What are the causes of elevated liver enzymes?

Causes of Elevated Liver Enzymes

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in developed countries, affecting 20-30% of the general population and up to 90% in diabetic patients. 1, 2

Hepatocellular Pattern (Elevated AST/ALT)

Most Common Causes

• NAFLD/Metabolic-Associated Fatty Liver Disease is the leading etiology, with prevalence reaching 70% in obese patients and 90% in diabetics, typically presenting with AST:ALT ratio <1 1, 2

• Alcohol-induced liver disease characteristically shows AST:ALT ratio >2, with AST levels usually 2-6 times the upper limit of normal in severe alcoholic hepatitis 1, 2

  • AST >500 IU/L or ALT >200 IU/L is uncommon in alcoholic hepatitis and should prompt evaluation for alternative causes 1

• Viral hepatitis (hepatitis B, C, A, and E) can cause marked transaminase elevations, with ALT >1000 U/L suggesting acute hepatitis A, E, or cytomegalovirus 1, 2

Drug-Induced Liver Injury

• Medication-induced hepatotoxicity requires a complete review of all prescription, over-the-counter, and herbal/dietary supplements 1
• Pioglitazone and other thiazolidinediones can cause hepatic enzyme elevations, with postmarketing reports of hepatitis and elevations ≥3 times the upper limit of normal 3

Cholestatic Pattern (Elevated Alkaline Phosphatase/GGT)

Intrahepatic Cholestasis

• Primary biliary cholangitis is characterized by positive anti-mitochondrial antibodies 1, 2

• Primary sclerosing cholangitis is often associated with inflammatory bowel disease, with no diagnostic serological markers existing and MRI potentially required for diagnosis 1, 2

• Drug-induced cholestasis can disrupt bile excretion 2

Extrahepatic Cholestasis

• Biliary obstruction from gallstones or tumors requires urgent assessment if bile ducts are dilated 1

• Hepatic metastases can cause elevated alkaline phosphatase in up to 67% of cases 1

Non-Hepatic Causes

Muscle-Related

• Rhabdomyolysis can elevate AST and should be excluded with serum CK measurement 1, 2

• Strenuous exercise can cause transient AST elevation 1, 2

Endocrine

• Thyroid disease, including both hypothyroidism and hyperthyroidism, can affect liver enzymes 1, 2

Hematologic

• Hemolysis can cause elevated AST 1, 2

Hyperbilirubinemia-Specific Causes

• Prehepatic causes (hemolytic anemias) cause unconjugated hyperbilirubinemia 2

• Gilbert syndrome causes transient unconjugated hyperbilirubinemia 2

• Hepatic inflammation (acute hepatitis) causes conjugated hyperbilirubinemia 2

• Obstructive biliopathy causes conjugated hyperbilirubinemia 2

Critical Clinical Context

• The BALLETS study found <5% of adults in primary care had a specific liver disease requiring treatment, with only 1.3% needing immediate intervention 1, 2

• Nearly 40% of adults with abnormal liver tests had fatty liver on ultrasound 1, 2

• Mild asymptomatic ALT/AST elevations (>1x to <3x ULN) without elevated bilirubin may be nonspecific, with more than 30% spontaneously normalizing during follow-up 2

Common Pitfalls

• Isolated elevated ferritin commonly reflects dysmetabolic iron overload syndrome rather than true hemochromatosis 1, 2

• Country of origin is the strongest predictor of viral hepatitis risk and should guide testing 1

• Neonatal cholestasis requires urgent pediatric consultation 1