Automated Passive Case-Finding for Advanced Liver Fibrosis in MASLD: The LiverSeek Programme (LiverSeek)
Towards Universal Screening for Metabolic Dysfunction-Associated Liver Fibrosis in Primary Care: Evaluation of a Single-Step, Laboratory Informatión System-Driven Automated Case-Finding Strategy (LiverSeek)
LiverSeek is a fully automated, passive case-finding programme for advanced liver fibrosis associated with metabolic dysfunction-associated steatotic liver disease (MASLD) in primary care. The programme operates through the Laboratory Information System (LIS; Modulab/Biwer Analytics) of the Clinical Biochemistry Laboratory at Hospital General Universitario Gregorio Marañón (HGUGM), covering approximately 350,000 inhabitants across 11 peri-urban primary care centres affiliated to SERMAS (Servicio Madrileño de Salud) in Madrid, Spain.
When a high-risk patient (age 50-75 years with ≥1 of: ALT above ULN + HbA1c ≥6.5%; ALT above ULN + BMI >30; BMI >30 + HbA1c ≥6.5%) undergoes a routine blood test in primary care, the LIS automatically calculates FIB-4. If FIB-4 >1.30, the system reflexively orders ELF and MASEF from the same serum sample, without any action required from the primary care clinician. Patients with a positive second-step NIT (ELF ≥9.8 or MASEF ≥0.33) receive an automatic alert directing them to the Hepatology Advanced Practice Nurse for VCTE (FibroScan) and clinical evaluation.
The primary objective is to evaluate the prevalence of hepatic fibrosis in the high-risk population using this single-step automated strategy. Secondary objectives include head-to-head diagnostic comparison of FIB-4+ELF vs FIB-4+MASEF vs FIB-4+FAST for histologically-confirmed endpoints (significant fibrosis ≥F2, advanced fibrosis ≥F3, at-risk MASH), evaluation of the Liver Risk Score, and a health-economic analysis. A sub-study evaluates a nurse-led structured lifestyle intervention in NIT-positive patients.
Descripción general del estudio
Estado
Descripción detallada
LiverSeek addresses a well-recognised implementation gap: despite guideline recommendations to screen for liver fibrosis in high-risk metabolic patients, fewer than one-third of eligible patients are assessed in clinical practice. Encounter-triggered programmes (e.g., SOLID, PRELUDE1) require primary care clinicians to initiate the assessment process, creating a dependency on clinician awareness and workload capacity that limits scalability.
LiverSeek adopts a fundamentally different model: the screening process is initiated passively by the LIS infrastructure, triggered by existing routine blood test data, with zero additional burden on the primary care clinician. This passive architecture is the programme's principal conceptual innovation.
NIT pathway and pre-specified thresholds:
Step 1 (LIS-triggered): FIB-4 calculated automatically. Threshold: >1.30 (EASL 2024) Step 2 (reflex, same serum sample): ELF (threshold ≥9.8) and MASEF (threshold ≥0.33, Youden J-point) Step 2 alternative (VCTE-based): VCTE ≥8.0 kPa; FAST score ≥0.50 (Youden J-point) NIT-positive patients → Hepatology APN visit (VCTE, anthropometrics, clinical assessment, EQ-5D-5L, IEXPAC, MEDAS dietary questionnaire) NIT-positive patients with VCTE ≥8.0 kPa → Hepatology physician consultation ± liver biopsy per clinical criteria
Histological sub-study: Liver biopsy specimens are scored using the NAFLD Activity Score (Kleiner 2005). At-risk MASH is defined as NAS ≥4 + fibrosis stage ≥F2. A target of approximately 300 evaluable biopsies is projected.
Lifestyle intervention sub-study: NIT-positive patients receive a single structured APN-delivered visit with a personalised SMART lifestyle protocol, with 24-week reassessment. Outcomes include changes in LSM, CAP, ALT, AST, GGT, HbA1c, FIB-4, and body composition (BIA).
Data management: REDCap electronic case report form, pseudonymised, restricted access.
Statistical approach: Prevalence with 95% CI (primary endpoint); AUROC with DeLong test for head-to-head NIT comparisons; sensitivity, specificity, PPV, NPV, LR+ and LR- for sequential algorithms; kappa for concordance. Health-economic analysis via CIBERehd.
