Designating upper reference limits (URLs) to liver function test alanine aminotransferase (ALT) runs the risk of overdiagnosing patients and ordering unnecessary tests, a group of experts wrote in an opinion article in July’s Clinical Chemistry.

To guide abnormal test result interpretations for ALT, American College of Gastroenterology (ACG) guidelines recommend a URL of 33 U/L for males and 25 U/L for females, indicating that a patient should seek further care if enzyme catalytic activity concentrations exceed these cutoffs. The North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) in the meantime, assesses ALT cutoffs by gender: 26 U/L for boys and 22 U/L for girls.

These guidelines fall short for several reasons, the authors cautioned, one of which is their recommended universal cutoffs for ALT fail to take analytical variations in lab assays into account. “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 measured by methods that give quite differing values,” wrote Mauro Panteghini, MD; Khosrow Adeli, MSc, PhD; Ferruccio Ceriotti, MD; Sverre Sandberg, MD, PhD; and Andrea Rita Horvath, MD, PhD. 

Providing useful information to assist in medical decisionmaking is one of laboratory medicine’s primary goals, Panteghini, professor and chair of clinical biochemistry and clinical molecular biology at the University of Milan Medical School, Milan, Italy, told CLN Stat. Such information should be obtained independent of measurement test kits and instruments, and also of the laboratory where the procedure is performed, he said. “One of the frequent laboratory problems is, however, the poor comparability of test results when they originate from different laboratories using different methods,” he explained.

With the ALT test, for which results have varied widely among different measurement procedures, method-dependent results require method-dependent cutoffs. “Guidelines established by scientific or professional bodies advocating use of universal limits for diagnosis and therapeutic intervention may create mistakes in clinical decisions when results obtained with different methods are interpreted,” according to Panteghini.

In addition to the analytical variation among laboratory assays measuring ALT, very different—or even inappropriate—criteria are often used to select a reference population to define the reference limits, he continued. “In particular, the evidence is that the recommended URLs are substantially lower when compared to those obtained in international studies that pay special attention to the population enrollment and subject selection, resulting in a marked increase of false positive results,” he said.

Clinicians often confuse URLs with decision limits, yet, their respective clinical meanings are completely different, Panteghini said. A reference interval typically represents a biological characteristic of a healthy population. Decision limits depend on clinical outcome and indicate whether a subject needs a specific medical intervention. The solution is not to eliminate URLs but to improve the way they’re derived through standardized and comparable laboratory methods and reliable selection of evaluated subjects. “If these conditions are realized, the obtained URLs can be universally applied without any further step,” Panteghini recommended.

The definition of a decision limit implies clinical outcome data, in addition to the fulfillment of the same high-level analytical requirements for the use of universal URLs, he added. “From the clinical point of view, decision limits are what we really need and URLs are just a surrogate for them,” Panteghini said.

Pick up the July issue of Clinical Chemistry to learn more about the shortcomings of these URLs for ALT, and which multidisciplinary measures serve as a better alternative to universal cutoffs.