Advertisement

Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events

Published:January 18, 2022DOI:https://doi.org/10.1016/j.jhep.2021.12.031

      Highlights

      • At their published cut-offs, FIB4 and VCTE stratify patients with NAFLD into subgroups with significantly different prognoses.
      • Compared to liver biopsy in NAFLD, VCTE has similar accuracy for the prediction of liver-related events.
      • With regards to clinical events, the FIB4-VCTE stepwise algorithm accurately discriminates at-risk patients with NAFLD.
      • This algorithm should be used in the referral pathway to a liver specialist.

      Background & Aims

      Previous studies on the prognostic significance of non-invasive liver fibrosis tests in non-alcoholic fatty liver disease (NAFLD) lack direct comparison to liver biopsy. We aimed to evaluate the prognostic accuracy of fibrosis-4 (FIB4) and vibration-controlled transient elastography (VCTE), compared to liver biopsy, for the prediction of liver-related events (LREs) in NAFLD.

      Methods

      A total of 1,057 patients with NAFLD and baseline FIB4 and VCTE were included in a multicenter cohort. Of these patients, 594 also had a baseline liver biopsy. The main study outcome during follow-up was occurrence of LREs, a composite endpoint combining cirrhosis complications and/or hepatocellular carcinoma. Discriminative ability was evaluated using Harrell’s C-index.

      Results

      FIB4 and VCTE showed good accuracy for the prediction of LREs, with Harrell’s C-indexes >0.80 (0.817 [0.768-0.866] vs. 0.878 [0.835-0.921], respectively, p = 0.059). In the biopsy subgroup, Harrell’s C-indexes of histological fibrosis staging and VCTE were not significantly different (0.932 [0.910-0.955] vs. 0.881 [0.832-0.931], respectively, p = 0.164), while both significantly outperformed FIB4 for the prediction of LREs. FIB4 and VCTE were independent predictors of LREs in the whole study cohort. The stepwise FIB4-VCTE algorithm accurately stratified the risk of LREs: compared to patients with “FIB4 <1.30”, those with “FIB4 ≥1.30 then VCTE <8.0 kPa” had similar risk of LREs (adjusted hazard ratio [aHR] 1.3; 95% CI 0.3–6.8), whereas the risk of LREs significantly increased in patients with “FIB4 ≥1.30 then VCTE 8.0-12.0 kPa” (aHR 3.8; 95% CI 1.3–10.9), and even more for those with “FIB4 ≥1.30 then VCTE >12.0 kPa” (aHR 12.4; 95% CI 5.1–30.2).

      Conclusion

      VCTE and FIB4 accurately stratify patients with NAFLD based on their risk of LREs. These non-invasive tests are alternatives to liver biopsy for the identification of patients in need of specialized management.

      Lay summary

      The amount of fibrosis in the liver is closely associated with the risk of liver-related complications in non-alcoholic fatty liver disease (NAFLD). Liver biopsy currently remains the reference standard for the evaluation of fibrosis, but its application is limited by its invasiveness. Therefore, we evaluated the ability of non-invasive liver fibrosis tests to predict liver-related complications in NAFLD. Our results show that the blood test FIB4 and transient elastography stratify the risk of liver-related complications in NAFLD, and that transient elastography has similar prognostic accuracy as liver biopsy. These results support the use of non-invasive liver fibrosis tests instead of liver biopsy for the management of patients with NAFLD.

