The next step in the non-invasive diagnosis of significant liver fibrosis
Lindvig KP et al, Lancet Gastroenterol Hepatol. 2025;10(1):55-67
Steatotic liver disease (SLD) is common, affecting up to 30% of the population. Non-invasive screening tests could help to identify individuals with a progressive form of SLD with the development of fibrosis/cirrhosis. In this study of nearly 7000 individuals from Denmark, Germany, and the United Kingdom, a new score was developed that can predict the presence of significant liver fibrosis with high accuracy based on age and 3 to 9 blood test results.
Background: Clinically significant liver fibrosis is associated with future adverse events in patients with steatotic liver disease. The authors designed a software tool for detection of clinically significant liver fibrosis in primary care.
Methods: In this prospective cohort study, they developed and validated LiverPRO using 6 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. They 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, the authors 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), they derived 466 multivariable models consisting of age in combination with 3 to 9 variables from a list of 9 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 AUC, 0.86 [95% confidence interval [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 3 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.