Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study

LiverScreen Consortium Investigators; Miquel Serra-Burriel; Adrià Juanola; Feliu Serra-Burriel; Maja Thiele; Isabel Graupera; Elisa Pose; Guillem Pera; Ivica Grgurevic; Llorenç Caballeria; Salvatore Piano; Laurens Van Kleef; Mathias Reichert; Dominique Roulot; Juan M. Pericas; Jörn M Schattenberg; Emmanuel A Tsochatztis; Indra Neil Guha; Montserrat Garcia-Retortillo; Rosario Hernández; Jordi Hoyo; Matilde Fuentes; Carmen Expósito; Alba Martínez; Patricia Such; Anita Madir; Sönke Detlefsen; Marta Tonon; Andrea Martini; Ann T Ma; Judith Pich; Eva Bonfill; Marta Juan; Anna Soria; Marta Carol; Jordi Gratacós-Ginès; Rosa M Morillas; Pere Toran; J M Navarrete; Antoni Torrejón; Céline Fournier; Anne Llorca; Anita Arslanow; Harry J. de koning; Fernando Cucchietti; Michael Manns; Phillip N Newsome; Rubén Hernáez; Alina Allen; Paolo Angeli; Robert J de Knegt; Tom H Karlsen; Peter Galle; Vincent Wai-Sun Wong; Núria Fabrellas; Laurent Castera; Aleksander  Krag; Frank Lammert; Patrick S. Kamath; Pere Ginès

doi:10.1016/S0140-6736(23)01174-1

Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study

LiverScreen Consortium Investigators, Miquel Serra-Burriel, Adrià Juanola, Feliu Serra-Burriel, Maja Thiele, Isabel Graupera, Elisa Pose, Guillem Pera, Ivica Grgurevic, Llorenç Caballeria, Salvatore Piano, Laurens Van Kleef, Mathias Reichert, Dominique Roulot, Juan M. Pericas, Jörn M Schattenberg, Emmanuel A Tsochatztis, Indra Neil Guha, Montserrat Garcia-Retortillo, Rosario HernándezJordi Hoyo, Matilde Fuentes, Carmen Expósito, Alba Martínez, Patricia Such, Anita Madir, Sönke Detlefsen, Marta Tonon, Andrea Martini, Ann T Ma, Judith Pich, Eva Bonfill, Marta Juan, Anna Soria, Marta Carol, Jordi Gratacós-Ginès, Rosa M Morillas, Pere Toran, J M Navarrete, Antoni Torrejón, Céline Fournier, Anne Llorca, Anita Arslanow, Harry J. de koning, Fernando Cucchietti, Michael Manns, Phillip N Newsome, Rubén Hernáez, Alina Allen, Paolo Angeli, Robert J de Knegt, Tom H Karlsen, Peter Galle, Vincent Wai-Sun Wong, Núria Fabrellas, Laurent Castera, Aleksander Krag, Frank Lammert, Patrick S. Kamath, Pere Ginès^*

^*Corresponding author for this work

Medicine and Health

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes.

METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort).

FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4.

INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care.

FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

Original language	English
Pages (from-to)	988-996
Number of pages	9
Journal	The Lancet
Volume	402
Issue number	10406
Early online date	9 Aug 2023
DOIs	https://doi.org/10.1016/S0140-6736(23)01174-1
Publication status	Published - 16 Sept 2023

Bibliographical note

Acknowledgments:
We acknowledge the help of Beatriz Márquez in the preparation of the manuscript. This project has received funding from he European Commission under the H20/20 program (847989) programme (847989). This study was also funded by Fondo de Investigación Sanitaria de Salud FIS PI18/01330 funded by Instituto de Salud Carlos III, Spanish Ministry of Economy, Industry, and Competitiveness and by the European Regional Development Fund (to NF). LiSyM funded by the German Ministry of Education and Research BMBF 031L0051 and 031L0257 (to FL).

Copyright:
© 2023 Elsevier Ltd. All rights reserved.