      Graphical abstract

      Keywords

      Linked Article

      • Low accuracy of FIB-4 test to identify people with diabetes at low risk of advanced fibrosis
        Journal of HepatologyVol. 77Issue 4
        • Preview
          We read with great interest the article by Boursier et al. recently published in Journal of Hepatology.1 In a multicentre cohort of patients with NAFLD, the authors examined the prognostic accuracy of the stepwise Fibrosis-4 (FIB-4) – vibration-controlled transient elastography (VCTE) algorithm for non-invasive fibrosis risk stratification,2 for the prediction of cirrhosis complications, hepatocellular carcinoma, and death. The algorithm proposes FIB-4 as a first step to identify individuals at low risk (FIB-4 <1.3) of advanced fibrosis who can be managed in primary care.
        • Full-Text
        • PDF
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Hepatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Taylor R.S.
        • Taylor R.J.
        • Bayliss S.
        • Hagstrom H.
        • Nasr P.
        • Schattenberg J.M.
        • et al.
        Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.
        Gastroenterology. 2020; 158: 1611-1625 e1612
        • Geier A.
        • Boursier J.
        Non-invasive diagnosis of patients with 'at-risk' NAFLD : only fibrosis counts?.
        Gut. 2020; 69: 1164-1165
        • EASL
        EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.
        J Hepatol. 2016; 64: 1388-1402
        • Chalasani N.
        • Younossi Z.
        • Lavine J.E.
        • Charlton M.
        • Cusi K.
        • Rinella M.
        • et al.
        The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases.
        Hepatology. 2018; 67: 328-357
        • Ratziu V.
        • Charlotte F.
        • Heurtier A.
        • Gombert S.
        • Giral P.
        • Bruckert E.
        • et al.
        Sampling variability of liver biopsy in nonalcoholic fatty liver disease.
        Gastroenterology. 2005; 128: 1898-1906
        • Davison B.A.
        • Harrison S.A.
        • Cotter G.
        • Alkhouri N.
        • Sanyal A.
        • Edwards C.
        • et al.
        Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials.
        J Hepatol. 2020; 73: 1322-1332
        • Xiao G.
        • Zhu S.
        • Xiao X.
        • Yan L.
        • Yang J.
        • Wu G.
        Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis.
        Hepatology. 2017; 66: 1486-1501
        • Boursier J.
        • Guillaume M.
        • Leroy V.
        • Irles M.
        • Roux M.
        • Lannes A.
        • et al.
        New sequential combinations of non-invasive fibrosis tests provide an accurate diagnosis of advanced fibrosis in NAFLD.
        J Hepatol. 2019; 71: 389-396
        • Vali Y.
        • Lee J.
        • Boursier J.
        • Spijker R.
        • Loffler J.
        • Verheij J.
        • et al.
        Enhanced liver fibrosis test for the non-invasive diagnosis of fibrosis in patients with NAFLD: a systematic review and meta-analysis.
        J Hepatol. 2020; 73: 252-262
        • Mehta S.H.
        • Lau B.
        • Afdhal N.H.
        • Thomas D.L.
        Exceeding the limits of liver histology markers.
        J Hepatol. 2009; 50: 36-41
        • Angulo P.
        • Bugianesi E.
        • Bjornsson E.S.
        • Charatcharoenwitthaya P.
        • Mills P.R.
        • Barrera F.
        • et al.
        Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease.
        Gastroenterology. 2013; 145: 782-789 e784
        • Boursier J.
        • Vergniol J.
        • Guillet A.
        • Hiriart J.B.
        • Lannes A.
        • Le Bail B.
        • et al.
        Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.
        J Hepatol. 2016; 65: 570-578
        • Munteanu M.
        • Pais R.
        • Peta V.
        • Deckmyn O.
        • Moussalli J.
        • Ngo Y.
        • et al.
        Long-term prognostic value of the FibroTest in patients with non-alcoholic fatty liver disease, compared to chronic hepatitis C, B, and alcoholic liver disease.
        Aliment Pharmacol Ther. 2018; 48: 1117-1127
        • Hagstrom H.
        • Nasr P.
        • Ekstedt M.
        • Stal P.
        • Hultcrantz R.
        • Kechagias S.
        Accuracy of noninvasive scoring systems in assessing risk of death and liver-related endpoints in patients with nonalcoholic fatty liver disease.
        Clin Gastroenterol Hepatol. 2019; 17: 1148-1156 e1144
        • Sterling R.K.
        • Lissen E.
        • Clumeck N.
        • Sola R.
        • Correa M.C.
        • Montaner J.
        • et al.
        Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection.
        Hepatology. 2006; 43: 1317-1325
        • Srivastava A.
        • Gailer R.
        • Tanwar S.
