MACK‐3 (combination of hoMa, Ast and CK18): A promising novel biomarker for fibrotic non‐alcoholic steatohepatitis

Abstract

Abbreviations: 95% CI, 95% confidence interval; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under the receiver operating characteristic curve; BMI, body mass index; CK18, cytokeratin 18; F, fibrosis stage; FIB-4, fibrosis-4 index; HbA1c, glycated haemoglobin; HOMA, homeostatic model assessment of insulin resistance; MACK-3, combination of hoMa, Ast and CK18; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH, non-alcoholic steatohepatitis; NFS, NAFLD fibrosis score. Abstract Introduction: MACK-3 (combination of hoMa, Ast and CK18) was reported to be a good biomarker for the diagnosis of fibrotic non-alcoholic steatohepatitis (NASH). However, there is no external validation to date. Aim: To evaluate the accuracy of MACK-3 for the diagnosis of fibrotic NASH. Methodology: Consecutive adult non-alcoholic fatty liver disease (NAFLD) patients who had liver biopsy in a university hospital were included. MACK-3 was calculated using the online calculator using the following variables: fasting glucose, fasting insulin, aspartate aminotransferase (AST) and cytokeratin 18 (CK18). MACK-3 cut-offs ≤0.134 and ≥0.550 were used to predict absence and presence of fibrotic NASH, respectively. Histopathological examination of liver biopsy specimen was reported according to the NASH Clinical Research Network Scoring System. Results: Data for 196 subjects were analysed. MACK-3 was good for diagnosis of fibrotic NASH (area under receiver-operating characteristics curve [AUROC] 0.80), comparable to the Fibrosis-4 index (FIB4) and the NAFLD fibrosis score (NFS) and superior to the BARD score and CK18. MACK-3 was good for diagnosis of active NASH (AUROC 0.81) and was superior to other blood fibrosis tests. The overall accuracy, percentage of subjects in grey zone, sensitivity, specificity, positive predictive value and negative predictive value of MACK-3 for diagnosis of fibrotic NASH was 79.1%, 46.9%, 100%, 43.8%, 43.1% and 100%, respectively, while for diagnosis of active NASH was 90.0%, 39.3%, 84.2%, 81.4%, 88.9% and 74.5%, respectively. Conclusion: MACK-3 is promising as a non-invasive test for active NASH and fibrotic NASH and may be useful to identify patients who need more aggressive intervention. K E Y W O R D S active NASH, cytokeratin-18, fibrotic NASH, non-invasive test

CHAI and MACK‐3 as noninvasive indices for nonalcoholic steatohepatitis

“…To the Editor We read with interest the article by Chuah 1 This study validates a previous study by Boursier et al (2018) that provided an algorithm for the calculation of MACK-3, 2 followed by an online calculator (http://forge.info.univ-angers.fr/~gh/wstat/ mack3-calcu lator.php).…”

Accuracy of cytokeratin 18 (M30 and M65) in detecting non-alcoholic steatohepatitis and fibrosis: A systematic review and meta-analysis

“…Composed of three ingredients (HOMA, AST and CK-18) the AUC from the validation group (n = 846) was 0.85. MACK-3 had an AUC of 0.80 when evaluated in a separate study [24].…”

“…Three studies provided sufficient data for analysis of M30 in detecting fibrotic NASH, with a combined total of 1,271 participants (343 with fibrotic NASH) ( S5 Fig in S1 File). Two studies investigated M30 as part of a multimarker models; authors of both studies [24,55] provided accuracy data for M30 at seven threshold values we selected based on the data from the present meta-analysis (133, 200, 248, 292, 356, 395, and 464 U/L). This allowed us to apply the multiple thresholds model (15 thresholds), to calculate an AUC of 0.73 (95% CI: 0.57-0.85), mean sensitivity of 0.63 (95% CI: 0.39-0.82) and mean specificity of 0.73 (95% CI: 0.51-0.88) at a Youden-threshold value of 371 U/L.…”

Reply to: CHAI and MACK‐3 as noninvasive indices for nonalcoholic steatohepatitis

“…We greatly appreciate the letter from Polyzos and Kountouras 1 and their comments in relation to our article. 2 It is interesting to note that Polyzos et al have reported the use of a similar combination of homeostatic model assessment of insulin resistance (HOMA-IR), aspartate aminotransferase (AST) and cytokeratin-18 (CK-18), called CHAI, for the diagnosis of nonalcoholic steatohepatitis (NASH). 3 While it is widely known that HOMA-IR, AST and CK-18 are indicators of insulin resistance, hepatocyte injury and apoptosis, respectively, and reasonable to expect these markers to be elevated in more severe nonalcoholic fatty liver disease (NAFLD), the development of an acceptable algorithm for diagnostic use is not as straightforward.…”

“…The strength of MACK-3 lies in its ability to rule out fibrotic NASH given its excellent sensitivity and negative predictive value that were consistently shown in both studies. 2,5 With this test, the need for liver biopsy can hopefully be significantly reduced when screening for fibrotic NASH among the very large population of NAFLD patients.…”