Alcoholic hepatitis (AH), in its severe form, is associated

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1 LIVER FAILURE AND LIVER DISEASE Early Change in Bilirubin Levels Is an Important Prognostic Factor in Severe Alcoholic Hepatitis Treated With Prednisolone Philippe Mathurin, 1,2 Marcelle Abdelnour, 3,5 Marie-José Ramond, 4 Nicolas Carbonell, 5 Laetitia Fartoux, 5 Lawrence Serfaty, 5 Dominique Valla, 4 Raoul Poupon, 5 Jean-Claude Chaput, 3 and Sylvie Naveau 3 Early identification of patients with severe (discriminant function >32) biopsy-proven alcoholic hepatitis (AH) who are not responding to corticosteroids would be clinically relevant. Our goal was to develop simple criteria that will help physicians to promptly identify nonresponders to corticosteroids. A total of 238 patients were included. We used 6 months survival as an end point because of the rule requiring 6 months for listing alcoholic patients for transplantation. Overall survival at 1 and 6 months was 85% 2.3% and 64.3% 3.3%, respectively. An early change in bilirubin levels (ECBL) at 7 days (defined as bilirubin level at 7 days lower than bilirubin level on the first day of treatment) was observed in 73% of patients. At 7 days, in patients with ECBL, bilirubin decreased (84 75 mol/l [ mg/dl]), whereas it increased in patients without ECBL ( mol/l [ mg/dl], P <.0001). Ninety-five percent of patients with ECBL continued to have improved liver function during treatment. At 6 months, survival of patients with ECBL was significantly higher than that of patients without ECBL, 82.8% 3.3% versus 23% 5.8%, P < On multivariate analysis, ECBL, discriminant function and creatinine were independent prognostic variables, and ECBL had the most important prognostic value. In conclusion, ECBL is a very simple predictive factor for identifying nonresponders. A recommendation to discontinue corticosteroids after 7 days in patients without ECBL, suggested by our results, awaits additional confirmation. (HEPATOLOGY 2003;38: ) Alcoholic hepatitis (AH), in its severe form, is associated with a high risk of short-term mortality. Accurate identification of severe forms is now possible using the discriminant function of Maddrey (DF) 1,2 calculated as follows: 4.6 (prothrombin time control time [in seconds]) serum bilirubin (in micromoles per liter) 17. In the absence of treatment, patients with DF 32 survived in 65% and 50% of cases at 1 and 2 months. 1-4 Treatment of severe AH and identification of Abbreviations: AH, alcoholic hepatitis; DF, discriminant function of Maddrey; ECBL, early change in bilirubin levels; GGT, -glutamyl transpeptidase; PT, prothrombin time; ROC, area under the receiver-operating curve. From the Sce d Hépato-Gastroentérologie, 1 Hôpital Claude Hurriez, and 2 Inserm EPI 0114 Lille, and the Sces d Hépato-Gastroentérologie, 3 Hôpital Antoine Béclère, Clamart, 4 Hôpital Beaujon, Clichy, and 5 Hôpital Saint-Antoine, Paris, France. Received June 12, 2003; accepted September 16, Address reprint requests to: Philippe Mathurin, M.D., Service d Hépatogastroentérologie, Hôpital Claude Huriez 2 ème étage Est, Avenue Michel Polonovoski, CHRU Lille, 59037, France. p-mathurin@chru-lille.fr; fax: (33) Copyright 2003 by the American Association for the Study of Liver Diseases /03/ $30.00/0 doi: /j.hep efficacious therapies remains an important challenge for clinicians. To bring the controversy surrounding the efficacy of corticosteroids to an end, we recently combined the individual data of patients with DF 32 from the last 3 randomized placebo-controlled trials, as analysis of individual data seems to be more efficient than classical metaanalysis. We observed that corticosteroid patients had significantly higher survival at 28 days: 84.6% 3.4% versus 65.1% 4.8%. 3 This study supported the conclusions of the American College of Gastroenterology, which recommended glucocorticosteroids for patients with severe AH. 5 An important observation from our last study was the significant and early improvement in hepatic function of corticosteroid patients in comparison with placebo patients. Interestingly, this study suggested that patients with biological improvement had significantly better survival than patients without biological improvement at 28 days. However, we were not able to analyze survival data during a longer period of follow-up, because survival data from the Carithers study were available only at 28 days and the number of treated patients was not high enough

