I read with great interest the article by Lee et al.1 in HEPATOLOGY regarding the healthy upper limit of normal of serum alanine aminotransferase (ALT) for Korean liver donors with histologically normal livers. Like Prati et al.,2 they echo the claim for lowering the healthy upper limit of normal threshold of ALT. However, I have a few comments.
Serum ALT is an easily available, low-cost screening tool for detecting silent liver disease.3 To screen for disease, we must know what is healthy. In this respect, as in most clinical laboratory tests, we have taken recourse to the biostatistical theory of health as articulated by Christopher Boorse,4 who defined health (“freedom from disease”) as “the statistical normality of function, i.e., the ability to perform all typical physiological functions with at least typical efficiency.” Normal function means the statistically typical contribution of all the organism's parts and processes to the organism's overall goals of survival and reproduction. The group with respect to which a contribution is considered statistically typical is the reference class, “a natural class of organism of uniform functional design” and specifically an age group of a sex of a race of a species.4 Thus, the American Gastroenterological Association has defined the normal range of ALT as the mean ± 2 standard deviations of the ALT levels of the normal population,5 with ALT ranges often being stratified by sex but not by age.
The disadvantage of the biostatistical theory model is that normal, often interchangeably used with healthy, will vary according to the chosen reference class,6 such as voluntary blood donors and laboratory technicians.2, 3 The choice of the reference class causes interlaboratory variability in the reference range of ALT.7 Metabolically abnormal individuals presumed to have a high risk of underlying nonalcoholic fatty liver disease were excluded from the reference class in Prati et al.'s study,2 but they were found to have normal liver histology, albeit with statistically higher ALT levels, and were included in this study.1 Moreover, is the chosen reference class representative of the general population? Voluntary blood donors represent the healthiest subset of the general population, and this is reflected by their significantly lower mortality and incidence of cancer and transfusion-transmittable viral infections in comparison with the general population; this is due to self-selection (altruism) and strict screening guidelines.8, 9 Liver donors also undergo similarly strict selection procedures. Should reference ranges of ALT obtained from such cohorts be used for the general population? Finally, why did the authors exclude 627 individuals with simple steatosis from their reference class? Individuals with simple steatosis do not have different long-term outcomes vis-à-vis an age-matched and sex-matched general population.10
Another way of defining healthy levels involves outcome studies, which are based on the development of adverse events during long-term follow-up (e.g., blood pressure).11 Here, disease is defined as “a state that places individuals at increased risk of adverse consequences.”12 An increased ALT level, even within the present normal range, is definitely a predictor of future development of metabolic syndrome13 and has been associated with increased overall, cardiovascular, and liver disease–related mortality in some but not all studies.11 The future publication of outcome studies will guide us further in this respect.
Finally, race has never been used to select the reference class for ALT. The significant genetic component in ALT variability among twins, even after adjustments for age, sex, body mass index, and alcohol consumption,14 points to the possibility that normal values of ALT will vary according to race, and this may be an explanation for the slight difference in the upper limit of normal of “normal” ALT levels between Koreans and Italians.1, 2