**2.1.1 Etiology**

The etiology of ALF is one of the most important predictors of spontaneous outcome (Ostapowicz et al., 2002). The lowest mortality is seen with ALF secondary to acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity (~30%), hepatitis A virus infection (~50%), shock liver, and pregnancy-related ALF (Larson et al., 2005; Ostapowicz et al., 2002; Schiodt et al., 2003). In contrast, the non-transplant mortality for the remainder of causes, including ALF secondary to drug-induced liver injury, remains abysmal (80% to 100%) (O'Grady et al., 1988; Ostapowicz et al., 2002). Therefore, understanding which causes of ALF predominate in a particular region can help lead to the early evaluation and listing of these latter cases for OLT.

ALF secondary to drug-induced liver injury (DILI) predominates in Europe and North America, with a high prevalence of APAP-induced ALF in the US and United Kingdom (Hoofnagle et al., 1995; Larson et al., 2005; Ostapowicz et al., 2002; Schiodt et al., 1999; Williams, 1996). Viral hepatitis predominates in developing countries. The US ALF study group looked at 1198 patients with ALF over an 11 year period and a total of 133 (11.1%) subjects were deemed by expert opinion to have DILI ALF. Transplant-free (3-week) survival was poor (27.1%), but with successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio (PT/INR), and Model for End-Stage Liver Disease (MELD) scores (Reuben et al., 2010).

In the United Kingdom, the number of patients with APAP ALF has declined due to legislative changes in drug packaging, leading to an increase in the relative number of cryptogenic or seronegative cases (16% of all ALF). The majority (88%) of these latter ALF patients met King's College transplant criteria (see below), reflecting the low likelihood of spontaneous recovery (Wigg et al., 2005). A recent study from the UK suggested that OLT is a more favorable approach to managing patients with non-APAP induced ALF compared to patients with APAP induced ALF. This was predominantly due to the frequent psychosocial contraindications in patients with APAP induced ALF (Simpson et al., 2009).
