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.
調査の概要
状態
状態
条件
条件
詳細な説明
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.
研究の種類
研究の種類
入学 (推定)
入学
連絡先と場所
研究連絡先
研究連絡先
- 名前：Luis Ibáñez-Samaniego, MD, PhD
- 電話番号：+34 91 586 8308
- メール：luis.ibanez@salud.madrid.org
研究場所
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Madrid
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Madrid、Madrid、スペイン、28007
- 募集
- Hospital General Universitario Gregorio Marañón
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コンタクト：
- Luis Ibáñez-Samaniego, MD, PhD
- 電話番号：+34 91 586 8308
- メール：luis.ibanez@salud.madrid.org
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コンタクト：
- Susana Sanchez Berdial, Pharm
- メール：ssberdial@salud.madrid.org
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参加基準
適格基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
サンプリング方法
調査対象母集団
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
グループ/コホートの数
コホートと介入
グループ/コホートグループ/コホート |
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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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この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Prevalence of hepatic fibrosis detected by the automated single-step case-finding strategy
時間枠：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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二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Diagnostic accuracy of FIB-4+ELF versus FIB-4+MASEF for histologically-confirmed significant fibrosis (≥F2)
時間枠：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
時間枠：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
時間枠：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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協力者と研究者
協力者
協力者
捜査官
捜査官
- スタディチェア：Rafael Bañares, Full-Professor of Medicine、Universidad Complutense de Madrid, President of Spanish Association for the Study of the Liver (AEEH)
- スタディチェア：Magdalena Salcedo, MD, PhD、President of the Spanish Society of Liver Transplantation (SETH)
出版物と役立つリンク
一般刊行物
- 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.
研究記録日
主要日程の研究
研究開始 (実際)
研究開始
一次修了 (推定)
一次修了
研究の完了 (推定)
研究の完了
試験登録日
最初に提出
最初に提出
QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
最初の投稿 (実際)
最初の投稿
学習記録の更新
投稿された最後の更新 (実際)
投稿された最後の更新
QC基準を満たした最後の更新が送信されました
QC基準を満たした最後の更新が送信されました
最終確認日
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
その他の研究ID番号
- HEP-OSF2024 (その他の識別子：Hospital General Universitario Gregorio Marañón)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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