Tipo de estudio
Inscripción (Estimado)
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Luis Ibáñez-Samaniego, MD, PhD
- Número de teléfono: +34 91 586 8308
- Correo electrónico: luis.ibanez@salud.madrid.org
Ubicaciones de estudio
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Madrid
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Madrid, Madrid, España, 28007
- Reclutamiento
- Hospital General Universitario Gregorio Marañón
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Contacto:
- Luis Ibáñez-Samaniego, MD, PhD
- Número de teléfono: +34 91 586 8308
- Correo electrónico: luis.ibanez@salud.madrid.org
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Contacto:
- Susana Sanchez Berdial, Pharm
- Correo electrónico: ssberdial@salud.madrid.org
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
- Adulto
- Adulto Mayor
Acepta Voluntarios Saludables
Método de muestreo
Población de estudio
Descripción
Inclusion Criteria:
- Age between 50 and 75 years (inclusive)
- Routine blood test processed in the Clinical Biochemistry Laboratory of Hospital General Universitario Gregorio Marañón, ordered by a primary care physician in one of the 11 affiliated SERMAS primary care centres
Presence of at least one of the following metabolic risk factor combinations:
- ALT above the upper limit of normal AND HbA1c ≥6.5%
- ALT above the upper limit of normal AND BMI >30 kg/m²
- BMI >30 kg/m² AND HbA1c ≥6.5%
Exclusion Criteria:
- Age <50 years or >75 years
- Known pre-existing liver disease (significant or advanced fibrosis, cirrhosis, hepatocellular carcinoma, prior liver transplantation)
- Prior fibrosis assessment within the preceding 12 months.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
Cohortes e Intervenciones
Grupo / Cohorte |
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NIT-Negative Cohort
High-risk patients (age 50-75 years with ≥1 metabolic risk criterion) in whom FIB-4 was automatically calculated by the LIS and found to be ≤1.30.
These patients do not undergo further NIT evaluation and are followed as the non-exposed reference cohort.
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NIT-Positive Cohort
High-risk patients with FIB-4 >1.30 in whom ELF and MASEF were reflexively determined from the same serum sample.
Patients with ELF ≥9.8 or MASEF ≥0.33 are referred to the Hepatology Advanced Practice Nurse for VCTE (FibroScan) and clinical assessment.
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Prevalence of hepatic fibrosis detected by the automated single-step case-finding strategy
Periodo de tiempo: Within 3 months of index blood test
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Proportion of high-risk patients with a positive result on at least one confirmatory NIT (ELF ≥9.8, MASEF ≥0.33, or VCTE ≥8.0 kPa) among all patients in whom FIB-4 was automatically calculated by the LIS
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Within 3 months of index blood test
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Diagnostic accuracy of FIB-4+ELF versus FIB-4+MASEF for histologically-confirmed significant fibrosis (≥F2)
Periodo de tiempo: At time of liver biopsy
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Head-to-head AUROC comparison (DeLong method) of sequential NIT algorithms at pre-specified thresholds (ELF ≥9.8; MASEF ≥0.33) in biopsied patients.
Sensitivity, specificity, PPV, NPV reported.
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At time of liver biopsy
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Diagnostic accuracy of sequential NIT algorithms for at-risk MASH
Periodo de tiempo: At time of liver biopsy
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AUROC comparison of FIB-4+ELF, FIB-4+MASEF, and FIB-4+FAST (threshold ≥0.50) for histological at-risk MASH (NAS ≥4 + fibrosis ≥F2, Kleiner criteria) in biopsied patients
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At time of liver biopsy
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Cost-effectiveness of the automated single-step strategy versus standard of care
Periodo de tiempo: At study completion (September 2027)
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Health-economic analysis: diagnostic yield per euro spent, cost per case detected, and cost per QALY gained
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At study completion (September 2027)
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Colaboradores e Investigadores
Patrocinador
Colaboradores
Investigadores
- Silla de estudio: Rafael Bañares, Full-Professor of Medicine, Universidad Complutense de Madrid, President of Spanish Association for the Study of the Liver (AEEH)
- Silla de estudio: Magdalena Salcedo, MD, PhD, President of the Spanish Society of Liver Transplantation (SETH)
Publicaciones y enlaces útiles
Publicaciones Generales
- European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol. 2024 Sep;81(3):492-542. doi: 10.1016/j.jhep.2024.04.031. Epub 2024 Jun 7.