2 1364 MATHURIN ET AL. HEPATOLOGY, December 2003 Early identification of patients who will not benefit from corticosteroids, or so-called nonresponders to corticosteroids, would constitute an important advance in the management of severe AH. To our knowledge, no such criteria have been proposed in patients with severe AH treated with corticosteroids. The question of performing liver transplantation in patients with severe AH who are nonresponders to corticosteroids remains subject to debate. When confronted with the possibility of proposing liver transplantation to alcoholic patients in an emergency situation, physicians first need to determine which criteria can be used for listing patients after a short period of evaluation. 6 One approach may consist of the use of prognostic models that are designed to help in the prediction of patient survival. 7-9 However, the main limitation of such models is that none of them take into account the short-term influence of corticosteroids on management of severe AH. In this study of patients with severe AH treated with corticosteroids, we sought to determine simple criteria that will help physicians to promptly identify so-called nonresponders to corticosteroids. Patients and Methods Patients. In 3 French hospitals from July 1990 to July 2001 (Beaujon, Béclère, Saint-Antoine), we prospectively followed up patients with severe AH. The severity of AH was assessed by a DF value higher than 32. All patients with a DF value higher than 32 were treated with corticosteroids if they fulfilled the following criteria: (1) a history of longstanding alcoholism; (2) liver chemistry suggestive of AH; (3) the absence of uncontrolled infection or recent gastrointestinal hemorrhage ( 15 days); (4) transjugular liver biopsy, which was carried out for all patients; samples were fixed, paraffin-embedded, and conventionally stained. All patients had biopsy-proven alcoholic hepatitis characterized by hepatocellular necrosis and infiltration of polymorphonuclear leukocytes. We excluded from treatment patients with active peptic ulcer, neoplasm, nonalcoholic liver disease, active infection, or a positive test result for hepatitis B surface antigen and HIV antibodies. Patients were treated in the 3 centers using the same treatment protocol as in the French randomized controlled trial. 4 Prednisolone was given in a single dose of 40 mg each morning for 28 days. Patients unable to take oral medication received intravenous infusions of methylprednisolone (32 mg of methylprednisolone equivalent to 40 mg of prednisolone). Statistical Analysis. The following variables were assessed at admission: center, age, sex, alcohol intake, tobacco consumption, presence of encephalopathy, ascites, survival data, serum bilirubin level, prothrombin time, serum albumin level, serum aspartate aminotransferase, serum -glutamyl transpeptidase (GGT), serum creatinine, white blood cell count, polymorphonuclear count, and DF. During the treatment period, we analyzed, at 7, 14, 21, and 28 days, the evolution of biological features of liver function (bilirubin and prothrombin time). The schedule of collection of biological samples was identical to the protocol of the study by Ramond et al. 4 Collection of data was performed retrospectively in the 3 centers. Comparison of qualitative and quantitative variables was performed using 2 and Fisher exact tests and t test. Patient survival was estimated by the Kaplan-Meier method and compared by the log-rank test. All P values were two-tailed. Survivals were expressed in percentage SE. Survival was assessed by the intention-to-treat method. Clinical and biological baseline variables were included in univariate analysis. The cutoff level chosen for quantitative variables was the median value. We hypothesized that bilirubin improvement at 7 days (defined as bilirubin level at 7 days lower than bilirubin level on the first day of treatment) might be used to identify which patients would respond to treatment. In this study, bilirubin improvement at 7 days was called early change in bilirubin levels (ECBL). We sought to confirm whether ECBL was a valid criteria for promptly detecting patients with a high risk of short-term mortality. First, we analyzed whether bilirubin evolution was a better indicator of survival status than the other 2 indicators of evolution of liver function at 7 days: the evolutions of prothrombin time (PT) (difference between PT at day 0 and PT at day 7) and of DF (difference between DF at day 0 and DF at day 7). To compare those 3 indicators of evolution of liver function, we used logistic regression. 10 The accuracy of prediction of death for these 3 indicators was compared using the area under the receiver-operating curve (ROC), and the classification table that estimated the percent of patients correctly classified. We used 6 months survival as the endpoint as most centers in Europe and North America have adopted a rule requiring 6-month abstinence before patients are accepted for listing for liver transplantation. 6,11,12 To identify independent predictors, baseline variables that reached a univariate P value of.1 in the log-rank test were included in multivariate analysis. Proportional-hazards models were used to identify factors independently associated with survival. The significance of each factor was expressed by the regression coefficient and tested by the likelihood-ratio test. The validity of the Béclère model was tested in patients according to ECBL. 8,9 For each patient a risk score (R) was calculated using the following equation: R

