Liver Fibrosis Scores (FIB-4) Outperform Metabolic Indices in Predicting All-Cause Mortality and CVD Mortality Among Patients with MASLD: A Nationally Representative Cohort Study Based on NHANES 2011-2018

Liver Fibrosis Scores (FIB-4) Outperform Metabolic Indices in Predicting All-Cause Mortality and CVD Mortality Among Patients with MASLD: A Nationally Representative Cohort Study Based on NHANES 2011-2018 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Liver Fibrosis Scores (FIB-4) Outperform Metabolic Indices in Predicting All-Cause Mortality and CVD Mortality Among Patients with MASLD: A Nationally Representative Cohort Study Based on NHANES 2011-2018 Yiyang Liu, Ying Zhang, Ning Kang, Zhichao Zheng This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9169857/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background In metabolic dysfunction–associated steatotic liver disease (MASLD), both fibrosis burden and cardiometabolic dysregulation may contribute to adverse outcomes. However, the comparative prognostic value of a fibrosis-based index versus lipid- and insulin-resistance–related indices for near-term mortality risk stratification remains unclear. Methods We analysed adults with MASLD from the National Health and Nutrition Examination Survey (NHANES) 2011–2018. MASLD was defined by hepatic steatosis (Fatty Liver Index ≥ 60) plus at least one cardiometabolic risk factor. Mortality outcomes (all-cause mortality [ACM] and cardiovascular disease mortality [CVDM]) were ascertained via linkage to the National Death Index through 31 December 2019. Baseline fibrosis-4 index (FIB-4), atherogenic index of plasma (AIP), and triglyceride–glucose (TyG) index were evaluated as continuous (per 1-SD) and categorical measures (FIB-4 risk categories; tertiles for AIP and TyG). Associations with ACM and CVDM were assessed using survey-weighted multivariable Cox proportional hazards models. Restricted cubic splines examined potential non-linear relationships. Predictive discrimination at 5 years was evaluated using time-dependent ROC analyses (with competing-risk methods for CVDM). Results The analytic sample included 4,037 participants with MASLD (median follow-up ≈ 4.5 years), during which 222 ACM events and 66 CVDM events occurred. In fully adjusted, age-stratified Cox models, higher FIB-4 was consistently associated with increased ACM risk (per 1-SD: HR 1.24, 95% CI 1.09–1.41 for < 65 years; HR 1.34, 95% CI 1.20–1.50 for ≥ 65 years). Participants with high FIB-4 had markedly elevated ACM risk compared with low-risk counterparts (HR = 9.46, 95% CI = 2.58–34.60 for < 65 years; HR = 3.35, 95% CI = 2.14–5.26 for ≥ 65 years). For CVDM, FIB-4 was strongly associated with risk among participants aged ≥ 65 years (per 1-SD: HR = 1.37, 95% CI = 1.19–1.59; high-risk vs low-risk: HR = 5.59, 95% CI = 2.29–13.68), whereas AIP and TyG were not significant in this age stratum. FIB-4 demonstrated superior discrimination for 5-year mortality (ACM-AUC 0.763; CVDM-AUC 0.785) compared with AIP (ACM AUC 0.494; CVDM AUC 0.505) and TyG (ACM-AUC 0.522; CVDM-AUC 0.557). Conclusions In a contemporary, nationally representative US MASLD cohort with relatively short-term follow-up, baseline FIB-4 substantially outperformed AIP and TyG in stratifying and discriminating both all-cause and cardiovascular mortality risk, supporting fibrosis-oriented prognostic assessment for near-term risk evaluation in MASLD. Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigure3.tif Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 05 May, 2026 Reviewers agreed at journal 01 May, 2026 Reviews received at journal 30 Apr, 2026 Reviewers agreed at journal 21 Apr, 2026 Reviewers agreed at journal 20 Apr, 2026 Reviewers invited by journal 18 Apr, 2026 Editor assigned by journal 10 Apr, 2026 Submission checks completed at journal 10 Apr, 2026 First submitted to journal 06 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9169857","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":626721325,"identity":"f382c144-c5d1-423e-8f05-3ddfeff244d0","order_by":0,"name":"Yiyang Liu","email":"","orcid":"","institution":"Guangdong Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yiyang","middleName":"","lastName":"Liu","suffix":""},{"id":626721326,"identity":"6bbe45b4-062d-4e73-bbf9-4da9fcfd411b","order_by":1,"name":"Ying 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Based on NHANES 2011-2018","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":false,"email":"","identity":"cardiovascular-diabetology-endocrinology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Cardiovascular Diabetology – Endocrinology Reports","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"Unsupported Journal","inReviewEnabled":false,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9169857/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9169857/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn metabolic