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

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

January 2025

The Lancet Gastroenterology & Hepatology

10.1016/S2468-1253(24)00274-7

What pressing problem did this study address?

Liver disease affects more than one-third of adults worldwide. When detected early, liver disease can be managed through lifestyle interventions and treatments. However, accurately detecting liver disease can be challenging. Current screening tools like FIB-4 give many false positives and lead to unnecessary specialist referrals.

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What did this study find?

LiverPRO was developed and validated in almost 480,000 patients across different cohorts in Denmark, Germany, and the UK. In short, the findings showed that LiverPRO:

Detected liver fibrosis with an accuracy of 80% in a validation cohort with 6,468 patients

Correctly ruled out liver fibrosis in 81% of low-risk patients, compared to only 54% for FIB-4

Predicts the risk of liver-related events in primary care

Performs consistently across multiple cohorts with varying demographic and geographical characteristics

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Based on these results, LiverPRO was certified according to IVDR Class B and obtained CE-mark approval in 2024.

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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.

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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.

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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]).

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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.

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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.

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