What are the best reference values for a normal serum alanine transaminase activity (ALT)? Impact on the presumed prevalence of drug induced liver injury (DILI)

BackgroundIn clinical research, the definition of the upper limit of normal (ULN) is rarely detailed. For alanine transaminase (ALT), there are several definitions of ULN-ALT but no recognized global reference. Furthermore the inter-laboratory variability of results expressed using ULN-ALT is higher than using the actual value of ULN expressed in IU/L. Regulatory agencies still use ULN-ALT for the definition of drug adverse events such as drug induced liver disease (DILI).MethodsWe applied two extreme definitions of ULN-ALT (26 and 66 IU/L) in two populations with different liver disease risk: 7463 consecutive volunteers representative a low risk population, and 6865 consecutive patients hospitalized in a tertiary referral center. The same assay technique was used for both populations on fresh plasma in the same laboratory.ResultsIn the low risk population the liver disease estimates ranged from 0% to 1.99% according to ULN-ALT definition and gender; prevalence of liver disease as defined by Temple's criteria (3×ULN) decreased significantly with increased ULN-ALT threshold and prevalence of liver disease was lower in females compared to males (all P < 0.001). In the high risk population the estimates of liver disease prevalence ranged from 0.78% to 15.85%; disease prevalence using both Temple's corollary and Hy's law criteria (3×ULN-ALT and bilirubin >34 μmol/L) decreased significantly with increased ULN-ALT threshold and females compared to males. In the low risk population the two major factors associated with ULN variability were gender and BMI.ConclusionArtificial statistical modifications of the procedures chosen for the ULN-ALT definition change dramatically the prevalence of DILI estimates. A consensus in liver disease definitions seems mandatory for DILI studies in order to prevent misleading conclusions.