        • Trembling P.
        • Parkes J.
        • Rodger A.
        • et al.
        Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease.
        J Hepatol. 2019; 71: 371-378
        • Castera L.
        • Forns X.
        • Alberti A.
        Non-invasive evaluation of liver fibrosis using transient elastography.
        J Hepatol. 2008; 48: 835-847
        • Papatheodoridi M.
        • Hiriart J.B.
        • Lupsor-Platon M.
        • Bronte F.
        • Boursier J.
        • Elshaarawy O.
        • et al.
        Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease.
        J Hepatol. 2021; 74: 1109-1116
        • Mozes F.E.
        • Lee J.A.
        • Selvaraj E.A.
        • Jayaswal A.N.A.
        • Trauner M.
        • Boursier J.
        • et al.
        Diagnostic accuracy of non-invasive tests for advanced fibrosis in patients with NAFLD: an individual patient data meta-analysis.
        Gut. 2021;
        • Petta S.
        • Wong V.W.
        • Camma C.
        • Hiriart J.B.
        • Wong G.L.
        • Vergniol J.
        • et al.
        Serial combination of non-invasive tools improves the diagnostic accuracy of severe liver fibrosis in patients with NAFLD.
        Aliment Pharmacol Ther. 2017; 46: 617-627
        • Tsochatzis E.A.
        • Newsome P.N.
        Non-alcoholic fatty liver disease and the interface between primary and secondary care.
        Lancet Gastroenterol Hepatol. 2018; 3: 509-517
        • Kleiner D.E.
        • Brunt E.M.
        • Van Natta M.
        • Behling C.
        • Contos M.J.
        • Cummings O.W.
        • et al.
        Design and validation of a histological scoring system for nonalcoholic fatty liver disease.
        Hepatology. 2005; 41: 1313-1321
        • Boursier J.
        • Anty R.
        • Vonghia L.
        • Moal V.
        • Vanwolleghem T.
        • Canivet C.M.
        • et al.
        Screening for therapeutic trials and treatment indication in clinical practice: MACK-3, a new blood test for the diagnosis of fibrotic NASH.
        Aliment Pharmacol Ther. 2018; 47: 1387-1396
        • Bedossa P.
        • Consortium F.P.
        Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.
        Hepatology. 2014; 60: 565-575
        • Stekhoven D.J.
        • Buhlmann P.
        MissForest--non-parametric missing value imputation for mixed-type data.
        Bioinformatics. 2012; 28: 112-118
        • Harrell Jr., F.E.
        • Califf R.M.
        • Pryor D.B.
        • Lee K.L.
        • Rosati R.A.
        Evaluating the yield of medical tests.
        JAMA. 1982; 247: 2543-2546
        • Kang L.
        • Chen W.
        • Petrick N.A.
        • Gallas B.D.
        Comparing two correlated C indices with right-censored survival outcome: a one-shot nonparametric approach.
        Stat Med. 2015; 34: 685-703
        • Fine G.P.
        • Gray R.J.
        A proportional hazards model for the subdistribution of a competing risk.
        J Am Stat Assoc. 1999; 94: 496-509
        • Younossi Z.
        • Anstee Q.M.
        • Marietti M.
        • Hardy T.
        • Henry L.
        • Eslam M.
        • et al.
        Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
        Nat Rev Gastroenterol Hepatol. 2018; 15: 11-20
        • Estes C.
        • Anstee Q.M.
        • Arias-Loste M.T.
        • Bantel H.
        • Bellentani S.
        • Caballeria J.
        • et al.
        Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030.
        J Hepatol. 2018; 69: 896-904
        • Castera L.
        • Friedrich-Rust M.
        • Loomba R.
        Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease.
        Gastroenterology. 2019; 156: 1264-1281 e1264
        • Vilar-Gomez E.
        • Lou Z.
        • Kong N.
        • Vuppalanchi R.
        • Imperiale T.F.
        • Chalasani N.
        Cost effectiveness of different strategies for detecting cirrhosis in patients with nonalcoholic fatty liver disease based on United States health care system.
        Clin Gastroenterol Hepatol. 2020; 18: 2305-2314 e2312
        • Srivastava A.
        • Jong S.
        • Gola A.
        • Gailer R.
        • Morgan S.
        • Sennett K.
        • et al.
        Cost-comparison analysis of FIB-4, ELF and fibroscan in community pathways for non-alcoholic fatty liver disease.
        BMC Gastroenterol. 2019; 19: 122
        • Hagstrom H.
        • Talback M.
        • Andreasson A.
        • Walldius G.
        • Hammar N.
        Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease.
        J Hepatol. 2020; 73: 1023-1029
        • Kwok R.
        • Choi K.C.
        • Wong G.L.
        • Zhang Y.
        • Chan H.L.
        • Luk A.O.
        • et al.
        Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study.
        Gut. 2016; 65: 1359-1368