dysfunction–associated steatotic liver disease (MASLD), both fibrosis burden and cardiometabolic dysregulation may contribute to adverse outcomes. However, the comparative prognostic value of a fibrosis-based index versus lipid- and insulin-resistance–related indices for near-term mortality risk stratification remains unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe analysed adults with MASLD from the National Health and Nutrition Examination Survey (NHANES) 2011–2018. MASLD was defined by hepatic steatosis (Fatty Liver Index ≥ 60) plus at least one cardiometabolic risk factor. Mortality outcomes (all-cause mortality [ACM] and cardiovascular disease mortality [CVDM]) were ascertained via linkage to the National Death Index through 31 December 2019. Baseline fibrosis-4 index (FIB-4), atherogenic index of plasma (AIP), and triglyceride–glucose (TyG) index were evaluated as continuous (per 1-SD) and categorical measures (FIB-4 risk categories; tertiles for AIP and TyG). Associations with ACM and CVDM were assessed using survey-weighted multivariable Cox proportional hazards models. Restricted cubic splines examined potential non-linear relationships. Predictive discrimination at 5 years was evaluated using time-dependent ROC analyses (with competing-risk methods for CVDM).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe analytic sample included 4,037 participants with MASLD (median follow-up ≈ 4.5 years), during which 222 ACM events and 66 CVDM events occurred. In fully adjusted, age-stratified Cox models, higher FIB-4 was consistently associated with increased ACM risk (per 1-SD: HR 1.24, 95% CI 1.09–1.41 for \u0026lt; 65 years; HR 1.34, 95% CI 1.20–1.50 for ≥ 65 years). Participants with high FIB-4 had markedly elevated ACM risk compared with low-risk counterparts (HR = 9.46, 95% CI = 2.58–34.60 for \u0026lt; 65 years; HR = 3.35, 95% CI = 2.14–5.26 for ≥ 65 years). For CVDM, FIB-4 was strongly associated with risk among participants aged ≥ 65 years (per 1-SD: HR = 1.37, 95% CI = 1.19–1.59; high-risk vs low-risk: HR = 5.59, 95% CI = 2.29–13.68), whereas AIP and TyG were not significant in this age stratum. FIB-4 demonstrated superior discrimination for 5-year mortality (ACM-AUC 0.763; CVDM-AUC 0.785) compared with AIP (ACM AUC 0.494; CVDM AUC 0.505) and TyG (ACM-AUC 0.522; CVDM-AUC 0.557).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn a contemporary, nationally representative US MASLD cohort with relatively short-term follow-up, baseline FIB-4 substantially outperformed AIP and TyG in stratifying and discriminating both all-cause and cardiovascular mortality risk, supporting fibrosis-oriented prognostic assessment for near-term risk evaluation in MASLD.\u003c/p\u003e","manuscriptTitle":"Liver Fibrosis Scores (FIB-4) Outperform Metabolic Indices in Predicting All-Cause Mortality and CVD Mortality Among Patients with MASLD: A Nationally Representative Cohort Study Based on NHANES 2011-2018","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-27 09:43:35","doi":"10.21203/rs.3.rs-9169857/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-05T13:33:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"68662100041415704930095340886496268","date":"2026-05-01T08:23:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T21:35:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47200042693057466317247573359135230058","date":"2026-04-21T04:30:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"246312099648573076803813232224544148590","date":"2026-04-20T17:04:30+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-18T16:41:59+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-10T13:17:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-10T11:34:55+00:00","index":"","fulltext":""},{"type":"submitted","content":"Cardiovascular Diabetology – Endocrinology Reports","date":"2026-04-06T13:11:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":false,"email":"","identity":"cardiovascular-diabetology-endocrinology-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Cardiovascular Diabetology – Endocrinology Reports","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"Unsupported Journal","inReviewEnabled":false,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b1b845a4-9ded-4bb6-8d8c-206752688430","owner":[],"postedDate":"April 27th, 2026","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-05T13:33:53+00:00","index":20,"fulltext":""},{"type":"reviewerAgreed","content":"68662100041415704930095340886496268","date":"2026-05-01T08:23:44+00:00","index":19,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-30T21:35:33+00:00","index":17,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T09:43:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-27 09:43:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9169857","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9169857","identity":"rs-9169857","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}