Aminotransferases

Pathophysiology/Etiology
- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) are enzymes concentrated in hepatocytes.
- Hepatocellular injury (inflammation/necrosis) causes their release into the bloodstream, making them key markers of liver damage.
- ALT (Alanine aminotransferase) is more specific for the liver.
- AST (Aspartate aminotransferase) is also found in cardiac muscle, skeletal muscle, kidney, and brain.

Mnemonic

ALT for Liver

Clinical Interpretation & DDx
- The pattern and magnitude of elevation and the AST/ALT ratio are crucial for differential diagnosis.
- Degree of Elevation:
  - Mild Elevation (<5x ULN): Very common. Causes include non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, chronic viral hepatitis (B or C), medications, and hemochromatosis.
  - Marked Elevation (>1000 IU/L): Differential is narrow. Think:
    1. Ischemic hepatitis ("shock liver"): Often with very high LDH and rapid fall in AST/ALT.
    2. Acute viral hepatitis (A or B, not typically C).
    3. Toxin/Drug-induced liver injury (especially acetaminophen).
    4. Less common: Autoimmune hepatitis exacerbation, Budd-Chiari syndrome, Wilson's disease.
AST/ALT Ratio (De Ritis Ratio)
- AST/ALT > 2:1:
  - Classic finding in alcoholic liver disease.
  - Mechanism: Alcohol causes mitochondrial injury (rich in AST) and pyridoxal phosphate (Vitamin B6) deficiency, which is a necessary cofactor for ALT synthesis.
  - An elevated GGT further supports alcohol-related damage.
- AST/ALT < 1:
  - Most other causes of liver injury, including viral hepatitis and NAFLD.
- AST/ALT > 1 (but < 2):
  - Can be seen in progression to cirrhosis from various causes (e.g., NAFLD, viral hepatitis).
Differential Diagnosis Summary

Condition	Typical Transaminase Pattern	Key Features
Alcoholic Liver Disease	AST/ALT > 2:1, AST usually <500 IU/L	Macrocytosis, ↑ GGT, history of heavy alcohol use.
NAFLD/NASH	ALT > AST (Ratio < 1), mild elevation	Associated with metabolic syndrome (obesity, T2DM, dyslipidemia).
Acute Viral Hepatitis	ALT >> AST (both often >1000 IU/L)	Jaundice, fever, RUQ pain; positive viral serologies.
Ischemic Hepatitis	Massive ↑ AST & ALT (>1000s), rapid fall	Setting of shock/hypotension; markedly ↑ LDH.
Toxin/Drug Injury	Massive ↑ AST & ALT (>1000s)	History of exposure (e.g., acetaminophen overdose, isoniazid, statins).
Chronic Viral Hepatitis	Mild elevation, often ALT > AST	Often asymptomatic; AST/ALT ratio can increase with fibrosis.
Autoimmune Hepatitis	↑ ALT & AST, ↑ total protein/globulin	(+) ANA, anti-smooth muscle antibodies (ASMA).
Hemochromatosis	Mild ↑ ALT & AST, ↑ Ferritin, ↑ Iron sat	"Bronze diabetes," arthropathy, cardiomyopathy.
Wilson's Disease	↑ Transaminases, ↓ Ceruloplasmin	Neurologic/psychiatric symptoms, Kayser-Fleischer rings.

Extrahepatic Causes of Elevated Transaminases
- Muscle Injury: Rhabdomyolysis, vigorous exercise, polymyositis. Results in ↑ AST > ↑ ALT.
- Hemolysis: Can cause a mild rise in AST.
- Other: Celiac disease, thyroid disorders.