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Combination of Gene Expression Signature and Model for End-Stage Liver Disease Score Predicts Survival of Patients With Severe Alcoholic Hepatitis.

ABSTRACT: BACKGROUND & AIMS:Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables. METHODS:We obtained fixed liver biopsy samples from 71 consecutive patients diagnosed with severe AH and treated with corticosteroids from July 2006 through December 2013 in Brussels, Belgium (derivation cohort). Gene expression patterns were analyzed by microarrays and clinical data were collected for 180 days. We identified gene expression signatures and clinical data that are associated with survival without liver transplantation at 90 and 180 days after initiation of corticosteroid therapy. Findings were validated using liver biopsies from 48 consecutive patients with severe AH treated with corticosteroids, collected from March 2010 through February 2015 at hospitals in Belgium and Switzerland (validation cohort 1) and in liver biopsies from 20 patients (9 received corticosteroid treatment), collected from January 2012 through May 2015 in the United States (validation cohort 2). RESULTS:We integrated data on expression patterns of 123 genes and the model for end-stage liver disease (MELD) scores to assign patients to groups with poor survival (29% survived 90 days and 26% survived 180 days) and good survival (76% survived 90 days and 65% survived 180 days) (P < .001) in the derivation cohort. We named this assignment system the gene signature-MELD (gs-MELD) score. In validation cohort 1, the gs-MELD score discriminated patients with poor survival (43% survived 90 days) from those with good survival (96% survived 90 days) (P < .001). The gs-MELD score also discriminated between patients with a poor survival at 180 days (34% survived) and a good survival at 180 days (84% survived) (P < .001). The time-dependent area under the receiver operator characteristic curve for the score was 0.86 (95% confidence interval 0.73-0.99) for survival at 90 days, and 0.83 (95% confidence interval 0.71-0.96) for survival at 180 days. This score outperformed other clinical models to predict survival of patients with severe AH in validation cohort 1. In validation cohort 2, the gs-MELD discriminated patients with a poor survival at 90 days (12% survived) from those with a good survival at 90 days (100%) (P < .001). CONCLUSIONS:We integrated data on baseline liver gene expression pattern and the MELD score to create the gs-MELD scoring system, which identifies patients with severe AH, treated or not with corticosteroids, most and least likely to survive for 90 and 180 days.

SUBMITTER: Trepo E

PROVIDER: S-EPMC5847453 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Combination of Gene Expression Signature and Model for End-Stage Liver Disease Score Predicts Survival of Patients With Severe Alcoholic Hepatitis.

Trépo Eric E Goossens Nicolas N Fujiwara Naoto N Song Won-Min WM Colaprico Antonio A Marot Astrid A Spahr Laurent L Demetter Pieter P Sempoux Christine C Im Gene Y GY Saldarriaga Joan J Gustot Thierry T Devière Jacques J Thung Swan N SN Minsart Charlotte C Sersté Thomas T Bontempi Gianluca G Abdelrahman Karim K Henrion Jean J Degré Delphine D Lucidi Valerio V Rubbia-Brandt Laura L Nair Venugopalan D VD Nair Venugopalan D VD Moreno Christophe C Deltenre Pierre P Hoshida Yujin Y Franchimont Denis D

Gastroenterology 20171120 4

<h4>Background & aims</h4>Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables.<h4>Methods</h4>We obtained fixed liver biopsy samples from 71 consecutive patien ...[more]

PMID: 29158192

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Project description:Background & aimsSevere 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.MethodsAll 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.ResultsThe 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.ConclusionsThe high-risk ps-MELD score was associated with short-term survival in patients with severe AH.

