**2.1 Definition and etiology**

Acute liver failure (ALF) represents a clinical syndrome of varying etiologies that ultimately manifests as hepatic encephalopathy and coagulopathy (International Normalized Ratio [INR] greater than 1.5) in the setting of acute liver dysfunction. By definition, coagulopathy and hepatic encephalopathy occur within 6 months following the initial symptoms of hepatic dysfunction in a patient without chronic liver disease. The timing of development of hepatic encephalopathy after an initial presentation of jaundice helps further subdivide ALF into categories of hyper-acute (hepatic encephalopathy developing within 7 days of onset of jaundice), acute (8-28 days), and sub-acute (29-84 days).

The etiologies of ALF are numerous, and reversible causes must be actively sought. The most common etiology of ALF in the United States and United Kingdom is drug-induced, with acetaminophen toxicity the leading responsible agent. Other common classes of medications known to provoke ALF in susceptible patients include antimicrobials, antidepressants, antiepileptics, anti-hypertensives, HIV therapy, chemotherapeutic agents, lipid-lowering agents, and glucose-lowering agents. Analgesics and recreational drugs are also known causes of drug-induced ALF.

Additional etiologies of ALF include viral infections, including Hepatitis A, B, C, D, and E, as well as herpes simplex virus, varicella zoster virus, cytomegalovirus, and Epstein-Barr virus. Toxins responsible for ALF include *amanita phyloides* (mushrooms), herbal preparations, organic solvents, and bacterial toxins, such as *bacillus cereus*. Pregnancy-related conditions include the HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) and the acute fatty liver of pregnancy syndrome. Lymphoma, metastatic disease, hepatic ischemia, wilson disease, heat stroke, Budd-Chiari syndrome, autoimmune hepatitis, and extensive hepatic resection are other causes of ALF. Approximately 15-20% of patients with ALF have an undetermined cause.
