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 70% of obese patients. 1

Hepatocellular Pattern (Elevated ALT/AST)

Most Common Causes

• NAFLD/Metabolic-Associated Fatty Liver Disease: The leading cause in developed nations, with prevalence reaching 90% in diabetic patients, typically presenting with AST:ALT ratio <1 2, 1

• Alcohol-Induced Liver Disease: Characterized by AST:ALT ratio typically >2, with AST levels usually 2-6 times upper limit of normal in severe cases; AST >500 IU/L or ALT >200 IU/L is uncommon and should prompt evaluation for alternative causes 2, 1

• Viral Hepatitis:

  • Hepatitis B, C, A, and E can cause marked transaminase elevations 2
  • ALT >1000 U/L suggests acute hepatitis A, E, or cytomegalovirus 2, 1
  • Country of origin is the strongest predictor of viral hepatitis risk 2, 1

• Drug-Induced Liver Injury: Accounts for 10-50% of adults with elevated enzymes, especially over age 50, and nearly 25% of fulminant hepatic failure cases 3

  • Common culprits include acetaminophen, penicillin, oral contraceptives, anabolic steroids, and chlorpromazine 2
  • Herbal and dietary supplements must always be considered 3

• Autoimmune Hepatitis: Presents with elevated IgG and positive autoantibodies (anti-smooth muscle, antinuclear antibodies) 2

• Hereditary Disorders:

  • Hemochromatosis: Elevated ferritin and transferrin saturation >45% 2
  • Wilson's disease 4

Cholestatic Pattern (Elevated ALP/GGT)

Intrahepatic Causes

• Primary Biliary Cholangitis: Characterized by positive anti-mitochondrial antibodies 2, 1

• Primary Sclerosing Cholangitis: Often associated with inflammatory bowel disease; no diagnostic serological markers exist, and MRI may be required for diagnosis 2, 1

• Drug-Induced Cholestasis: Medications can disrupt bile excretion 2

Extrahepatic Causes

• Biliary Obstruction:
  • Cholelithiasis, choledocholithiasis, cholangitis 2
  • Cholangiocarcinoma or gallbladder cancer 2
  • Pancreatic tumors or pancreatitis causing extrinsic compression 2
  • Dilated bile ducts require urgent assessment 2, 1

Non-Hepatic Causes

Critical pitfall: Elevated liver enzymes do not always indicate primary liver disease 4

• Muscle Disorders: AST is less specific for liver injury and can be elevated in rhabdomyolysis; serum CK measurement should be obtained 2, 1

• Strenuous Exercise: Can cause transient AST elevation 2, 1

• Thyroid Disease: Both hypothyroidism and hyperthyroidism can affect liver enzymes 1

• Hemolysis: Can elevate AST 2, 1

• Malignancy-Related:

  • Hepatic metastases cause elevated alkaline phosphatase in up to 67% of cases 1
  • Hepatic vein thrombosis or congestive heart failure 1

Hyperbilirubinemia-Specific Causes

Unconjugated (Indirect)

• Prehepatic: Hemolytic anemias (sickle cell disease, thalassemia, hereditary spherocytosis, G6PD deficiency) 2

• Intrahepatic: Gilbert syndrome affects 5% of the American population; benign hereditary disorder causing transient unconjugated hyperbilirubinemia requiring no management 2

Conjugated (Direct)

• Hepatic Inflammation: Acute hepatitis (A, B, C, D, E, Epstein-Barr virus), alcohol-induced liver disease, autoimmune hepatitis 2

• Obstructive Biliopathy: All causes listed under cholestatic pattern above 2

Key Clinical Pearls

Important context: In the BALLETS study of 1,290 adults in primary care, <5% had a specific liver disease requiring treatment, and only 1.3% needed immediate intervention; nearly 40% with abnormal tests had fatty liver on ultrasound 2, 1

Common pitfall: Isolated elevated ferritin commonly reflects dysmetabolic iron overload syndrome (seen with alcohol excess, NAFLD, chronic liver disease) rather than true hemochromatosis 2, 1

Adaptation phenomenon: Mild asymptomatic ALT/AST elevations (>1x to <3x ULN) without elevated bilirubin may be nonspecific and related to NAFLD, dietary changes, or vigorous exercise; more than 30% spontaneously normalize during follow-up 2, 4