Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

Mozes, F.E.; Lee, J.A.; Vali, Y.; Alzoubi, O.; Staufer, K.; Trauner, M.; Paternostro, R.; Stauber, R.E.; Holleboom, A.G.; van Dijk, A.-.; Mak, A.L.; Boursier, J.; de Saint Loup, M.; Shima, T.; Bugianesi, E.; Gaia, S.; Armandi, A.; Shalimar,; Lupsor-Platon, M.; Wong, V.W.-.; Li, G.; Wong, G.L.-.; Cobbold, J.; Karlas, T.; Wiegand, J.; Sebastiani, G.; Tsochatzis, E.; Liguori, A.; Yoneda, M.; Nakajima, A.; Hagstrom, H.; Akbari, C.; Hirooka, M.; Chan, W.-.; Mahadeva, S.; Rajaram, R.; Zheng, M.-.; George, J.; Eslam, M.; Petta, S.; Pennisi, G.; Vigano, M.; Ridolfo, S.; Aithal, G.P.; Palaniyappan, N.; Lee, D.H.; Ekstedt, M.; Nasr, P.; Cassinotto, C.; de Ledinghen, V.; Berzigotti, A.; Mendoza, Y.P.; Noureddin, M.; Truong, E.; Fournier-Poizat, C.; Geier, A.; Martic, M.; Tuthill, T.; Anstee, Q.M.; Harrison, S.A.; Bossuyt, P.M.; Pavlides, M.; Daly, A.K.; Govaere, O.; Cockell, S.; Tiniakos, D.; Bedossa, P.; Burt, A.; Oakley, F.; Cordell, H.J.; Day, C.P.; Wonders, K.; Missier, P.; Mcteer, M.; Vale, L.; Oluboyede, Y.; Breckons, M.; Zafarmand, H.; Lee, J.; Nieuwdorp, M.; Verheij, J.; Ratziu, V.; Clement, K.; Patino-Navarrete, R.; Pais, R.; Paradis, V.; Schuppan, D.; Schattenberg, J.M.; Surabattula, R.; Myneni, S.; Straub, B.K.; Vidal-Puig, T.; Vacca, M.; Rodrigues-Cuenca, S.; Allison, M.; Kamzolas, I.; Petsalaki, E.; Campbell, M.; Lelliott, C.J.; Davies, S.; Oresic, M.; Hyotylainen, T.; Mcglinchey, A.; Mato, J.M.; Millet, O.; Dufour, J.-.; Masoodi, M.; Harrison, S.; Neubauer, S.; Mozes, F.; Akhtar, S.; Olodo-Atitebi, S.; Banerjee, R.; Kelly, M.; Shumbayawonda, E.; Dennis, A.; Andersson, A.; Wigley, I.; Romero-Gomez, M.; Gomez-Gonzalez, E.; Ampuero, J.; Castell, J.; Gallego-Duran, R.; Fernandez, I.; Montero-Vallejo, R.; Karsdal, M.; Rasmussen, D.G.K.; Leeming, D.J.; Sinisi, A.; Musa, K.; Sandt, E.; Tonini, M.; Rosso, C.; Marra, F.; Gastaldelli, A.; Svegliati, G.; Francque, S.; Vonghia, L.; Driessen, A.; Kechagias, S.; Yki-Jarvinen, H.; Porthan, K.; Arola, J.; van Mil, S.; Papatheodoridis, G.; Cortez-Pinto, H.; Rodrigues, C.M.P.; Valenti, L.; Pelusi, S.; Miele, L.; Trautwein, C.; Reissing, J.; Francis, S.; Bradley, C.; Hockings, P.; Schneider, M.; Newsome, P.; Hubscher, S.; Wenn, D.; Rosenquist, C.; Trylesinski, A.; Mayo, R.; Alonso, C.; Duffin, K.; Perfield, J.W.; Chen, Y.; Yunis, C.; Harrington, M.A.; Miller, M.; Chen, Y.; Mcleod, E.J.; Ross, T.; Bernardo, B.; Scholch, C.; Ertle, J.; Younes, R.; Oldenburger, A.; Coxson, H.; Ostroff, R.; Alexander, L.; Biegel, H.; Kjaer, M.S.; Harder, L.M.; Davidsen, P.; Ellegaard, J.; Balp, M.-.; Brass, C.; Jennings, L.; Loffler, J.; Applegate, D.; Shankar, S.; Torstenson, R.; Linden, D.; Llorca, A.; Kalutkiewicz, M.; Pepin, K.; Ehman, R.; Horan, G.; Ho, G.; Tai, D.; Chng, E.; Patterson, S.D.; Billin, A.; Doward, L.; Twiss, J.; Thakker, P.; Derdak, Z.; Landgren, H.; Lackner, C.; Gouw, A.; Hytiroglou, P.