3 HEPATOLOGY, Vol. 38, No. 6, 2003 MATHURIN ET AL (age in years) (encephalopathy) Log e (bilirubin in mol/l) (albumin in g/l). Survival function for the Béclère model was at 6 months S exp.(r 3.058). Differences between observed and simulated survival were calculated with their 95% CI according to the method of Machin and Gardner. 8,13 Results Table 1. Clinical and Biochemical Features Number of patients 238 Male: n (%) 115 (48.3%) Age (y): median (range) 49.6 ( ) Maddrey function: median (range) 45.5 ( ) Bilirubin ( mol/l): median (range) 214 (32-672) Prothrombin time (seconds): median (range) 19.5 ( ) Albumin (g/l): median (range) 27.8 (12-49) Child-Pugh score: median (range) 10 (7-13) Serum creatinine ( mol/l): median (range) 70 (4-596) AST (IU/L): median (range) 93 (15-394) GGT (IU/L): median (range) 140 (7-1,115) White blood cells (no./mm 3 ): median (range) 10,820 (2,200-64,000) Polymorphonuclear count (no./mm 3 ): median (range) 8,540 (900-43,000) Daily alcohol intake (g/d): median (range) 120 (40-400) Presence of ascites: n (%) 152 (75.6%)* Encephalopathy: n (%) 62 (26%) *The data presence of ascites were not available for 37 patients. Clinical, Biochemical, and Histologic Characteristics of Patients With DF > 32. From July 1990 to February 2001, 267 patients with biopsy-proven AH were treated with corticosteroids. We retrospectively recalculated the DF function and identified 28 patients (13 male and 15 female) with a DF 32 (23 without encephalopathy and 5 with encephalopathy); DF could not be calculated in 1 patient. These 29 patients were excluded from this study. A total of 238 patients were included in the analysis. The characteristics of these 238 patients with DF 32 or encephalopathy are given in Table 1. The median duration of hospitalization before the initiation of therapy was 6 days (95% CI: 5-7 days). Overall survival of 238 treated patients with DF 32 was 85% 2.3% at 1 month, 76.7% 2.8% at 2 months, 64.3% 3.3% at 6 months (Fig. 1), 57.6% 3.5% at 1 year, and 51.4% 3.7% at 2 years. These survival curves are very similar to those observed in previous studies that evaluated patients with severe AH treated with corticosteroids. Survival was similar in the 3 institutions (Saint-Antoine, Béclère, and Beaujon): 88.3% 5.5% versus 86.7% 3.6% versus 82.5% 3.7% at 1 month, and 59.8% 9.8% versus 64.2% 5.4% versus 64.4% 4.6% at 6 months (NS). Evolution of Biological Features From Time of Admission Until Initiation of Corticosteroids. From admission until the initiation of corticosteroids, bilirubin ( mol/l) and PT ( 0, seconds) increased slightly, although aspartate aminotransferase and GGT decreased: IU/L and IU/L, respectively. There were no significant differences in survival between patients with a spontaneous increase in bilirubin from admission until treatment and patients with a spontaneous decrease in bilirubin from admission until treatment: 83.6% 3.9% versus 89.8% 3.7% at 1 month, and 59.7% 5.4% versus 73.4% 5.5% at 6 months. ECBL. After 7 days of treatment, the evolution of hepatic function was available in 209 patients and was missing in 29 patients. Using Child-Pugh criteria, the area under the curve was 0.64 and the percent of patients correctly classified was 63.3%. For evolution of prothrombin time after 7 days of treatment, the area under the ROC curve was 0.62 and the percent of patients correctly classified was 58.1%. For evolution of Maddrey function after 7 days of treatment, the area under the ROC curve was 0.73 and the percent of patients correctly classified was 67.3%. For evolution of bilirubin after 7 days of treatment, the area under the ROC curve was 0.82 and the percent of patients correctly classified was 78%. Improvement in Maddrey function was related to bilirubin improvement in 86% of patients. An ECBL was observed in 153 patients (73.2%). The proportions of patients with ECBL were similar in the 3 centers (Saint-Antoine, Béclère, and Beaujon): 70.6% versus 73.1% versus 74%. The proportion of patients with ECBL was not significantly different between patients with a spontaneous increase in bilirubin from admission until treatment and patients with a spontaneous decrease in bilirubin from admission until treatment: Fig. 1. Survival at 6 months of 238 patients with a DF 32 who were prospectively treated with corticosteroids.