Keywords

Humans
Prognosis
Prospective Studies
Liver Cirrhosis/diagnosis
Risk Factors
Fibrosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/S0140-6736(23)01174-1Licence: None: All rights reserved

Cite this

LiverScreen Consortium Investigators, 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, J. M., Schattenberg, J. M., Tsochatztis, E. A., Guha, I. N., Garcia-Retortillo, M., ... Ginès, P. (2023). Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study. The Lancet, 402(10406), 988-996. https://doi.org/10.1016/S0140-6736(23)01174-1

@article{5a01a93d0a6f464a957f32a35692e9cb,

title = "Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study",

abstract = "BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes.METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort).FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4.INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care.FUNDING: European Commission under the H20/20 programme; Fondo de Investigaci{\'o}n Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).",

keywords = "Humans, Prognosis, Prospective Studies, Liver Cirrhosis/diagnosis, Risk Factors, Fibrosis",

author = "{LiverScreen Consortium Investigators} and Miquel Serra-Burriel and Adri{\`a} Juanola and Feliu Serra-Burriel and Maja Thiele and Isabel Graupera and Elisa Pose and Guillem Pera and Ivica Grgurevic and Lloren{\c c} Caballeria and Salvatore Piano and {Van Kleef}, Laurens and Mathias Reichert and Dominique Roulot and Pericas, {Juan M.} and Schattenberg, {J{\"o}rn M} and Tsochatztis, {Emmanuel A} and Guha, {Indra Neil} and Montserrat Garcia-Retortillo and Rosario Hern{\'a}ndez and Jordi Hoyo and Matilde Fuentes and Carmen Exp{\'o}sito and Alba Mart{\'i}nez and Patricia Such and Anita Madir and S{\"o}nke Detlefsen and Marta Tonon and Andrea Martini and Ma, {Ann T} and Judith Pich and Eva Bonfill and Marta Juan and Anna Soria and Marta Carol and Jordi Gratac{\'o}s-Gin{\`e}s and Morillas, {Rosa M} and Pere Toran and Navarrete, {J M} and Antoni Torrej{\'o}n and C{\'e}line Fournier and Anne Llorca and Anita Arslanow and {de koning}, {Harry J.} and Fernando Cucchietti and Michael Manns and Newsome, {Phillip N} and Rub{\'e}n Hern{\'a}ez and Alina Allen and Paolo Angeli and {de Knegt}, {Robert J} and Karlsen, {Tom H} and Peter Galle and Wong, {Vincent Wai-Sun} and N{\'u}ria Fabrellas and Laurent Castera and Aleksander Krag and Frank Lammert and Kamath, {Patrick S.} and Pere Gin{\`e}s",

note = "Acknowledgments: We acknowledge the help of Beatriz M{\'a}rquez in the preparation of the manuscript. This project has received funding from he European Commission under the H20/20 program (847989) programme (847989). This study was also funded by Fondo de Investigaci{\'o}n Sanitaria de Salud FIS PI18/01330 funded by Instituto de Salud Carlos III, Spanish Ministry of Economy, Industry, and Competitiveness and by the European Regional Development Fund (to NF). LiSyM funded by the German Ministry of Education and Research BMBF 031L0051 and 031L0257 (to FL). Copyright: {\textcopyright} 2023 Elsevier Ltd. All rights reserved.",

year = "2023",

month = sep,

day = "16",

doi = "10.1016/S0140-6736(23)01174-1",

language = "English",

volume = "402",

pages = "988--996",

journal = "The Lancet",

issn = "0140-6736",

publisher = "Elsevier",

number = "10406",

}

LiverScreen Consortium Investigators, 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, Hernández, R, Hoyo, J, Fuentes, M, Expósito, C, Martínez, A, Such, P, Madir, A, Detlefsen, S, Tonon, M, Martini, A, Ma, AT, Pich, J, Bonfill, E, Juan, M, Soria, A, Carol, M, Gratacós-Ginès, J, Morillas, RM, Toran, P, Navarrete, JM, Torrejón, A, Fournier, C, Llorca, A, Arslanow, A, de koning, HJ, Cucchietti, F, Manns, M, Newsome, PN, Hernáez, R, Allen, A, Angeli, P, de Knegt, RJ, Karlsen, TH, Galle, P, Wong, VW-S, Fabrellas, N, Castera, L, Krag, A, Lammert, F, Kamath, PS & Ginès, P 2023, 'Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study', The Lancet, vol. 402, no. 10406, pp. 988-996. https://doi.org/10.1016/S0140-6736(23)01174-1

