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1 Journal of Hepatology 42 (2005) Evaluation of the increase in model for end-stage liver disease (DMELD) score over time as a prognostic predictor in patients with advanced cirrhosis: risk factor analysis and comparison with initial MELD and Child Turcotte Pugh score Teh-Ia Huo 1,2, *, Jaw-Ching Wu 1,3, Han-Chieh Lin 1,2, Fa-Yauh Lee 1,2, Ming-Chih Hou 1,2, Pui-Ching Lee 2, Full-Young Chang 1,2, Shou-Dong Lee 1,2 1 National Yang-Ming University School of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC 2 Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC 3 Department of Medical Education and Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC See Editorial, pages Background/Aims: The model for end-stage liver disease (MELD) has been used to prioritize cirrhotic patients awaiting liver transplantation. The change in MELD score over time (DMELD) may have additional prognostic value. We investigated the ability of DMELD to predict the outcome of advanced cirrhosis and prospectively assessed the factors associated with increasing DMELD. Methods: Risk factors were determined in 58 prospectively followed-up patients. The predictive power of DMELD, initial MELD and Child Turcotte Pugh (CTP) score was compared by using c-statistic in 351 patients. Results: Ascites (PZ0.020) and hepatic encephalopathy (PZ0.023) were significantly associated with increasing MELD score at 3 months. The area under receiver operating characteristic (ROC) curve for DMELD/month was compared with for MELD (PZ0.130) and for CTP score (P!0.001) at 6 months; the area was 0.822, and 0.528, respectively (PZ0.018 and!0.001, respectively) at 12 months. DMELD/month O2.5 was the only significant prognostic predictor at 6 (odds ratio: 9.8, P!0.001) and 12 months (odds ratio: 16.3, P!0.001) in multivariate logistic analysis. Conclusions: Increasing MELD score is associated with the onset of ascites and encephalopathy. DMELD is superior to initial MELD and CTP scores to predict intermediate term outcome in patients with advanced cirrhosis. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Child Turcotte Pugh; International normalized ratio; Liver cirrhosis; Liver transplantation; MELD; DMELD 1. Introduction Received 20 July 2004; received in revised form 24 November 2004; accepted 15 January 2005; available online 31 March 2005 * Corresponding author. Address: Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC. Tel.: C x3352; fax: C /C address: tihuo@vghtpe.gov.tw (T.-I. Huo). Abbreviations: CTP, Child Turcotte Pugh; HCC, hepatocellular carcinoma; INR, international normalized ratio; MELD, model for end-stage liver disease; DMELD, change of MELD score over time; ROC curve, receiver operating characteristic curve. Patients with decompensated liver cirrhosis frequently have adverse clinical outcomes and limited survival. For these patients, liver transplantation is the only definite treatment modality to effectively prolong their lifespan. However, patients on the waiting list of transplantation far outnumber the potential cadaveric or living liver donors. As a result, the number of patients dying while on the waiting list is progressively increasing in recent years [1] /$30.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi: /j.jhep

2 T.-I. Huo et al. / Journal of Hepatology 42 (2005) The donor livers are allocated to the recipients according to the severity of underlying disease. The OPTN (Organ Procurement and Transplantation Network) in the United States suggested to use the Child Turcotte Pugh (CTP) score, ABO blood type and waiting time to define the priority of organ allocation based on the UNOS (United Network of Organ Sharing) criteria. However, recently published data from the US suggested that the performance of CTP score may not be superior to a new scoring system, MELD (Model for End-stage Liver Disease) [2 4], and the liver allocation system has changed from a status-based algorithm to one using a continuous MELD severity score to prioritize adult patients on the waiting list. The calculation of MELD score is based on 3 biochemical variables (serum bilirubin, creatinine and international normalized ratio (INR) of prothrombin time), which are readily available, more objective and reproducible than the conventional variables used in the CTP scoring system. The MELD scoring system has been shown to more accurately predict 3-month mortality than the CTP system for OPTN/UNOS status 2A and 2B patients in a multi-center survey in the US [4]. Its accuracy for outcome prediction in patients with decompensated cirrhosis has also been confirmed in the Europe [5,6]. In addition to the initial MELD score, the change in MELD score over time (DMELD) has been proposed as an additional predictive factor of adverse outcomes [7]. Patients who have rapidly worsening MELD may have a higher short- or mid-term mortality than patients with stable MELD. However, this proposal has not been established because the clinical scenario may widely vary among those with increasing DMELD [8]. In addition, the risk factors associated with worsening MELD score have not been evaluated. In this study, we have investigated the factors in connection with the increase of MELD in a prospective cohort of patients with moderately advanced cirrhosis. By inclusion of an additional retrospective cohort, we have compared the ability of DMELD with that of the initial MELD and CTP score in outcome prediction. 