant disease, particularly in cholestatic processes 1

2. Attributing elevation solely to NAFLD without exclusion of other causes: Always rule out other etiologies, especially in patients with risk factors 3

3. Overlooking medication-induced injury: Drug-induced liver disease may account for 10-50% of adult patients with elevated enzymes, especially in patients over age 50 4

4. Failing to consider extrahepatic causes: Endocrine disorders, muscle injury, and other systemic conditions can cause liver enzyme elevations 5

5. Not evaluating for alcohol use: Even when another cause is identified, alcohol can be a contributing factor 3