Causes of Elevated Liver Enzymes
The most common causes of elevated liver enzymes are nonalcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ARLD), viral hepatitis, and drug-induced liver injury, with NAFLD being the predominant etiology in developed countries affecting 20-30% of the general population. 1
Hepatocellular Pattern (Elevated AST/ALT)
Most Common Causes
Nonalcoholic fatty liver disease (NAFLD) is the leading cause, with prevalence increasing to 70% in obese patients and 90% in those with diabetes 1
Alcohol-related liver disease typically presents with an AST:ALT ratio >2 (often >3 in advanced disease), compared to <1 in NAFLD 2, 1
Viral hepatitis including hepatitis B, C, A, and E can cause marked transaminase elevations 2, 1
Drug-induced liver injury from prescription medications, over-the-counter drugs, and herbal/dietary supplements 2, 1
Less Common Hepatocellular Causes
- Autoimmune hepatitis characterized by raised IgG and positive autoantibodies (ANA, ASMA, anti-LKM-1) 2, 1
- Hemochromatosis with elevated ferritin and transferrin saturation >45% 2
- Wilson's disease particularly in younger patients 5
Cholestatic Pattern (Elevated Alkaline Phosphatase/GGT)
- Primary biliary cholangitis with positive anti-mitochondrial antibodies 2, 1
- Primary sclerosing cholangitis often associated with inflammatory bowel disease 2, 1
- No diagnostic serological markers exist; MRI may be required 2
- Biliary obstruction from gallstones or tumors requiring urgent assessment if bile ducts are dilated 2
Non-Hepatic Causes
Critical pitfall: Not all elevated liver enzymes originate from liver disease. 1
- Muscle disorders can elevate AST, which is less liver-specific than ALT 1
- Strenuous exercise causes transient AST elevation 1
- Thyroid disease (both hypo- and hyperthyroidism) affects liver enzymes 1
- Hemolysis elevates AST 1
- Rhabdomyolysis should be excluded with serum CK measurement 2
Malignancy-Related Causes
- Hepatic metastases cause elevated alkaline phosphatase in up to 67% of cases 2
- Biliary obstruction from tumors 2
- Hepatic vein thrombosis or congestive heart failure 2
Initial Diagnostic Approach
History Must Include:
- Alcohol consumption quantified in units per week, consider AUDIT-C screening 2, 1
- Complete medication review including all prescription, over-the-counter, and herbal/dietary supplements 2, 1
- Metabolic syndrome features: obesity, hypertension, diabetes, dyslipidemia 2, 1
- Family history of liver disease or autoimmune conditions 2
Core Laboratory Panel:
The standard liver aetiology screen should include 2:
- Hepatitis B surface antigen (HBsAg)
- Hepatitis C antibody with reflex PCR if positive
- Anti-mitochondrial antibody
- Anti-smooth muscle antibody
- Antinuclear antibody
- Serum immunoglobulins
- Simultaneous serum ferritin and transferrin saturation
First-Line Imaging:
- Abdominal ultrasound is the initial imaging test with 84.8% sensitivity and 93.6% specificity for moderate to severe hepatic steatosis 2, 1
Key Clinical Pearls
- In the BALLETS study of 1,290 adults in primary care, <5% had a specific liver disease requiring treatment, with only 1.3% needing immediate intervention 2
- Nearly 40% of adults with abnormal liver tests had fatty liver on ultrasound, and one-quarter were neither overweight nor excessive alcohol drinkers 2
- An isolated elevated ferritin commonly reflects dysmetabolic iron overload syndrome (seen with alcohol excess or NAFLD) rather than true hemochromatosis 2
- Neonatal cholestasis (conjugated bilirubin >25 μmol/L) requires urgent pediatric consultation 2