Development, validation, and prognostic evaluation of LiverPRO for the prediction of significant liver fibrosis in primary care: a prospective cohort study

Katrine P. Lindvig, Katrine H. Thorhauge, Johanne K. Hansen, Maria Kjærgaard, Camilla D. Hansen, Stine Johansen, Ellen Lyngbeck, Mads Israelsen, Peter Andersen, Katrine T. Bech, Nikolaj Torp, Helle L. Schnefeld, Sönke Detlefsen, Sören Möller, Isabel Graupera, Morten B. Trelle, Steen Antonsen, Rebecca Harris, Line L. Kårhus, Kirsten S. BjørnsboCharlotte Brøns, Torben Hansen, Andreas Geier, Heiner Wedemeyer, Stefan Zeuzem, Jörn M. Schattenberg, Pere Ginès, Indra Neil Guha, Aleksander Krag*, Maja Thiele

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

1 Citationer (Scopus)

Abstract

Background: Clinically significant liver fibrosis is associated with future adverse events in patients with steatotic liver disease. We designed a software tool for detection of clinically significant liver fibrosis in primary care. Methods: In this prospective cohort study, we developed and validated LiverPRO using six independent cohorts from Denmark, Germany, and England that included patients from primary and secondary care with steatotic liver disease related to alcohol or metabolic dysfunction. We used clinically significant fibrosis (histology stage ≥F2) and advanced fibrosis (≥F3) as outcomes for variable selection in the development cohort and built the model with fractional polynomial regression. In all cohorts, we independently validated the tool for prediction of elevated liver stiffness by transient elastography (≥8 kPa and ≥12 kPa) and for the 2-year and 5-year risk of liver-related events. Diagnostic performance was assessed using the area under the receiver operating curve (AUC), with clinical performance evaluated through sensitivity, specificity, and Harrell's C-statistic for prognostic purposes. Findings: In the development cohort (n=462), we derived 466 multivariable models consisting of age in combination with three to nine variables from a list of nine blood tests (aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, international normalised ratio, albumin, sodium, bilirubin, platelet count, and cholesterol). In the development cohort, LiverPRO diagnosed clinically significant fibrosis with good accuracy (transient elastography ≥8 kPa area under the receiver operating characteristic curve [AUC] 0·86 [95% CI 0·83–0·90]). In the DECIDE validation cohort (n=6468), LiverPRO detected participants with a transient elastography of 8 kPa or higher with good accuracy (AUC 0·80 [95% CI 0·78–0·82]), comparable to enhanced liver fibrosis testing (0·78 [0·75–0·80]) and the LiverRisk score (0·81 [0·79–0·84]), but superior to the Fibrosis-4 index (0·69 [0·66–0·72]) and NAFLD Fibrosis Score (0·74 [0·72–0·77]). Findings were consistent in three other validation cohorts (n=2554), albeit accuracy was slightly lower. Using a rule-out cutoff of less than 25% (indicating no further examinations required), LiverPRO had a rule-out sensitivity of 80·6% (95% CI 76·4–84·3) and a rule-out negative predictive value of 98·0% (95% CI 97·5–98·4) in the DECIDE cohort. Similarly, with a rule-out cutoff of less than 1·3, FIB-4 had a rule-out sensitivity of 53·8% (48·5–58·9) and a rule-out negative predictive value of 95·8% (95·1–96·4). For rule-in thresholds, using a cutoff of more than 65% (indicating referral to a hepatologist required) LiverPRO had a rule-in specificity of 95·5% (95% CI 94·9–96·0) and a rule-in positive predictive value of 33·0% (95% CI 28·5–37·8) in the DECIDE cohort whereas FIB-4, with a rule-in threshold of 2·67, had a rule-in specificity of 98·7% (94·9–96·0) and a rule-in positive predictive value 35·6% (27·0–44·9). Using UK Biobank data, LiverPRO predicted liver-related events with a C-statistic of 0·80 (0·77–0·84) at 2 years. Interpretation: LiverPRO reliably identifies clinically significant liver fibrosis and elevated liver stiffness, predicts the risk of liver-related events in primary care, and is adaptable to the availability of different liver blood test analytes. On the basis of these results LiverPRO was certified according to IVDR class b, obtaining European CE approval in 2024. Funding: EU Horizon 2020 research and innovation programme and Novo Nordisk Foundation.

OriginalsprogEngelsk
TidsskriftThe Lancet Gastroenterology and Hepatology
Vol/bind10
Udgave nummer1
Sider (fra-til)55-67
Antal sider13
ISSN2468-1253
DOI
StatusUdgivet - 2025

Bibliografisk note

Funding Information:
This research was conducted using data from UK Biobank, a major biomedical database (project ID number: 94859). We wish to acknowledge the valuable contribution made by the nurses and secretaries in the outpatient clinic at the Department of Gastroenterology and Hepatology, Odense University Hospital, as well as the contributions from Odense Patient Explorative Network (made by Anna Mejldal) and the GALAXY and LiverScreen consortia. Writing and editorial assistance was provided by Julia Granerod of Dr JGW Consulting, and the funds for her assistance was provided from the Eureka and the Innovation Fund Denmark funded through the EuroStars grant, given to Odense University Hospital with Aleksander Krag as the main partner in the project. This study received funding from the Danish Advanced Technology Foundation and the European Union's Horizon 2020 Research and Innovation Program (grant agreement number 668031, GALAXY consortium). The Novo Nordisk Foundation's Challenge program (grant agreement number 16OC0016692 MicrobLiver consortium) funded data collection for the development cohort. The Novo Nordisk Foundation (grant agreement number 20OC0059393, DECIDE project) and the European Union's Horizon 2020 Research and Innovation Program (grant agreement number H2020 847989, LiverScreen consortium) funded data collection for the DECIDE cohort. The Innovation Fund Denmark (grant agreement number 9122\u201300119A, InnoExplorer grant), The Eureka and the Innovation Fund Denmark funded through the EuroStars grant (E83 \u2013 LiverPRO 2043\u201300004B), the InnoExplorer Grant (9122\u201300119A), the InnoFounder grant (2113\u201300023B), and the University of Southern Denmark's PhD stipends and Region of Southern Denmark's PhD stipends funded KL's (first author) PhD programme. The Toyota Foundation and AP Moeller Foundation funded purchase of the FibroScan and Aixplorer systems for ultrasound elastography. Siemens Healthcare A/S (Ballerup, Denmark) provided the assays used for the Enhanced Liver Fibrosis test without restrictions. The German SLD-Registry is financially supported by Advanz Pharma Specialty Medicine Deutschland GmbH/Intercept Pharma Europe and Gilead Sciences (grants to Deutsche Leberstiftung) as well as Novo Nordisk Pharma GmbH (directly via Leberstiftungs-GmbH). The sponsors of the study had no role in the study design, in the collection, analysis, or interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.

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© 2025 Elsevier Ltd

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