Naoto Fujiwara1, Eric Trépo2, Indu Raman3, Quan-Zhen Li3, Delphine Degré2, Thierry Gustot2, Christophe Moreno2, Yujin Hoshida4. 1. Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, Dallas, Texas; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 2. Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology, Cliniques universitaires de Bruxelles Hôpital Erasme, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. 3. Microarray Core Facility, Department of Immunology, BioCenter, University of Texas Southwestern Medical Center, Dallas, Texas. 4. Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, Dallas, Texas. Electronic address: Yujin.Hoshida@UTSouthwestern.edu.
Abstract
BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability. METHODS: All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients. RESULTS: The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P < .001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve, >0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices. CONCLUSIONS: The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.
BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability. METHODS: All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients. RESULTS: The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P < .001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve, >0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices. CONCLUSIONS: The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.
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Authors: Tongqi Qian; Naoto Fujiwara; Bhuvaneswari Koneru; Atsushi Ono; Naoto Kubota; Arun K Jajoriya; Matthew G Tung; Emilie Crouchet; Won-Min Song; Cesia Ammi Marquez; Gayatri Panda; Ayaka Hoshida; Indu Raman; Quan-Zhen Li; Cheryl Lewis; Adam Yopp; Nicole E Rich; Amit G Singal; Shigeki Nakagawa; Nicolas Goossens; Takaaki Higashi; Anna P Koh; C Billie Bian; Hiroki Hoshida; Parissa Tabrizian; Ganesh Gunasekaran; Sander Florman; Myron E Schwarz; Spiros P Hiotis; Takashi Nakahara; Hiroshi Aikata; Eisuke Murakami; Toru Beppu; Hideo Baba; Sangeeta Bhatia; Masahiro Kobayashi; Hiromitsu Kumada; Austin J Fobar; Neehar D Parikh; Jorge A Marrero; Steve Hategekimana Rwema; Venugopalan Nair; Manishkumar Patel; Seunghee Kim-Schulze; Kathleen Corey; Jacqueline G O'Leary; Goran B Klintmalm; David L Thomas; Mohammed Dibas; Gerardo Rodriguez; Bin Zhang; Scott L Friedman; Thomas F Baumert; Bryan C Fuchs; Kazuaki Chayama; Shijia Zhu; Raymond T Chung; Yujin Hoshida Journal: Gastroenterology Date: 2021-12-22 Impact factor: 33.883