Clinical meaning
Acute liver failure (ALF) is defined as severe hepatic injury with coagulopathy (INR ≥ 1.5) and hepatic encephalopathy in a patient without preexisting cirrhosis, occurring within 26 weeks of symptom onset. The classification is subdivided by tempo: hyperacute (< 7 days, e.g., acetaminophen), acute (7–21 days), and subacute (> 21 days to 26 weeks). The pathophysiology centers on massive hepatocyte necrosis or apoptosis. In acetaminophen toxicity (the most common cause in the US and Canada), the cytochrome P450 enzyme CYP2E1 converts acetaminophen to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is normally conjugated by glutathione, but when glutathione stores are depleted (overdose, chronic alcohol use, malnutrition), NAPQI binds to hepatocyte mitochondrial proteins, causing oxidative stress, mitochondrial dysfunction, and centrilobular necrosis (zone 3 of the hepatic acinus). In viral hepatitis-induced ALF (hepatitis A, B, rarely E), immune-mediated hepatocyte destruction occurs via cytotoxic CD8+ T cells and NK cells targeting viral antigens on hepatocyte surfaces. The consequences of massive hepatocyte loss include: (1) loss of synthetic function — decreased clotting factor production (II, V, VII, IX, X) causing coagulopathy, decreased albumin production causing ascites and edema; (2) loss of metabolic function — impaired ammonia clearance leading to cerebral edema and encephalopathy (ammonia crosses the blood-brain barrier and is converted to glutamine by astrocytes, causing osmotic swelling), impaired lactate clearance causing lactic acidosis, impaired drug metabolism; (3) loss of immune function — decreased complement production and impaired Kupffer cell function predisposing to sepsis (the leading cause of death in ALF). Cerebral edema is the most feared complication and leading cause of death, resulting from astrocyte swelling due to intracellular glutamine accumulation (osmotic theory) and loss of cerebral autoregulation. The King's College Criteria remain the most widely validated prognostic tool for determining the need for liver transplantation.