doi:10.1016/S2468-1253(23)00141-3

Background: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. Methods: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <–1·455 vs –1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. Findings: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. Interpretation: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. Funding: Innovative Medicines Initiative 2 (*The LITMUS investigators)

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis / F.E. Mozes, J.A. Lee, Y. Vali, O. Alzoubi, K. Staufer, M. Trauner, R. Paternostro, R.E. Stauber, A.G. Holleboom, A.-. van Dijk, A.L. Mak, J. Boursier, M. de Saint Loup, T. Shima, E. Bugianesi, S. Gaia, A. Armandi, Shalimar, M. Lupsor-Platon, V.W.-. Wong, G. Li, G.L.-. Wong, J. Cobbold, T. Karlas, J. Wiegand, G. Sebastiani, E. Tsochatzis, A. Liguori, M. Yoneda, A. Nakajima, H. Hagstrom, C. Akbari, M. Hirooka, W.-. Chan, S. Mahadeva, R. Rajaram, M.-. Zheng, J. George, M. Eslam, S. Petta, G. Pennisi, M. Vigano, S. Ridolfo, G.P. Aithal, N. Palaniyappan, D.H. Lee, M. Ekstedt, P. Nasr, C. Cassinotto, V. de Ledinghen, A. Berzigotti, Y.P. Mendoza, M. Noureddin, E. Truong, C. Fournier-Poizat, A. Geier, M. Martic, T. Tuthill, Q.M. Anstee, S.A. Harrison, P.M. Bossuyt, M. Pavlides, A.K. Daly, O. Govaere, S. Cockell, D. Tiniakos, P. Bedossa, A. Burt, F. Oakley, H.J. Cordell, C.P. Day, K. Wonders, P. Missier, M. Mcteer, L. Vale, Y. Oluboyede, M. Breckons, H. Zafarmand, J. Lee, M. Nieuwdorp, J. Verheij, V. Ratziu, K. Clement, R. Patino-Navarrete, R. Pais, V. Paradis, D. Schuppan, J.M. Schattenberg, R. Surabattula, S. Myneni, B.K. Straub, T. Vidal-Puig, M. Vacca, S. Rodrigues-Cuenca, M. Allison, I. Kamzolas, E. Petsalaki, M. Campbell, C.J. Lelliott, S. Davies, M. Oresic, T. Hyotylainen, A. Mcglinchey, J.M. Mato, O. Millet, J.-. Dufour, M. Masoodi, S. Harrison, S. Neubauer, F. Mozes, S. Akhtar, S. Olodo-Atitebi, R. Banerjee, M. Kelly, E. Shumbayawonda, A. Dennis, A. Andersson, I. Wigley, M. Romero-Gomez, E. Gomez-Gonzalez, J. Ampuero, J. Castell, R. Gallego-Duran, I. Fernandez, R. Montero-Vallejo, M. Karsdal, D.G.K. Rasmussen, D.J. Leeming, A. Sinisi, K. Musa, E. Sandt, M. Tonini, C. Rosso, F. Marra, A. Gastaldelli, G. Svegliati, S. Francque, L. Vonghia, A. Driessen, S. Kechagias, H. Yki-Jarvinen, K. Porthan, J. Arola, S. van Mil, G. Papatheodoridis, H. Cortez-Pinto, C.M.P. Rodrigues, L. Valenti, S. Pelusi, L. Miele, C. Trautwein, J. Reissing, S. Francis, C. Bradley, P. Hockings, M. Schneider, P. Newsome, S. Hubscher, D. Wenn, C. Rosenquist, A. Trylesinski, R. Mayo, C. Alonso, K. Duffin, J.W. Perfield, Y. Chen, C. Yunis, M.A. Harrington, M. Miller, Y. Chen, E.J. Mcleod, T. Ross, B. Bernardo, C. Scholch, J. Ertle, R. Younes, A. Oldenburger, H. Coxson, R. Ostroff, L. Alexander, H. Biegel, M.S. Kjaer, L.M. Harder, P. Davidsen, J. Ellegaard, M.-. Balp, C. Brass, L. Jennings, J. Loffler, D. Applegate, S. Shankar, R. Torstenson, D. Linden, A. Llorca, M. Kalutkiewicz, K. Pepin, R. Ehman, G. Horan, G. Ho, D. Tai, E. Chng, S.D. Patterson, A. Billin, L. Doward, J. Twiss, P. Thakker, Z. Derdak, H. Landgren, C. Lackner, A. Gouw, P. Hytiroglou. - In: THE LANCET. GASTROENTEROLOGY & HEPATOLOGY. - ISSN 2468-1253. - 8:8(2023 Aug), pp. 704-713. [10.1016/S2468-1253(23)00141-3]

