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).

BACKGROUND: In 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). METHODS: We 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. RESULTS: In 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. CONCLUSION: Artificial 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.