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Vol. 19. Núm. 5.
Páginas 579-580 (septiembre - octubre 2020)
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Vol. 19. Núm. 5.
Páginas 579-580 (septiembre - octubre 2020)
Letter to the Editor
Open Access
Enriched MACK-3 following CHAI and MACK-3 for the noninvasive diagnosis of nonalcoholic steatohepatitis
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Stergios A. Polyzos
Autor para correspondencia
spolyzos@auth.gr

Corresponding author at:
First Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
Jannis Kountouras
Second Medical Clinic, School of Medicine, Aristotle University of Thessaloniki, Ippokration Hospital, Thessaloniki, Greece
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Dear Editor,

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.

Abbreviations

ALT

alanine aminotransferase

AST

aspartate aminotransaminase

AUROC

area under the receiver operating characteristic curve

CHAI

CK-18 HOMA-IR AST index

CK

cytokeratin

FIB-4

fibrosis-4 index

HOMA-IR

homeostasis model assessement insulin resistance

MACK-3

HOMA-IR AST CK-18 index

MAFLD

metabolic associated fatty liver disease

MetS

metabolic syndrome

NASH

nonalcoholic steatohepatitis

NAFL

nonalcoholic fatty liver

NAFLD

nonalcoholic fatty liver disease

NFS

NAFLD fibrosis score

ROC

receiver operating characteristic

Conflict of interest

None.

Acknowledgments

Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References
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S.A. Polyzos, C.S. Mantzoros.
Necessity for timely noninvasive diagnosis of nonalcoholic fatty liver disease.
Metabolism, 63 (2014), pp. 161-167
[2]
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MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.
Gastroenterology, 158 (2020), pp. 1999-2014
[3]
S.A. Polyzos, E.S. Kang, C. Boutari, E.J. Rhee, C.S. Mantzoros.
Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis.
[4]
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Adipocytokines and cytokeratin-18 in patients with nonalcoholic fatty liver disease – introduction of CHA index.
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Nonalcoholic fatty liver disease: updates on associations with the metabolic syndrome and lipid profile and effects of treatment with PPAR-gamma agonists.
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Copyright © 2020. Fundación Clínica Médica Sur, A.C.
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