American Liver Guidelines and Cutoffs for “Normal” ALT: A Potential for Overdiagnosis

In 2 recent American clinical guidelines dealing with laboratory tests for evaluation of liver disease, key recommendations relate to alanine aminotransferase (ALT) 6 upper reference limits (URLs) to be used as action limits in interpreting abnormal results of this enzyme (1, 2). In adults, the American College of Gastroenterology (ACG) recommends ALT URLs of 33 U/L for males and 25 U/L for females, respectively, and that individuals with enzyme catalytic activity concentrations above these URLs should be further investigated (1). In children, experts of the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) state that the interpretation of ALT should be based upon gender-specific URLs (26 U/L for boys and 22 U/L for girls). We have some reservations about the universal application of these ALT cutoffs and we are concerned that the implementation of these recommendations may lead to overdiagnosis and unnecessary further testing. The contentious issues and our opinion about those are summarized below. The first problem is the analytical variation among commercial assays measuring ALT. The mentioned guidelines recommend the use of universal cutoffs for ALT without considering any differences between laboratory assays. Reassuring statements are rather reported as follows: “interlaboratory differences for ALT levels have not been reported to differ significantly” (1) or “the [ ALT ] assay is standardized between facilities” (2). In principle, fixed limits, be they medical decision thresholds or URLs, can be used only if the laboratory test in question is standardized and if this standardization is implemented in laboratories using the same limits. Despite the availability of a reference measurement system (RMS) for standardizing ALT results in clinical samples, the current evidence is, however, that ALT is still …