What is the definition of acute liver injury?

Definition of Acute Liver Injury

Acute liver injury is defined by any of the following criteria: 1) Alanine aminotransferase (ALT) level ≥5x upper limit of normal (ULN), 2) Alkaline phosphatase (ALP) level ≥2 ULN (particularly with elevated gamma-glutamyl transpeptidase in the absence of bone disease), or 3) ALT level ≥3 ULN with simultaneous total bilirubin level >2 ULN. 1

Diagnostic Criteria

The definition of acute liver injury includes specific laboratory thresholds:

• ALT level ≥5x upper limit of normal (ULN) 1
• ALP level ≥2 ULN (particularly if concomitantly elevated GGT in the absence of bone disease) 1
• ALT level ≥3 ULN and simultaneous total bilirubin (TB) level >2 ULN 1

For patients with abnormal baseline liver tests, the ULN should be replaced by the mean baseline values obtained prior to exposure to the suspect agent, and increases should be proportionate to this modified baseline 1.

Pattern Classification

Acute liver injury can be further classified according to the R value, which is defined as: (ALT/ULN)/(ALP/ULN) 1:

• Hepatocellular pattern: R ≥5 1
• Cholestatic pattern: R ≤2 1
• Mixed pattern: R value >2 and <5 1

Note: AST can replace ALT when ALT is unavailable 1.

Clinical Presentations

Acute liver injury may present with various histological patterns depending on the causative agent:

• Hepatocellular necrosis: Most common form, involving hepatic parenchyma and producing hepatocellular jaundice 1
• Cholestatic/mixed injury: Seen with certain toxins like methylenedianiline and paraquat 1
• Microvesicular steatosis: Characterized by tiny fat droplets in hepatocyte cytoplasm 1
• Toxicant-associated steatohepatitis (TASH): Characterized by steatosis, inflammatory infiltrates, and ballooning hepatocytes 1

Severity Grading

The severity of acute liver injury can be graded as follows 1:

• Grade 1: Elevated ALT/ALP meeting criteria for liver injury but bilirubin <2 ULN 1
• Grade 2: Elevated ALT/ALP meeting criteria for liver injury and bilirubin ≥2 ULN, or symptomatic hepatitis 1
• Grade 3: Elevated ALT/ALP meeting criteria for liver injury, bilirubin ≥2 ULN, and one of the following:
  • INR ≥1.5
  • Ascites and/or encephalopathy (without underlying cirrhosis)
  • Other organ failure due to liver injury 1
• Grade 4: Death or transplantation due to liver injury 1

Important Considerations

• Isolated increases in GGT activity are not markers of cellular damage but rather indicate enzyme induction 1
• The values used for classification should be those available when liver injury is first recognized 1
• Due to differences in clearance kinetics of ALT and ALP, the injury pattern may shift to a cholestatic/mixed signature over time 1
• In occupational liver diseases, the standard classification used for idiosyncratic drug-induced acute liver failure may not apply due to the direct, massive, and rapid liver damage induced by chemicals 1
• Fulminant liver failure with symptoms appearing 24-48 hours after chemical exposure may occur with certain toxins 1

Clinical Implications

• Acute liver injury can progress to acute liver failure if not properly managed 2
• Early recognition and discontinuation of the offending agent is crucial 3
• N-acetylcysteine may be indicated to prevent or lessen hepatic injury in cases of acetaminophen toxicity 4
• The ALT/LD ratio can help differentiate between viral hepatitis and other causes of acute liver injury 5