The noninvasive diagnosis of nonalcoholic steatohepatitis (NASH) and advanced hepatic fibrosis remain hot issues in the field of nonalcoholic fatty liver disease (NAFLD) [1], recently renamed to metabolic (dysfunction)-associated fatty liver disease (MAFLD) [2]. Appropriate noninvasive indices target to limit the need of liver biopsy, facilitate the follow-up of patients and enable the set up of clinical trials for this highly prevalent, with epidemic characteristics, disease without any approved treatment [3].
In 2013, we initially introduced cytokeratin [CK]-18, homeostasis model assessement insulin resistance [HOMA-IR], aspartate transaminase [AST] Index (CHAI) [4], which was shown to be higher in patients with NASH than simple nonalcoholic fatty liver (NAFL). The area under the receiver operating characteristic (ROC) curve (AUROC) of CHAI to differentiate NASH from NAFL was 0.72, presenting satisfactory specificity (80%), albeit low sensitivity (46%) [4].
In 2018, Boursier et al. introduced HOMA-IR, AST and CK-18 (MACK-3), as an index of fibrotic NASH (defined as NAFLD activity score ≥4 and fibrosis stage [F] ≥2) [5], by using exactly the same combination of parameters as CHAI. MACK-3 showed an AUROC of 0.85 with high specificity (94%) and sensitivity (90%) for the diagnosis of fibrotic NASH [5]. Subsequently, the authors provided an online calculator (http://forge.info.univ-angers.fr/∼gh/wstat/mack3-calculator.php). In 2019, Chuah et al. validated MACK-3, with AUROC of 0.80 and comparable accuracy of NAFLD fibrosis score (NFS) and fibrosis-4 index (FIB-4) for fibrotic NASH [6].
In 2020, Gao et al. further validated MACK-3 and extended it by adding platelets count and the presence of metabolic syndrome (MetS) [7]. This enriched MACK-3, named “novel nomogram”, provided AUROC of 0.85 with sensitivity 79% and 95%, and specificity 95% and 89% in the training and validation cohort, respectively, for the diagnosis of fibrotic NASH. Notably, when the enhanced MACK-3 was combined with the liver stiffness measurement of vibration-controlled transient elastography in a sequential approach, 68% and 47% of liver biopsies could have been avoided in the training and validation cohort, respectively [7].
CHAI/MACK-3 consists of parameters that reflect insulin resistance (HOMA-IR), hepatocellular dysfunction (AST) and hepatocellular apoptosis (CK-18), all contributing to the pathogenesis of MAFLD [8]. The inclusion of AST instead of ALT in CHAI/MACK-3 may seem paradoxical, since higher alanine aminotransferase (ALT) than AST appears to differentiate MAFLD from other liver diseases presenting with hepatic steatosis (e.g. alcoholic or drug-induced fatty liver disease); however, higher AST seems to be a better predictor of advanced disease within MAFLD patients, when the diagnosis of MAFLD is established [9]. Gao et al. added platelets and MetS to MACK-3 [7], which had been previously incorporated in other noninvasive indices of NASH and fibrosis, including NFS [10] and FIB-4 [11] (platelets) or Nice Model [12] (MetS), the latter being in close association with MAFLD [13].
In conclusion, the use of CK-18, HOMA-IR and AST for the noninvasive diagnosis and management of fibrotic NASH has been validated by three independent groups [5–7]. Whether the addition of other parameters essentially adds to the diagnostic accuracy of the CHAI/MACK-3 remains to be validated by further studies.
AbbreviationsALT alanine aminotransferase aspartate aminotransaminase area under the receiver operating characteristic curve CK-18 HOMA-IR AST index cytokeratin fibrosis-4 index homeostasis model assessement insulin resistance HOMA-IR AST CK-18 index metabolic associated fatty liver disease metabolic syndrome nonalcoholic steatohepatitis nonalcoholic fatty liver nonalcoholic fatty liver disease NAFLD fibrosis score receiver operating characteristic
None.
Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