4 1366 MATHURIN ET AL. HEPATOLOGY, December 2003 Fig. 2. Survival curves at 6 months in treated patients according to ECBL. 75.3% versus 76.6%. At day 0 before treatment, there were no significant differences between patients with ECBL and patients without ECBL in terms of sex ratio (46% vs. 50% of male patients), daily alcohol intake ( g vs g), bilirubin ( mol/l vs mol/l), albumin ( g/l vs g/l), GGT ( vs ), aspartate aminotransferase ( UI/L vs UI/L, P.04), or leukocyte count (12, /mn 3 vs. 13,006 1,208/mn 3 ). Conversely, patients with ECBL were younger ( years vs years, P.03) and had lower levels of PT ( seconds vs seconds, P.002) and creatinine ( vs , P.02). During the 6-month follow-up, 26 patients were lost to follow-up and recurrence of alcoholism occurred in 28% of cases without significant differences between patients with ECBL and patients without ECBL: 30.3% versus 21.6%. At 7 days, in patients with ECBL, bilirubin decreased ( mol/l), whereas bilirubin increased in patients without ECBL ( mol/l, P.0001). After 28 days of corticosteroid treatment, 93% of patients with an ECBL continued to show improved liver function during the 28 days of treatment. Indeed, at 28 days, hepatic function was better in patients with ECBL than in patients without ECBL: bilirubin ( mol/l vs mol/l, P.001), PT ( seconds vs seconds, P.0001), and Maddrey function (30 2 vs , P.0001). Survival of patients with ECBL was significantly higher than that of patients without ECBL at 28 days, 6 months (Fig. 2), 12 months, and 24 months: 96% 1.6% versus 58.8% 6.6% (P.0001), 82.8% 3.3% versus 23% 5.8% (P.0001), 75% 3.9% versus 18% 5.6% (P.0001), and 66.5% 4.5% versus 14.4% 5.5% (P.0001). Causes of deaths after 6 months of follow-up were not significantly different between patients with ECBL and patients without ECBL, and are listed in Table 2. Univariate Prognostic Analysis of Patients With DF > 32. In univariate analysis we analyzed the prognostic value of clinical and biological variables in survival at 6 months. In univariate analysis, 12 variables reached a P value.1 as prognostic factors (Table 3): the presence of ascites (P.01), sex (P.05), age (P.02), encephalopathy (P.0002), ECBL (P.00001), Maddrey function (P.0002), serum bilirubin (P.007), prothrombin time (P.08), Child-Pugh score (P.02), serum creatinine (P.001), serum albumin (P.05), and serum gamma glutamyl transpeptidase (P.05). Multivariate Prognostic Analysis of Patients With DF > 32. Because the Maddrey function combined bilirubin and prothrombin time, only this function was included in multivariate analysis. The Pugh score was not included in multivariate analysis because it used the same variables as the Maddrey function. After inclusion of candidate variables in a proportional-hazards model that reached a univariate P value of.1 by the log-rank test, age (P.0002), creatinine (P.02), Maddrey function (P.0001), and ECBL (P ) were independent prognostic factors at 6 months (Table 4). Insignificant variables were excluded so that the final model included only significant variables (Table 5). In this final model, age, creatinine, Maddrey function, and ECBL were still independent prognostic variables (Table 4). This final model, which included only significant variables, explained 35% (R 2 ) of survival variability at 6 months (P.00001). Béclère Model and ECBL. The observed 6-month survival of patients according to ECBL was markedly different from that expected using the Béclère model. For patients with ECBL, observed survival (82.8%, 95% CI: 76.8%-89.4%) was significantly higher than simulated survival (57.1%, 95% CI: 49%-65.1%, P ). Table 2. Causes of Death During the 6-Month Follow-Up Period Patients with ECBL (n 153) Patients Without ECBL (n 56) Total number of deaths Hepatocellular insufficiency: n (%) 7 (30.4%) 12 (28.6%) Digestive bleeding: n (%) 4 (17.4%) 11 (26.2%) Sepsis: n (%) 9 (39.1%) 14 (33.3%) Hepatocellular carcinoma: n (%) 0 (0%) 1 (2.4%) Alcohol-related: n (%) 0 1 (2.4%) Related to liver disease 1 (4.3%) 2 (5%) Causes not related to liver: n (%) 2 (8.7%) 1 (1.2%)