2. Patients and methods 2.1. Patients Patient population consisted of two parts in this study. To investigate the risk factors associated with DMELD, we have prospectively assessed the changes of MELD score in 58 patients during a one-year period from January 2003 to December The MELD scores were determined at both initial visit and 3-month later. All of them belonged to CTP class B (with a CTP score of 7, 8 or 9) to fulfill the minimal listing criteria for liver transplantation [9], and had an expected survival of at least 3 months upon evaluation. None of these patients had coexisting hepatocellular carcinoma (HCC) or human immunodeficiency virus (HIV) infection at enrollment. To determine the prognostic value of DMELD, we have included another retrospective cohort of patients with a discharge diagnosis of liver cirrhosis observed in a 4-year period from January 1999 to December 2002 in our institution. The following criteria were used in accordance with the prospective cohort for patient selection: (1) an initial CTP score of 7 or more, (2) no coexisting HCC or HIV infection, (3) serial determination of serum bilirubun, serum creatinine and INR for at least 2 times within an interval of no longer than 4 months, (4) known survival status and cause of death among the mortalities. Of the 1168 patients who were identified from a prospective patient database, 299 patients fulfilled the inclusion criteria. Among them, 6 patients who underwent liver transplantation during the follow-up period were excluded; the remaining 293 patients, in conjunction with the prospective patient cohort, were entered for analysis. The nature of this study was fully explained to the patients according to the standards of Declaration of Helsinki, and this study complies with current ethical guidelines. The underlying etiology of cirrhosis was attributed to hepatitis B virus infection if patients were seropositive for hepatitis B surface antigen (HBsAg, RIA kits, Abbott Laboratories, North Chicago, IL, USA) and attributed to hepatitis C virus (HCV) infection if patients were seropositive for antibody against HCV (anti-hcv) by a second-generation enzyme immunoassay (Abbott Laboratories, IL). The diagnosis of liver cirrhosis was based on the characteristic findings including physical stigmata of cirrhosis, decreased serum albumin and increased serum globulin levels, computed tomography or ultrasonography findings of nodular liver surface, coarsened echogenicity of liver parenchyma, enlarged spleen and/or ascites, and detection of esophageal varices by endoscopy. The severity of ascites was classified into 3 categories: mild (easily controlled with diuretics), moderate (partially responsive to diuretics) and refractory (diuretics resistant) ascites. The stage of encephalopathy was classified into 4 grades as reported [10] MELD and DMELD score The MELD equation used to calculate the severity score was as follows: 9.57!log e (creatinine mg/dl) C3.78!log e (bilirubin mg/dl) C11.2! log e (INR) C6.43 (constant for liver disease etiology) [4]. Minimal values are set to 1.0 for calculation purposes. The maximal serum creatinine level considered within the MELD score equation is 4.0 mg/dl. DMELD was defined as the difference between the initial and second MELD score (DMELDZsecond MELD score- initial MELD score). The rate of increase in DMELD was calculated by dividing DMELD by the interval in months between the determination of the initial and second MELD score Statistical methods Chi-squared test or Fisher s exact test (two-tailed) was used for categorical data, and Mann Whitney ranked sum test or Kruskal Wallis test was used when appropriate for continuous data. To determine the factors associated with DMELD, variables including age, sex, etiology of cirrhosis, serum biochemistries, the initial MELD and CTP score, portal hypertension-related complications such as ascites, recent (!4 weeks) history of hepatic encephalopathy, spontaneous bacterial peritonitis or esophageal varices bleeding, were analyzed. Factors that were significant in univariate analysis were entered into multivariate logistic regression analysis to determine the adjusted odds ratio (OR) and 95% confidence interval (CI). Pearson s or Spearman s correlation analysis was used to estimate the correlation between DMELD/month and initial MELD and CTP score. To assess the ability of MELD, DMELD and CTP score in predicting the risk of death, our analysis was performed by measuring the concordance (c-statistic) equivalent to the area under the receiver operating characteristic (ROC) curve [11]. Comparison of the area under ROC curves was done using the method of Hanley and McNeil [12]. The outcome was assessed as 6-month and 12-month mortality. The variables, including age, sex, etiology of cirrhosis, serum biochemistries, initial CTP and MELD score, and DMELD/month, were entered into multivariate logistic regression analysis or Cox proportional hazard model in survival analysis to determine the risk ratio. Since DMELD/month was not foreseeable at the starting point, it was treated as a time-dependent covariate and was analyzed along with other variables in the Cox model [13]. All statistical analyses were conducted using SPSS for Windows version 12 (SPSS Inc., Chicago, IL) and MedCalc for Windows version 4.2 (MedCalc Software, Mariakerke, Belgium). For all tests, a P value less than 0.05 was considered statistically significant.