Project description:Importance: Severe alcoholic hepatitis (AH) is a highly lethal disease with a 3-month mortality up to 50%. Corticosteroids are the current standard of care although nearly 40% of the patients do not respond and accurate pre-treatment predictors of survival are lacking. Objective: To develop a prognostic score based on molecular and clinical variables before initiation of corticosteroids. Design, Setting, and Participants: Gene expression profiling of fixed liver biopsy obtained for diagnosis of severe AH assessed in 3 independent cohorts (1 prospective cohort for prognostic gene signature and integrative score derivation, and 2 retrospective cohorts for validation). Samples were obtained from 4 European and 1 US medical centers between July 2006 and February 2015. Exposures: Biopsy proven severe AH patients treated with corticosteroids. Main Outcome Measures: Identification of a gene signature combined with a validated clinical index to develop an integrative prognostic score of survival without death or liver transplantation in a derivation cohort (n=71). Prognostic performance of the score was validated in an independent multi-center validation cohort 1 (n=48). Finally, the score was implemented in an FDA-approved clinical diagnostic platform (NanoString) and tested in another independent validation cohort 2 (n=20). Results: A prognostic score, integrating a 123-gene signature and the model for end-stage liver disease (gs-MELD score), was defined in the derivation cohort, in which poor- and good-prognosis patients were discriminated with a cut-off value of 2.66 at 3 months (event-free survival rates of 32% vs. 76%, respectively, p<.001) and 6 months (26% vs. 65%, respectively, p<.001). In the validation cohort 1, the score similarly discriminated poor- and good-prognosis patients at 3 months (43%, [95% CI, 26%-70%] vs. 96% [95% CI, 89%-100%], respectively, p<.001, c-index of 0.83 [95% CI, 0.66-0.99]) and 6 months (34% [95% CI, 18%-61%] vs 84% [95% CI, 72%-100%], respectively, p<.001, c-index of 0.80 [95% CI, 0.66-0.94]), and outperformed other existing clinical indices. The NanoString-based gs-MELD score remained predictive of 3- (p=.03) and 6-month (p=.009) even-free survival in the validation cohort 2. Conclusion and Relevance: The gs-MELD score, incorporating clinically applicable gene signature test and the MELD score, enables pre-treatment survival prediction in severe AH patients.

Project description:AimTo verify the value of Gutuo Jiejiu decoction in improving the survival of patients with severe alcoholic hepatitis (SAH).MethodsWe performed a retrospective cohort study in consecutive patients diagnosed with SAH at the Teaching Hospital of Chengdu University of Traditional Chinese Medicine and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine. The traditional Chinese medicine formula Gutuo Jiejiu decoction was employed as an exposure factor. Patients from the Teaching Hospital of Chengdu University of Traditional Chinese Medicine who had been treated with Gutuo Jiejiu decoction + prednisone were assigned to an observation group, and patients from Shuguang Hospital, Shanghai University of Traditional Chinese Medicine who had been treated with prednisone alone were selected as a control group. A retrospective analysis was performed by comparing age, alcohol intake, and clinical parameters of liver injury before and after treatment. Additionally, the 3- and 12-mo survival rates and the occurrence of complications were analyzed.ResultsOne hundred and twenty-eight eligible patients were selected from 175 cases with SAH, of which 68 were assigned to the observation group and the other 60 to the control group. No significant difference was found in the patients' baseline characteristics (P > 0.05). However, significant improvements of 90-d survival rate [56/68 (82.4%) vs 27/60 (45.0%), P = 0.0000] and 365-d survival rate [48/68 (70.6%) vs 13/60 (21.7%), P = 00000] were observed in the observation group after treatment. After the first 3 mo of treatment, more improvements in the clinical parameters and scoring systems related to liver injury occurred in the observation group than in the control group (P < 0.05). After treatment for 12 mo, the differences in the clinical parameters and scoring systems related to liver injury between the two groups were more significant (P < 0.05). No significant differences in complications and adverse effects were found between the two groups.ConclusionGutuo Jiejiu decoction could improve the survival rates and clinical parameters of liver injury in patients with SAH, and may represent a new option for treating SAH.

Dataset Information

Combination of Gene Expression Signature and Model for End-Stage Liver Disease Score Predicts Survival of Patients With Severe Alcoholic Hepatitis.

Publications

Combination of Gene Expression Signature and Model for End-Stage Liver Disease Score Predicts Survival of Patients With Severe Alcoholic Hepatitis.

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