Influence of Local Reference Populations on Upper Limits of Normal for Serum Alanine Aminotransferase Levels

Chronic liver disease can progress to cirrhosis if not detected early and appropriate interventions taken when possible. Serum levels of alanine aminotransferase (ALT, SGPT) and aspartate aminotransferase (AST, SGOT) are commonly measured during routine health care to detect such unsuspected liver disease. Care providers often use the reporting laboratory’s ALT upper reference limit (upper limit of normal, ULN) or a multiple thereof (e.g., 1.5 × ULN) to trigger further evaluation. Such evaluation can be expensive and invasive, yet ignoring aminotransferase elevations can allow life-threatening liver disease to progress if not recognized and treated appropriately. Therefore, how clinical laboratories define their own ALT ULN values is critically important in determining the risk benefit ratio of further evaluation. For technical reasons related to sample stability, validated standards are not used to establish a ULN for ALT and AST1. Instead, laboratories use locally-defined reference populations to establish their own reference ranges for these tests. The criteria used to include and exclude individuals from this important cohort directly determine the value of the test in identifying the presence of disease2. As obesity increases in the general population, such reference populations could increasingly include individuals with unsuspected nonalcoholic fatty liver disease (NAFLD) which would skew the upper reference limit to inappropriately high levels. One recent population study excluded people at risk for NAFLD and concluded that the “healthy range” for serum ALT should be up to 30 U/L for men and 19 U/L for women3. Although some have argued that this would lead to unnecessary medical expenditures and further burden our healthcare system4, 5, large population studies in Korea have demonstrated increased prevalence of NAFLD6 and increased liver-related mortality in middle aged adults with ALT levels between 20 and 40 U/L compared to those with ALT < 20 U/L7. The Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN), a group of eight academic institutions assembled by and in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to study fatty liver disease, began to design clinical studies in 2002 and considered using an ALT value greater than the ULN as an entry criterion for its major pediatric treatment trial8. However, variability was found in the ALT ULN values reported by clinical laboratories at CRN clinical centers that could confound the inclusion of homogeneous patient cohorts in this and other studies. The study described here was undertaken to establish the causes of the variability reported by laboratories of their self-defined ULN using results of analyses of samples distributed to clinical laboratories as part of annual accreditation by the College of American Pathologists (CAP).