Liver Fibrosis, Metabolic Dysfunction-Associated Steatotic Liver Disease, Non-alcoholic Fatty Liver Disease NAFLD, Obesity, Obesity Type 2 Diabetes Mellitus, Type 2 Diabetes Mellitus
Conditions
Keywords
MASLD, MAFLD, NAFLD, liver fibrosis, FIB-4, ELF, MASEF, screening, passive screening, advanced practice nurse, lifestyle intervention
Brief summary
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.
Detailed description
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.
Interventions
None listed
Sponsors
Hospital General Universitario Gregorio Marañon
Instituto de Investigación Sanitaria Gregorio Marañón
Consorcio Centro de Investigación Biomédica en Red (CIBER)
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Age between 50 and 75 years (inclusive) 2. 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 3. 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
1. Age \<50 years or \>75 years 2. Known pre-existing liver disease (significant or advanced fibrosis, cirrhosis, hepatocellular carcinoma, prior liver transplantation) 3. Prior fibrosis assessment within the preceding 12 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prevalence of hepatic fibrosis detected by the automated single-step case-finding strategy | Within 3 months of index blood test | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Diagnostic accuracy of FIB-4+ELF versus FIB-4+MASEF for histologically-confirmed significant fibrosis (≥F2) | At time of liver biopsy | 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. |
| Diagnostic accuracy of sequential NIT algorithms for at-risk MASH | At time of liver biopsy | 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 |
| Cost-effectiveness of the automated single-step strategy versus standard of care | At study completion (September 2027) | Health-economic analysis: diagnostic yield per euro spent, cost per case detected, and cost per QALY gained |
Countries
Spain
Contacts
CONTACTLuis Ibáñez-Samaniego, MD, PhD
STUDY_CHAIRRafael Bañares, Full-Professor of Medicine
Universidad Complutense de Madrid, President of Spanish Association for the Study of the Liver (AEEH)
STUDY_CHAIRMagdalena Salcedo, MD, PhD
President of the Spanish Society of Liver Transplantation (SETH)
Outcome results
None listed