What are the causes of elevated liver enzymes?

Causes of Elevated Liver Enzymes

The most common causes of elevated liver enzymes are nonalcoholic fatty liver disease (NAFLD) and alcohol-induced liver disease, which together account for the vast majority of cases in developed countries. 1

Most Common Causes (Mild Elevations)

Primary Hepatic Causes

Nonalcoholic Fatty Liver Disease (NAFLD)

• NAFLD is the most common liver disorder in Western countries, affecting 20-30% of the general population, increasing to 70% with obesity and 90% with diabetes mellitus 1
• Characterized by AST:ALT ratio <1 1, 2
• NAFLD is the main reason for unexplained elevated liver enzymes in asymptomatic patients 1

Alcohol-Induced Liver Disease

• AST:ALT ratio is generally >2:1, which is highly suggestive of this etiology 1, 2
• Critical to obtain accurate alcohol history, as intake is often underreported 1

Uncommon Hepatic Causes

Viral Hepatitis

• Chronic hepatitis B and C cause fluctuating ALT elevations 1, 2
• For marked elevations (ALT >1000 U/L), consider acute viral hepatitis including hepatitis A, E, and cytomegalovirus 1

Drug-Induced Liver Injury

• Should be assessed by pattern: hepatocellular, cholestatic, or mixed 2
• Requires careful medication history including prescribed, over-the-counter, herbal, and illicit drugs 1

Hereditary Hemochromatosis

• Identified by raised ferritin and transferrin saturation >45% 1, 2
• Note: Isolated elevated ferritin commonly reflects dysmetabolic iron overload in NAFLD or alcohol excess, not hemochromatosis 1

Rare Hepatic Causes

• Alpha-1 antitrypsin deficiency 1, 2
• Autoimmune hepatitis: suggested by raised IgG and positive autoantibodies 1
• Wilson disease 1, 2
• Primary biliary cholangitis: cholestatic pattern with positive anti-mitochondrial antibody 1
• Primary sclerosing cholangitis: consider in patients with inflammatory bowel disease or family history of autoimmune disease 1

Non-Hepatic Causes

Muscle-Related Elevations

• Intensive exercise, particularly weight lifting, can cause acute ALT/AST elevations that mimic liver injury 2
• Muscle injury or rhabdomyolysis confirmed by markedly elevated creatine kinase 2
• While ALT is more liver-specific, it is present in skeletal muscle and can be elevated with significant muscle damage 2

Other Extrahepatic Causes

• Hemolysis, myopathy, thyroid disease (particularly if AST predominates over ALT) 1

Pattern Recognition for Diagnosis

Hepatocellular Pattern (Predominant Transaminase Elevation)

• Suggests viral hepatitis, genetic liver diseases (Wilson disease, hemochromatosis), drug-induced injury, or NAFLD 1

Cholestatic Pattern (Predominant Alkaline Phosphatase and GGT)

• Requires ultrasound to distinguish intrahepatic from extrahepatic cholestasis 1
• Intrahepatic: primary/secondary sclerosing cholangitis, genetic transporter defects, drug-induced 1
• Extrahepatic: bile duct obstruction from stones or tumors 1

Isolated GGT Elevation

• Observed in alcoholic or non-alcoholic fatty liver disease and infiltrating liver diseases 3

Critical Diagnostic Approach

Initial Core Panel 1

• Hepatitis B surface antigen and hepatitis C antibody
• Ferritin and transferrin saturation
• Autoimmune markers (ANA, anti-smooth muscle antibody, immunoglobulins)
• Metabolic syndrome assessment (BMI, glucose, lipids)
• Careful alcohol history (consider phosphatidylethanol if underreporting suspected) 1

Important Caveats

• In the BALLETS study of 1,290 adults with abnormal liver tests, <5% had a specific liver disease requiring immediate intervention 1
• When liver tests were repeated after 1 month, 84% remained abnormal, so don't simply repeat the same tests without investigating the cause 1
• Dilated bile ducts require urgent assessment and possible hospital referral 1
• Immediate referral indicated for unexplained jaundice or suspicion of hepatobiliary malignancy 1