An acute liver injury corresponds to an increase in liver test values over less than 3 months. In contrast, a chronic liver injury is an increase in liver test values over more than 3 months. Severe liver injury refers to the presence of, in order of increasing severity, jaundice, prothrombin level below 50%, and hepatic

encephalopathy. ALT is the most, sensitive and the most, specific routine laboratory test, available to detect early liver damage. Thus, any elevation of ALT above the upper limit, of the Inhibitors,research,lifescience,medical laboratory should be considered and any significant increase in ALT during the early phase, most, notably in repeated-dose studies in healthy volunteers, may lead to discontinuation of Inhibitors,research,lifescience,medical development, of a drug. The value of 2N is often considered as a threshold to define a potentially clinically significant, abnormality (PCSA). However, ALT elevation to levels above the upper limit, of normal range (ULN) has been observed in healthy young subjects treated only with placebo with a prevalence ranging from 12% to 22% Inhibitors,research,lifescience,medical in the literature (Table I). 21-23 This prevalence increases after placebo

treatment lasting more than 1 week. In a recent review of data gathered from 152 hospitalized healthy young male volunteers participating in randomized, double-blind, placebo-controlled, 14-day, ascending-multiple-dose safety studies, the prevalence of ALT levels above ULN was 18.4%, with 13% having an abnormality of liver tests (value between N and 2N) and 5% a liver Inhibitors,research,lifescience,medical injury (value above 2N). Infectious disease (mononucleosis, toxoplasmosis, or viral infection) may explain this elevation in a few subjects, but it generally remains unexplained. The usual causes

of increases in ALT and AST, such as AMN-107 cell line physical activity (30% to 40% increase in ALT and 30% to 70% increase in AST associated with an increase in creatine phosphokinase [CPK]),hypercaloric and hyperglucidic Inhibitors,research,lifescience,medical diet. (100% increase in ALT and AST),24,25 excessive consumption of alcohol (20% to 30% increase in ALT and AST), and overweight (10% to 60% increase in ALT and AST), can be ruled out. Indeed, overweight. subjects are excluded from participating in such studies and the restrictions during the study (alcohol intake forbidden, standardized normal diet, and no strenuous physical activities) are easy to control as the subjects are hospitalized throughout GPX6 the study. Table I. ALT increase above upper limit of normal range in healthy subjects treated with placebo. * Unpublished communication, 1991; ** unpublished communication, 1996. The duration of hospitalization may have a major impact on the prevalence of transaminase elevation on placebo, since most cases occur during the second week of hospitalization. One factor may be an imbalance between reduced physical activity and maintained caloric intake.