Author information

¹Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK; Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.

²Hepatology Unit, CHU Bordeaux & INSERM U1312, Bordeaux University, Bordeaux, France.

³Department of Medical Imaging, Regional Institute of Gastroenterology and Hepatology, Octavian Fodor", University of Medicine and Pharmacy "Iuliu Hatieganu" Cluj-Napoca, Romania.

⁴Gastroenterology and Hepatology Unit, Department of Health Promotion Sciences Maternal and Infantile Care, Internal Medicine and Medical Specialities, Promise, University of Palermo, Italy.

⁵Liver-Gastroenterology Department, University Hospital, Angers, France.

⁶Center for Alcohol Research, University of Heidelberg, Germany; National Liver Institute, Menoufia University, Egypt; Institute of Systems, Molecular and Integrative Biology, University of Liverpool, UK.

⁷University of Florence, Department of Experimental and Clinical Medicine, Florence, Italy.

⁸Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Denmark.

⁹Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.

¹⁰Service d'hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France.

¹¹Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK.

¹²Service d'hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; Université Paris-Cité, Inserm, Centre de recherche sur l'inflammation, UMR 1149, Paris, France.

¹³Center for Alcohol Research, University of Heidelberg, Germany.

¹⁴Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK. Electronic address: e.tsochatzis@ucl.ac.uk.

Abstract

Background & aims: Agile scores, including liver stiffness measurements (LSM) and routine clinical/laboratory biomarkers, have been developed for advanced fibrosis (F≥3) and cirrhosis (F4), respectively, in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We independently validated the diagnostic accuracy of these scores in MASLD, alcohol-related liver disease (ALD) and chronic hepatitis B or C (CHB/C) and assessed them in clinical algorithms with FIB-4 and LSM.

Methods: We included 4,243 patients (MASLD: 912, ALD: 386, CHB: 597, CHC: 2,348) with LSM, liver biopsy and laboratory tests within 6 months. FIB-4, Agile 3+ and Agile 4 scores were calculated.

Results: For F≥3, the diagnostic accuracy of Agile 3+ and LSM were similar in MASLD (AUC: 0.86 vs. 0.86, p = 0.831) and ALD (0.92 vs. 0.94, p = 0.123). For cirrhosis, Agile 4 was similar to LSM in MASLD (0.89 vs. 0.90, p = 0.412) and ALD (0.94 vs. 0.95, p = 0.513). Agile 3+/4 performed worse than LSM in CHB/C. Using predefined dual thresholds of 90% sensitivity/specificity, correct classification rates in MASLD were 66% vs. 61% using Agile 3+ vs. LS dual cut-offs and 71% vs. 67% in ALD, respectively. When using Agile 3+ or LSM as a second step after FIB-4 >1.3, correct classification rates were higher with Agile 3+ than LSM, both for MASLD (75% vs. 71%) and ALD (76% vs. 72%), with fewer indeterminate results. Positive agreement of LSM and Agile 3+/4 significantly increased the specificity of a diagnosis of advanced fibrosis/cirrhosis.

Conclusion: Agile 3+ and Agile 4 have equal diagnostic accuracy with LSM in both MASLD and ALD but result in fewer indeterminate results. Sequential use of FIB-4 and Agile 3+/4 or concurrent Agile 3+/4 and LSM can be used to further optimize F≥3 diagnosis.

Impact and implications: As of today, it is accepted that there will be no single non-invasive test or an isolated cut-off for identifying patients with advanced chronic liver disease. Here, we confirmed that Agile 3+ and Agile 4 scores are useful alternatives to simple liver stiffness measurement in diagnosing advanced fibrosis/cirrhosis in steatotic liver disease, but they do not perform as well in chronic viral hepatitis. Agile scores can help optimize the diagnosis of advanced fibrosis/cirrhosis in a dual cut-off strategy by reducing the number of indeterminate results either alone or in a sequential strategy after FIB-4. The combination of Agile scores and liver stiffness measurement can further increase our confidence in a positive diagnosis of advanced fibrosis/cirrhosis. These novel combination strategies can be useful tools to predict the likelihood of advanced stages of liver disease with the highest possible accuracy in a secondary/tertiary healthcare setting.