- Graupera I, Thiele M, Castera L, Pera G, Piano S, Soria A, Fabrellas N, Toran P, Chacon C, Bech KT, Schnefeld HL, Tonon M, Incicco S, Moussy J, Levy V, Madir A, Kukic S, Jan Havaj D, Adamcova-Selcanova S, Pustjens J, van Kleef LA, Jimenez-Masip A, Pages L, Zoncape M, Weber SN, Galle PR, Harris R, Ibanez-Samaniego L, Morillas RM, Diaz A, Detlefsen S, Serra-Burriel M, Arslanow A, Andersen P, Pich J, Bonfill E, Korenjak M, Fournier-Poizat C, Llorca A, Gourmelon MC, de Koning HJ, Perez-Guasch M, Thu Ma A, Juanola A, Pose E, Arteaga I, Villesen I, Hansen JK, Calvino V, Gagliardi R, Boutouria B, Pastrovic F, Kujundzic PD, Zilincanova D, Sulejova KK, Rojo D, de Knegt RJ, Melo MD, Torrejon A, Hernandez-Ibanez R, Hoyo J, Munoz L, Lopez-Martos R, Griffin SJ, Manns M, Karlsen TH, Newsome PN, Kamath PS, Banares R, Guha IN, Schattenberg JM, Lammert F, Tsochatzis E, Brouwer WP, Pericas JM, Skladany L, Grgurevic I, Roulot D, Angeli P, Krag A, Caballeria L, Gines P; LiverScreen Consortium Investigators. Prevalence of liver fibrosis in the general population (the LiverScreen project): a multinational European cohort study. Lancet. 2026 Apr 11;407(10537):1448-1458. doi: 10.1016/S0140-6736(26)00354-5.
- Serra-Burriel M, Juanola A, Serra-Burriel F, Thiele M, Graupera I, Pose E, Pera G, Grgurevic I, Caballeria L, Piano S, van Kleef L, Reichert M, Roulot D, Pericas JM, Schattenberg JM, Tsochatztis EA, Guha IN, Garcia-Retortillo M, Hernandez R, Hoyo J, Fuentes M, Exposito C, Martinez A, Such P, Madir A, Detlefsen S, Tonon M, Martini A, Ma AT, Pich J, Bonfill E, Juan M, Soria A, Carol M, Gratacos-Gines J, Morillas RM, Toran P, Navarrete JM, Torrejon A, Fournier C, Llorca A, Arslanow A, de Koning HJ, Cucchietti F, Manns M, Newsome PN, Hernaez R, Allen A, Angeli P, de Knegt RJ, Karlsen TH, Galle P, Wong VW, Fabrellas N, Castera L, Krag A, Lammert F, Kamath PS, Gines P; LiverScreen Consortium Investigators. Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study. Lancet. 2023 Sep 16;402(10406):988-996. doi: 10.1016/S0140-6736(23)01174-1. Epub 2023 Aug 9.
- Kjaergaard M, Lindvig KP, Thorhauge KH, Andersen P, Hansen JK, Kastrup N, Jensen JM, Hansen CD, Johansen S, Israelsen M, Torp N, Trelle MB, Shan S, Detlefsen S, Antonsen S, Andersen JE, Graupera I, Gines P, Thiele M, Krag A. Using the ELF test, FIB-4 and NAFLD fibrosis score to screen the population for liver disease. J Hepatol. 2023 Aug;79(2):277-286. doi: 10.1016/j.jhep.2023.04.002. Epub 2023 Apr 21.
- Noureddin M, Truong E, Mayo R, Martinez-Arranz I, Minchole I, Banales JM, Arrese M, Cusi K, Arias-Loste MT, Bruha R, Romero-Gomez M, Iruzubieta P, Aller R, Ampuero J, Calleja JL, Ibanez-Samaniego L, Aspichueta P, Martin-Duce A, Kushner T, Ortiz P, Harrison SA, Anstee QM, Crespo J, Mato JM, Sanyal AJ. Serum identification of at-risk MASH: The metabolomics-advanced steatohepatitis fibrosis score (MASEF). Hepatology. 2024 Jan 1;79(1):135-148. doi: 10.1097/HEP.0000000000000542. Epub 2023 Jul 24.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Actual)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades del sistema endocrino
- Procesos Patológicos
- Trastornos Nutricionales
- Enfermedades metabólicas
- Sobrenutrición
- Peso corporal
- Enfermedades del Sistema Digestivo
- Trastornos del metabolismo de la glucosa
- Diabetes mellitus
- Enfermedades del HIGADO
- Exceso de peso
- Fibrosis
- Hígado graso
- Condiciones Patológicas, Signos y Síntomas
- Enfermedades Nutricionales y Metabólicas
- Signos y síntomas
- Obesidad
- Diabetes Mellitus, Tipo 2
- Enfermedad del hígado graso no alcohólico
- Cirrosis hepática
Otros números de identificación del estudio
- HEP-OSF2024 (Otro identificador: Hospital General Universitario Gregorio Marañón)
Plan de datos de participantes individuales (IPD)
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Descripción del plan IPD
Información sobre medicamentos y dispositivos, documentos del estudio
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