Apoptosis in Nonalcoholic Steatohepatitis With Normal Aminotransferase Values: Zooming in on Cytokeratin 18 Fragments

Abstract

Recent years have witnessed an increasing inter­ est in the relationship between alanine amino­ transferase (ALT) and nonalcoholic fatty liver disease (NAFLD) [1]. Traditionally, increased ALT concentrations are believed to be a conse­ quence of liver injury in NAFLD and are, thus, widely used as a surrogate marker of this condi­ tion [2]. However, studies assessing the specificity and sensitivity of ALT as a marker of NAFLD have been limited and efforts to identify reliable cut­off values for this enzyme, in order to facili­ tate the identification of subjects with NAFLD, have generated conflicting results [3]. Another issue inherent to the use of ALT as a biomarker of NAFLD is the possible confounding factors that might cause ALT elevation [4]. For example, small amounts of alcohol consumption, as well as hepatotoxic medications, may act as confounding factors in the association between increased ALT concentrations and NAFLD. These caveats not­ withstanding, ALT can be considered an accept­ able marker for NAFLD in epidemio logical studies. By contrast, caution should exercised regarding the use of ALT for diagnostic and mon­ itoring purposes in the clinical care of NAFLD patients [5]. Another problem with the use of ALT as a diagnostic or monitoring biomarker of NAFLD is the existence of two isoforms of this enzyme, termed ALT1 and ­2 [6]. Jadhao and colleagues have previously demon strated that murine ALT2 gene expression is induced two­ fold in fatty livers of obese mice [7]. By contrast, the expression of murine ALT1 was unchanged. This raises a question regarding which ALT form is actually measured in serum in the settings of standard clinical chemistry. It is now widely accepted that the full histo­ logical spectrum of NAFLD may be found in patients with normal ALT. Francanzani and coworkers have convincingly demonstrated that