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Validation of the Blood Test MACK-3 for the Noninvasive Diagnosis of Fibrotic Nonalcoholic Steatohepatitis: An International Study With 1924 Patients

Canivet CM 1 , Zheng MH 2 , Qadri S 3 , Vonghia L 4 , Chuah KH 5 , Costentin C 6 Show all authors , George J 7 , Armandi A 8 , Adams LA 9 , Lange NF 10 , Blanchet O 11 , Moal V 12 , Younes R 8 , Roux M 13 , Chan WK 5 , Sturm N 14 , Eslam M 7 , Bugianesi E 8 , Wang Z 9 , Dufour JF 15 , Francque S 4 , Yki-Järvinen H 3 , Zheng KI 2 , Boursier J 16

Affiliations 

  • 1 Service d'Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Universitaire d'Angers, Angers, France; Laboratoire HIFIH UPRES EA3859, SFR ICAT 4208, Université d'Angers, Angers, France
  • 2 Nonalcoholic Fatty Liver Disease Research Center, Department of Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
  • 3 Department of Medicine, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, University Hospital of Helsinki, Helsinki, Finland
  • 4 Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
  • 5 Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 6 Grenoble Institute for Advanced Biosciences, Research Center UGA/Inserm U 1209/CNRS 5309, Université Grenoble Alpes, Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire Grenoble-Alpes, Grenoble, France
  • 7 Storr Liver Centre, Westmead Hospital, University of Sydney, New South Wales, Australia
  • 8 Dipartimento di Scienze Mediche, Università di Torino, Turin, Italy
  • 9 Medical School, University of Western Australia, Perth, Australia
  • 10 Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Graduate School for Health Sciences, University of Bern, Bern, Switzerland
  • 11 CRB-BB-0033-00038, Angers University Hospital, Angers, France
  • 12 Biochemistry Department, Angers University Hospital, Angers, France
  • 13 Laboratoire HIFIH UPRES EA3859, SFR ICAT 4208, Université d'Angers, Angers, France
  • 14 Service d'Anatomie et de Cytologie Pathologique, Centre Hospitalier Universitaire Grenoble-Alpes, La Tronche, France
  • 15 Centre des Maladies Digestives, Lausanne, Switzerland; Swiss Nonalcoholic Steatohepatitis Foundation, Bern, Switzerland
  • 16 Service d'Hépato-Gastroentérologie et Oncologie Digestive, Hôpital Universitaire d'Angers, Angers, France; Laboratoire HIFIH UPRES EA3859, SFR ICAT 4208, Université d'Angers, Angers, France. Electronic address: JeBoursier@chu-angers.fr
Clin Gastroenterol Hepatol, 2023 Nov;21(12):3097-3106.e10.
PMID: 37031715 DOI: 10.1016/j.cgh.2023.03.032

Abstract

BACKGROUND & AIMS: Drug development in nonalcoholic steatohepatitis (NASH) is hampered by a high screening failure rate that reaches 60% to 80% in therapeutic trials, mainly because of the absence of fibrotic NASH on baseline liver histology. MACK-3, a blood test including 3 biomarkers (aspartate aminotransferase, homeostasis model assessment, and cytokeratin 18), recently was developed for the noninvasive diagnosis of fibrotic NASH. We aimed to validate the diagnostic accuracy of this noninvasive test in an international multicenter study.

METHODS: A total of 1924 patients with biopsy-proven nonalcoholic fatty liver disease from 10 centers in Asia, Australia, and Europe were included. The blood test MACK-3 was calculated for all patients. FibroScan-aspartate aminotransferase score (FAST), an elastography-based test for fibrotic NASH, also was available in a subset of 655 patients. Fibrotic NASH was defined as the presence of NASH on liver biopsy with a Nonalcoholic Fatty Liver Disease Activity Score of 4 or higher and fibrosis stage of F2 or higher according to the NASH Clinical Research Network scoring system.

RESULTS: The area under the receiver operating characteristic of MACK-3 for fibrotic NASH was 0.791 (95% CI 0.768-0.814). Sensitivity at the previously published MACK-3 threshold of less than 0.135 was 91% and specificity at a greater than 0.549 threshold was 85%. The MACK-3 area under the receiver operating characteristic was not affected by age, sex, diabetes, or body mass index. MACK-3 and FAST results were well correlated (Spearman correlation coefficient, 0.781; P < .001). Except for an 8% higher rate of patients included in the grey zone, MACK-3 provided similar accuracy to that of FAST. Both tests included 27% of patients in their rule-in zone, with 85% specificity and 35% false positives (screen failure rate).

CONCLUSIONS: The blood test MACK-3 is an accurate tool to improve patient selection in NASH therapeutic trials.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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