TY - JOUR

T1 - Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population

T2 - a multicohort study

AU - LiverScreen Consortium Investigators

AU - Serra-Burriel, Miquel

AU - Juanola, Adrià

AU - Serra-Burriel, Feliu

AU - Thiele, Maja

AU - Graupera, Isabel

AU - Pose, Elisa

AU - Pera, Guillem

AU - Grgurevic, Ivica

AU - Caballeria, Llorenç

AU - Piano, Salvatore

AU - Van Kleef, Laurens

AU - Reichert, Mathias

AU - Roulot, Dominique

AU - Pericas, Juan M.

AU - Schattenberg, Jörn M

AU - Tsochatztis, Emmanuel A

AU - Guha, Indra Neil

AU - Garcia-Retortillo, Montserrat

AU - Hernández, Rosario

AU - Hoyo, Jordi

AU - Fuentes, Matilde

AU - Expósito, Carmen

AU - Martínez, Alba

AU - Such, Patricia

AU - Madir, Anita

AU - Detlefsen, Sönke

AU - Tonon, Marta

AU - Martini, Andrea

AU - Ma, Ann T

AU - Pich, Judith

AU - Bonfill, Eva

AU - Juan, Marta

AU - Soria, Anna

AU - Carol, Marta

AU - Gratacós-Ginès, Jordi

AU - Morillas, Rosa M

AU - Toran, Pere

AU - Navarrete, J M

AU - Torrejón, Antoni

AU - Fournier, Céline

AU - Llorca, Anne

AU - Arslanow, Anita

AU - de koning, Harry J.

AU - Cucchietti, Fernando

AU - Manns, Michael

AU - Newsome, Phillip N

AU - Hernáez, Rubén

AU - Allen, Alina

AU - Angeli, Paolo

AU - de Knegt, Robert J

AU - Karlsen, Tom H

AU - Galle, Peter

AU - Wong, Vincent Wai-Sun

AU - Fabrellas, Núria

AU - Castera, Laurent

AU - Krag, Aleksander

AU - Lammert, Frank

AU - Kamath, Patrick S.

AU - Ginès, Pere

N1 - Acknowledgments: We acknowledge the help of Beatriz Márquez in the preparation of the manuscript. This project has received funding from he European Commission under the H20/20 program (847989) programme (847989). This study was also funded by Fondo de Investigación Sanitaria de Salud FIS PI18/01330 funded by Instituto de Salud Carlos III, Spanish Ministry of Economy, Industry, and Competitiveness and by the European Regional Development Fund (to NF). LiSyM funded by the German Ministry of Education and Research BMBF 031L0051 and 031L0257 (to FL). Copyright: © 2023 Elsevier Ltd. All rights reserved.

PY - 2023/9/16

Y1 - 2023/9/16

N2 - BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes.METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort).FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4.INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care.FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

AB - BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes.METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort).FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4.INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care.FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

KW - Humans

KW - Prognosis

KW - Prospective Studies

KW - Liver Cirrhosis/diagnosis

KW - Risk Factors

KW - Fibrosis

U2 - 10.1016/S0140-6736(23)01174-1

DO - 10.1016/S0140-6736(23)01174-1

M3 - Article

C2 - 37572680

SN - 0140-6736

VL - 402

SP - 988

EP - 996

JO - The Lancet

JF - The Lancet

IS - 10406

ER -

Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study

Abstract

Bibliographical note

Keywords

UN SDGs

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