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MEFIB vs MAST and FAST: Not a competition but useful tools

Published:November 09, 2022DOI:https://doi.org/10.1016/j.jhep.2022.10.020

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      We read with interest the article by Kim et al.
      • Kim B.K.
      • Tamaki N.
      • Imajo K.
      • Yoneda M.
      • Sutter N.
      • Jung J.
      • et al.
      Head to head comparison between MEFIB, MAST, and FAST for detecting stage 2 fibrosis or higher among patients with NAFLD.
      which as its primary objective, compared MEFIB to MAST and FAST for the identification of significant fibrosis (≥F2). The secondary objective compared the diagnostic accuracies of these tests for the identification of at-risk NASH. The latter objective is a welcome effort to determine if MEFIB can assess at-risk NASH. Nevertheless, we believe that the primary objective compares “apples to oranges,” as MAST and FAST were not created to assess ≥ F2. Rather, they are composite, continuous, balanced tests to assess at-risk NASH (NASH with NAS ≥4 and ≥ F2) to increase enrollment in RCTs and reduce the number of required biopsies.
      • Noureddin M.
      • Truong E.
      • Gornbein J.A.
      • Saouaf R.
      • Guindi M.
      • Todo T.
      • et al.
      MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis.
      ,
      • Newsome P.N.
      • Sasso M.
      • Deeks J.J.
      • Paredes A.
      • Boursier J.
      • Chan W.K.
      • et al.
      FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study.
      In the at-risk NASH analysis, the AUC for MEFIB performed better in the entire cohort and the US cohort. Two cohorts are used in assessing the performance of a non-invasive test (NIT), with initial testing in one cohort and subsequent validation in another. Thus, in this scenario, the analysis of “the entire cohort” could be misleading and driven by the US cohort. Indeed, the AUC of MEFIB performed numerically worse than did MAST in the Japanese cohort which calls for further validation in other cohorts.
      We also emphasize that the positive predictive value (PPV) of NITs is highly dependent on the prevalence of a condition in a cohort: The current cohort was significantly enriched with fibrosis, i.e., in 51.2% of patients, whereas at-risk NASH was present in 31.4%. The >50% figure is much higher than in the original real-world cohorts, where the MAST score was developed and validated.
      • Noureddin M.
      • Truong E.
      • Gornbein J.A.
      • Saouaf R.
      • Guindi M.
      • Todo T.
      • et al.
      MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis.
      Despite that factor and when compared in the current cohorts, the PPV values using the rule in and rule out values for MAST and MEFIB (Table 3) did not differ in the entire cohort and were numerically better for MAST in that cohort as well as in the Japanese cohort.
      In addition, while the authors mention that MEFIB’s rule-in criteria covered more of the study population than did MAST, the significance for the indeterminate zone was downplayed. Although the NPV value was better for MEFIB than for MAST and FAST, the indeterminate zone was strikingly better for MAST. This finding is important for clinical trials screening, as the number of liver biopsies needed to be performed within the indeterminate zone, will be significantly higher if the MEFIB score is used rather than MAST. For instance, in an analysis of 2000 patients enrolled in a phase 3 RCT, where a similar number of patients are expected to be screened, using MEFIB for screening leads to ∼494 biopsies, whereas using MAST leads to ∼170 biopsies. Indeed, the number of patients correctly classified as NASH + F2,3 and 4 was higher with MAST than MEFIB and FAST (69.4% vs 57% and 45%, respectively) (Fig).
      Figure thumbnail gr1
      Figure 1The correct classified cases of NASH F2,3,4 «at-risk NASH »: Correctly classified (CC) = True negative for rule-out cutoff + true positive for rule-in cutoff/total. MEFIB: CC = (217 + 106)/563 = 57.4%. MAST: CC = (303 + 88)/563 = 69.4%. FAST: CC = (199 + 56)/563 = 45.3%.
      Importantly, using FIB-4 has its own issues, as many patients in the low and indeterminate zone have had either significant or advanced fibrosis in clinical trials, eventually had liver-related outcomes, and/or performed less well in type 2 diabetics.
      • Hagstrom H.
      • Talback M.
      • Andreasson A.
      • Walldius G.
      • Hammar N.
      Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease.
      An example is a 50-year-old with NAFLD who had AST of 45 U/L, ALT of 60 U/L, platelet count of 270 X 109/L, MRI-PDFF of 15%, MRE of 4 kPa, CAP score of 345 db/m, and stiffness of 12 kPa. Such a patient will have a “non-concerning” FIB-4 of 1.08 (the first test in MEFIB), whereas his MRE, transient elastography, MAST (=0.304) and FAST scores (=0.67) indicate significant fibrosis or at-risk NASH. Age is also an important variable in the FIB-4 score, and this factor is not tested with MEFIB.
      • McPherson S.
      • Hardy T.
      • Dufour J.F.
      • Petta S.
      • Romero-Gomez M.
      • Allison M.
      • et al.
      Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis.
      Of note, cost is a consideration with MRIs, thus the FAST score is overall easier to apply.
      Lastly, MEFIB is not suitable for monitoring response to NASH pharmacologic treatments given the way the score is calculated. This is in contrast to MAST and FAST where the continuous values change in response to different therapeutic agents and the thresholds for what constitute a meaningful therapeutic response are being established as part of ongoing clinical trials.
      In summary, the study by Kim et al. does not demonstrate that MEFIB is better than MAST or FAST, as the cohorts had conflicting results in the AUC of at-risk NASH, which is the appropriate head-to head comparison. Also, the MEFIB had a larger indeterminate zone than MAST, which can subsequently lead to more biopsies in NASH RCTs. Future studies to clarify the utility of each of these tests in the management of at-risk NASH are urgently needed.

      Conflict of interest statement

      MN has been on the advisory board/consultant for 89BIO, Altimmune, BI, Gilead, cohBar, Cytodyn, Pfizer, Novo Nordisk, EchoSens, Madrgial, NorthSea, Prespecturm, Terns, Sami-Sabina group, Siemens and Roche diagnostic; MN has received research support from Allergan, Akero, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Madrigal, Novartis, Pfizer, Shire, Viking and Zydus; MN is a shareholder or has stocks in Anaetos, Chrownwell, Ciema, Rivus Pharma and Viking.

      Authors' contributions

      MN participated in the design of the study, supervised the study, interpreted the data, and drafted the manuscript. LC, NA and SH: interpreted the data, helped draft the manuscript, interpreted the data and critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

      Financial support

      None.

      References

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        • Imajo K.
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        Head to head comparison between MEFIB, MAST, and FAST for detecting stage 2 fibrosis or higher among patients with NAFLD.
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        • Truong E.
        • Gornbein J.A.
        • Saouaf R.
        • Guindi M.
        • Todo T.
        • et al.
        MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis.
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        • Sasso M.
        • Deeks J.J.
        • Paredes A.
        • Boursier J.
        • Chan W.K.
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        • Talback M.
        • Andreasson A.
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