5 HEPATOLOGY, Vol. 38, No. 6, 2003 MATHURIN ET AL Table 3. Prognostic Significance at 6 Months According to the Log-Rank Test in Baseline Variables Included in Univariate Analysis Conversely, for patients without ECBL, observed survival (23%, 95% CI: 13.3%-36.5%) was significantly lower than simulated survival (45.8%, 95% CI: 31.5%-60%, P.03). Discussion No. of Patients 6-Month Survival SE P-Value of Log-Rank Test Male % Female % P.05 Age 49.4 y % Age 49.4 y % P.02 Patients with ECBL % P Patients without ECBL % Maddrey function % P.0002 Maddrey function % Bilirubin 213 mol/l % P.007 Bilirubin 213 mol/l % Prothrombin time 19.5 sec % P.08 Prothrombin time 19.5 sec % Serum albumin 27.9 g/l % Serum albumin 27.9 g/l % P.05 Child-Pugh score % Child-Pugh score % P.02 Serum creatinine 70 mol/l % Serum creatinine 70 mol/l % P.001 GGT 140 IU/L % GGT 140 IU/L % P.05 AST 93 IU/L % AST 93 IU/L % P.7 Daily alcohol intake 120 g/d % P.15 Daily alcohol intake 120 g/d % White blood cells 11,600/mn % P.8 White blood cells 11,600 cells/mm % Absence of ascites % Presence of ascites % P.01 Absence of encephalopathy % P.0002 Presence of encephalopathy % NOTE. The cutoff level chosen for quantitative variables was the median value. In patients with DF 32 treated with corticosteroids, we observed that (1) at baseline, age, Maddrey discriminant function, and creatinine were independent prognostic factors; (2) after the initiation of corticosteroid therapy, 75% of patients had an ECBL; (3) ECBL was an important predictive factor for survival; and (4) only 25% of patients without an ECBL, the so-called nonresponders to corticosteroids, were still alive at 6 months. Our analysis showed that bilirubin evolution at 7 days is clinically very useful in promptly predicting those patients who will die during the 6-month period. We showed that bilirubin evolution had a higher predictive value than the other 2 indicators of evolution of liver function (PT and Maddrey). To determine a simple criteria that will help physicians in current practice, we defined ECBL as a qualitative indicator of bilirubin evolution instead of using bilirubin evolution as a quantitative variable. However, this post-hoc analysis can only be used to generate hypotheses concerning the duration of corticosteroid therapy and liver transplantation. The benefit of corticosteroids has been debated worldwide because analysis of randomized controlled trials gave controversial results, 1,2,4,14-22 mainly because of wide heterogeneity in the severity of liver disease. 3,23-25 This study, like the most recently published studies in a highly selected group with DF 32, confirmed that corticosteroid therapy was associated with 85% survival at 28 days. 1,3,4,26,27 To make progress in the management of patients with severe AH, at least 3 approaches might be useful: (1) the evaluation of new therapies such as anti tumor necrosis factor- antibodies or pentoxifylline as proposed by some investigators 26,28 ; (2) early identification of patients who will not benefit from corticosteroids; and (3) earlier selection of candidates with severe AH who might be listed for liver transplantation. 6 In this study, we focused on early identification of patients resistant to corticosteroids with a higher risk of death to target a novel strategy of treatment. In these patients, liver transplantation constitutes one of the possible therapeutic options. Recently, several studies questioned the potential role of liver transplantation in patients with AH. Unfortunately, none of those studies Table 4. Prognostic Factors Associated With Death at 6 Months According to Proportional-Hazards Analysis Prognostic Factor Regression Coefficient Standard Error Significance (P Value) Odds Ratio (95% CI) Sex ( ) Age ( ) Early change in bilirubin levels ( ) Maddrey function ( ) Serum creatinine ( ) Serum albumin ( ) Serum gamma glutamyl transpeptidase ( ) Presence of ascite ( ) Presence of encephalopathy ( )