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

Mozes F. E.;Lee J. A.;Vali Y.;Alzoubi O.;Staufer K.;Trauner M.;Paternostro R.;Stauber R. E.;Holleboom A. G.;van Dijk A. -M.;Mak A. L.;Boursier J.;de Saint Loup M.;Shima T.;Bugianesi E.;Gaia S.;Armandi A.;Shalimar;Lupsor-Platon M.;Wong V. W. -S.;Li G.;Wong G. L. -H.;Cobbold J.;Karlas T.;Wiegand J.;Sebastiani G.;Tsochatzis E.;Liguori A.;Yoneda M.;Nakajima A.;Hagstrom H.;Akbari C.;Hirooka M.;Chan W. -K.;Mahadeva S.;Rajaram R.;Zheng M. -H.;George J.;Eslam M.;Petta S.;Pennisi G.;Vigano M.;Ridolfo S.;Aithal G. P.;Palaniyappan N.;Lee D. H.;Ekstedt M.;Nasr P.;Cassinotto C.;de Ledinghen V.;Berzigotti A.;Mendoza Y. P.;Noureddin M.;Truong E.;Fournier-Poizat C.;Geier A.;Martic M.;Tuthill T.;Anstee Q. M.;Harrison S. A.;Bossuyt P. M.;Pavlides M.;Daly A. K.;Govaere O.;Cockell S.;Tiniakos D.;Bedossa P.;Burt A.;Oakley F.;Cordell H. J.;Day C. P.;Wonders K.;Missier P.;McTeer M.;Vale L.;Oluboyede Y.;Breckons M.;Zafarmand H.;Lee J.;Nieuwdorp M.;Verheij J.;Ratziu V.;Clement K.;Patino-Navarrete R.;Pais R.;Paradis V.;Schuppan D.;Schattenberg J. M.;Surabattula R.;Myneni S.;Straub B. K.;Vidal-Puig T.;Vacca M.;Rodrigues-Cuenca S.;Allison M.;Kamzolas I.;Petsalaki E.;Campbell M.;Lelliott C. J.;Davies S.;Oresic M.;Hyotylainen T.;McGlinchey A.;Mato J. M.;Millet O.;Dufour J. -F.;Masoodi M.;Harrison S.;Neubauer S.;Mozes F.;Akhtar S.;Olodo-Atitebi S.;Banerjee R.;Kelly M.;Shumbayawonda E.;Dennis A.;Andersson A.;Wigley I.;Romero-Gomez M.;Gomez-Gonzalez E.;Ampuero J.;Castell J.;Gallego-Duran R.;Fernandez I.;Montero-Vallejo R.;Karsdal M.;Rasmussen D. G. K.;Leeming D. J.;Sinisi A.;Musa K.;Sandt E.;Tonini M.;Rosso C.;Marra F.;Gastaldelli A.;Svegliati G.;Francque S.;Vonghia L.;Driessen A.;Kechagias S.;Yki-Jarvinen H.;Porthan K.;Arola J.;van Mil S.;Papatheodoridis G.;Cortez-Pinto H.;Rodrigues C. M. P.;L. Valenti;S. Pelusi;Miele L.;Trautwein C.;Reissing J.;Francis S.;Bradley C.;Hockings P.;Schneider M.;Newsome P.;Hubscher S.;Wenn D.;Rosenquist C.;Trylesinski A.;Mayo R.;Alonso C.;Duffin K.;Perfield J. W.;Chen Y.;Yunis C.;Harrington M. A.;Miller M.;Chen Y.;McLeod E. J.;Ross T.;Bernardo B.;Scholch C.;Ertle J.;Younes R.;Oldenburger A.;Coxson H.;Ostroff R.;Alexander L.;Biegel H.;Kjaer M. S.;Harder L. M.;Davidsen P.;Ellegaard J.;Balp M. -M.;Brass C.;Jennings L.;Loffler J.;Applegate D.;Shankar S.;Torstenson R.;Linden D.;Llorca A.;Kalutkiewicz M.;Pepin K.;Ehman R.;Horan G.;Ho G.;Tai D.;Chng E.;Patterson S. D.;Billin A.;Doward L.;Twiss J.;Thakker P.;Derdak Z.;Landgren H.;Lackner C.;Gouw A.;Hytiroglou P.

2023

Abstract

Background: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. Methods: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <–1·455 vs –1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. Findings: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. Interpretation: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. Funding: Innovative Medicines Initiative 2 (*The LITMUS investigators)

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				Settore MED/09 - Medicina Interna
			
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				ago-2023
			
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				THE LANCET. GASTROENTEROLOGY & HEPATOLOGY
			
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				https://dx.doi.org/10.1016/S2468-1253(23)00141-3
			
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