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Non-invasive tests for evaluating treatment response in NAFLD

Published:August 22, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.015

      Keywords

      Abbreviations:

      NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic steatohepatitis)

      Linked Article

      • Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study
        Journal of HepatologyVol. 76Issue 3
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          Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study.
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      To the Editor:
      We read with great interest the intriguing and clinically very relevant study by Rinella et al., wherein they used non-invasive tests (NITs) to evaluate the therapeutic response to obeticholic acid (OCA).
      • Rinella M.E.
      • Dufour J.F.
      • Anstee Q.M.
      • Goodman Z.
      • Younossi Z.
      • Harrison S.A.
      • et al.
      Non-invasive evaluation of response to obeticholic acid in patients with NASH: results from the REGENERATE study.
      The study is based on the 18-month interim results from the phase III REGENERATE trial, in which 931 patients with non-alcoholic steatohepatitis (NASH) and fibrosis stage F2 or F3 were randomized to receive placebo or two different OCA doses. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase as well as fibrosis scores, including FIB-4, enhanced liver fibrosis (ELF), FibroMeter, FibroTest and FibroScan-AST score, were determined and vibration-controlled transient elastography (VCTE) was assessed during the study period of 18 months. A reduction of aminotransferases, the different fibrosis scores and VCTE was observed in OCA- compared to placebo-treated patients. AST and ALT reduction was most evident in patients with improvement of fibrosis ≥1 stage. Aminotransferase levels, however, also improved in OCA-treated patients with no change or even with worsening in fibrosis stage, suggesting that these changes are unrelated to fibrosis. This is in line with a previous study showing that aminotransferases decrease with improvement of histological disease activity in non-alcoholic fatty liver disease (NAFLD), but do not significantly correlate with worsening of NAFLD.
      • Tsutsui M.
      • Tanaka N.
      • Kawakubo M.
      • Sheena Y.
      • Horiuchi A.
      • Komatsu M.
      • et al.
      Serum fragmented cytokeratin 18 levels reflect the histologic activity score of nonalcoholic fatty liver disease more accurately than serum alanine aminotransferase levels.
      In Rinella et al.’s study, ELF score changes were more pronounced in patients with fibrosis worsening than with improvement, whereas FIB-4 changes equally reflected fibrosis worsening and improvement.
      • Rinella M.E.
      • Dufour J.F.
      • Anstee Q.M.
      • Goodman Z.
      • Younossi Z.
      • Harrison S.A.
      • et al.
      Non-invasive evaluation of response to obeticholic acid in patients with NASH: results from the REGENERATE study.
      The FIB-4 score was developed to rule-in or -out advanced fibrosis by using two cut-off values.
      European Association for the Study of the Liver
      EASL clinical practice guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update.
      However, a long-term follow-up study of NAFLD patients revealed that changes of FIB-4 are only weakly associated with fibrosis progression in NAFLD.
      • Balkhed W.
      • Åberg F.O.
      • Nasr P.
      • Ekstedt M.
      • Kechagias S.
      Repeated measurements of non-invasive fibrosis tests to monitor the progression of non-alcoholic fatty liver disease: a long-term follow-up study.
      The ELF score considers markers of extracellular matrix remodeling and revealed a high diagnostic performance for the detection of advanced fibrosis in NAFLD.
      European Association for the Study of the Liver
      EASL clinical practice guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update.
      An early NIT, which detects early signs of fibrogenesis, remains to be established. We suggest that the M30 cell death biomarker, which measures caspase-cleaved cytokeratin-18 (CK-18) fragments after their release from apoptotic hepatocytes, might be very useful to detect fibrosis changes in response to treatment. Studies in HCV-mediated liver damage revealed that M30 is a sensitive NIT that can already be elevated in patients with normal aminotransferase levels but fibrotic liver injury.
      • Bantel H.
      • Lügering A.
      • Heidemann J.
      • Volkmann X.
      • Poremba C.
      • Strassburg C.P.
      • et al.
      Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury.
      ,
      • Kronenberger B.
      • Wagner M.
      • Herrmann E.
      • Mihm U.
      • Piiper A.
      • Sarrazin C.
      • et al.
      Apoptotic cytokeratin 18 neoepitopes in serum of patients with chronic hepatitis C.
      Moreover, patients with NAFLD and low FIB-4, who would not be considered for further risk stratification according to current guidelines, might benefit from serological M30 detection. We have very recently observed in a NAFLD cohort (n = 103) that patients with low FIB-4 but elevated M30 levels had NASH in the majority of cases, from which more than half showed histological signs of fibrosis (43% with F2/F3 fibrosis). Since inflammation and apoptotic liver injury triggers fibrogenesis, M30 levels significantly correlate with liver fibrosis.
      • Canbay A.
      • Friedman S.
      • Gores G.J.
      Apoptosis: the nexus of liver injury and fibrosis.
      • Feldstein A.E.
      • Wieckowska A.
      • Lopez A.R.
      • Liu Y.C.
      • Zein N.N.
      • McCullough A.J.
      Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study.
      • Joka D.
      • Wahl K.
      • Moeller S.
      • Schlue J.
      • Vaske B.
      • Bahr M.J.
      • et al.
      Prospective biopsy-controlled evaluation of cell death biomarkers for prediction of liver fibrosis and nonalcoholic steatohepatitis.
      • Tamimi T.I.
      • Elgouhari H.M.
      • Alkhouri N.
      • Yerian L.M.
      • Berk M.P.
      • Lopez R.
      • et al.
      An apoptosis panel for nonalcoholic steatohepatitis diagnosis.
      Indeed, CK-18 cleavage is an early event in hepatocyte apoptosis that is causally linked to stellate cell activation and fibrogenesis. Although M30 is not primarily a fibrosis marker, its level encompasses a biological plausibility that should be useful for monitoring therapeutic effects on fibrosis. Rinella et al. found a robust dose-dependent reduction of M30 levels in OCA-compared to placebo-treated patients with NASH at month 18. Despite the important findings, however, no information was provided on M30 levels at different time points in the course of treatment with respect to changes in the fibrosis stage. With regard to the close correlation of M30 with liver injury and fibrogenesis, it would be interesting to know how this biomarker reflects fibrosis progression or regression, as shown for other NITs.
      Since apoptosis is an early event in the pathogenesis of NAFLD and fibrosis development,
      • Canbay A.
      • Friedman S.
      • Gores G.J.
      Apoptosis: the nexus of liver injury and fibrosis.
      the M30 marker might detect a broader range of disease severity and therefore might represent a suitable NIT for monitoring the NAFLD course. M30 is currently used in various clinical studies evaluating novel drugs in NAFLD. Further data from these trials are required to evaluate the suitability of M30, as a single marker or in combination with other parameters, for monitoring disease progression and treatment response in NAFLD.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      All authors drafted and approved the final manuscript.

      Supplementary data

      The following are the supplementary data to this article:

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