6 1368 MATHURIN ET AL. HEPATOLOGY, December 2003 Table 5. Final Model Including Only Significant Variables at 6 Months According to Proportional-Hazards Analysis Prognostic Factor Regression Coefficient Standard Error Significance (P Value) Odds Ratio (95% CI) Age ( ) Early change in bilirubin levels ( ) Maddrey function ( ) Serum creatinine ( ) selected patients with DF 32 nor took into consideration the survival effect of corticosteroids. 6,29-31 Therefore, in this highly selected subgroup of treated patients, no criteria had been evaluated to identify patients who might be considered for alternative therapies. In this study, we observed that patients with ECBL were younger than nonresponders, suggesting that an inflammatory background might interfere with the response to steroids. Progress in understanding the network of intercellular and intracellular signals among Kupffer cells, monocytes, and neutrophils could provide new insights into our understanding of the corticosteroid effect in severe AH Experimental and clinical findings to date suggest that proinflammatory cytokines, such as tumor necrosis factor and interleukin 8, constitute the main effector molecules in alcohol-induced liver injury. 33,36-38 We and others showed that, during corticosteroid therapy, polymorphonuclear neutrophil activation, intracellular adhesion molecule 1 expression, and proinflammatory cytokines were reduced. 39,40 Further studies are required to determine whether the pattern of cytokines and the inflammatory profile are associated with the response to treatment. Moreover, future studies evaluating new drugs will need to take into account the biological effect in addition to survival outcome. Studies have been carried out to evaluate the efficacy of liver transplantation in alcoholic cirrhosis to distinguish patients who will benefit most from the procedure. 8,9 Based on appropriate methodology, some investigators have recommended the use of prognostic models to predict survival of patients with alcoholic cirrhosis. However, not all models used in alcoholic cirrhosis can be applied to the specific setting of patients with severe AH, for several reasons. Such models were not developed in the specific subgroup with severe AH. As an example, the Model for End-Stage Liver Disease score was created to estimate survival of patients undergoing transjugular intrahepatic portosystemic shunt. 7 In this study we observed that the Béclère model was not able to predict 6-month survival of patients according to ECBL. Indeed, this prognostic model did not integrate the short-term influence of corticosteroids on management of severe AH. In conclusion, this study observed that ECBL is a simple and powerful criterion for helping to identify patients who are responders to corticosteroids. In current practice, and in light of this study, we suggest that corticosteroid therapy be interrupted in nonresponders after 7 days of treatment. However, the recommendation to discontinue corticosteroids after 7 days in patients without ECBL awaits future confirmation from additional studies. References 1. Carithers RL Jr, Herlong HF, Diehl AM, Shaw EW, Combes B, Fallon HJ, Maddrey WC. Methylprednisolone therapy in patients with severe alcoholic hepatitis: a randomized multicenter trial. Ann Intern Med 1989;110: Maddrey WC, Boitnott JK, Bedine MS, Weber FL, Mezey E, White RI. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978;75: Mathurin P, Mendenhall C, Carithers RL Jr, Ramond MJ, Maddrey WC, Garstide P, Rueff B, et al. 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