3 828 T.-I. Huo et al. / Journal of Hepatology 42 (2005) Results 3.1. Factors associated with increasing DMELD score Of the 58 prospectively followed-up patients (mean age: 65G11 years; 46 male), the initial and second MELD scores 3 months later were 10.9G2.5 and 14.5G3.2, respectively (mean DMELD, 3.6G3.0). Nine (16%) patients had a negative direction of DMELD. None of these patients underwent liver transplantation during the follow-up period. Patients who had ascites (nz15) or hepatic encephalopathy (nz11) more frequently had increasing MELD scores (Table 1); the increase in MELD score between the initial and second MELD at 3 months was 4.9G3.4 vs. 3.1G2.7 (PZ0.020) for patients with and without ascites, and 5.2G 1.8 vs. 3.1G3.0 (PZ0.023) for patients with and without hepatic encephalopathy, respectively. The changes in MELD score were not statistically different among other clinical and biochemical parameters. With multivariate analysis, ascites (OR: 12.4, 95% CI: , PZ0.005) and hepatic encephalopathy (OR: 16.6, 95% CI: , Table 1 Risk factor analysis for the increase of MELD score at 3 months Variables No. of patients Increase of DMELD mean (SD) Age (years) O65/%65 35/ (3.0)/3.5 (2.9) Sex Male/female 46/ (3.1)/4.4 (2.4) Etiology of cirrhosis HBsAg (C)/HBsAg (K) 43/ (3.1)/3.4 (2.7) Serum albumin (g/dl) O3/%3 25/ (3.2)/4.0 (2.7) Serum bilirubin (mg/dl) O2/%2 17/ (2.4)/3.7 (3.2) Serum creatinine (mg/dl) O1.3/%1.3 21/ (3.5)/3.8 (2.8) INR of prothrombin time O1.1/%1.1 33/ (2.7)/3.8 (3.4) Ascites Yes/no 15/ (3.4)/3.1 (2.7) SBP Yes/no 6/ (2.9)/3.5 (2.9) Hepatic encephalopathy Yes/no 11/ (1.8)/3.1 (3.0) EV bleeding Yes/no 9/ (2.9)/3.3 (2.8) Initial MELD score O12/!12 21/ (2.7)/3.5 (3.0) Initial CTP score /8/9 24/21/ (3.2)/4.3 (2.6)/ 3.7 (3.0) Abbreviations: EV, esophageal varices; SBP, spontaneous bacterial peritonitis. P PZ0.003) were independent risk factors associated with the increase of DMELD O6 points at 3 months. Subgroup analysis showed the grade of ascites (mild in 6, moderate in 6 and refractory in 3 patients) and the stage of hepatic encephalopathy (stage I II in 7 and stage III IV in 4 patients) was not significantly associated with the increase of DMELD Comparison of DMELD with initial MELD and CTP score in predicting mortality A total of 351 Chinese patients were included in the analysis (Table 2). The median interval between the initial and second MELD measurement was 3 months (range, 1 4 months); 27, 20, 35 and 18% of patients were determined at an interval of 1-, 2-, 3- and 4-month, respectively. The cumulative 6- and 12-month mortality rate was 12% (42/ 351) and 21% (68/319), respectively. Of the patients who died at or before 6 months, 29, 16, 39 and 16% had their DMELD determined at an interval of 1-, 2-, 3-, and 4- month, respectively. For those who died at or before 12 months, 31, 19, 34 and 16% were determined at the corresponding interval, respectively. There were no significant differences between the interval of MELD determination and mortality (PO0.1). The mean DMELD per month was 1.5G1.3 (range, K1.9 to 6.7) among all patients; 12% of patients had a negative direction of DMELD. The relation between the change of DMELD/ month, initial MELD and CTP score and mortality were shown in Table 3. The cumulative mortality rate at 6-month and 12-month was 1.2 and 1.4%, respectively for patients with DMELD/month!0.5, and the rate increased up to 17.5 and 31.7%, respectively for patients with DMELD/month Table 2 Characteristics of patients undergoing comparison of DMELD, initial MELD and CTP score Number of patients (prospective/retrospective 351 (17/83) cohort, %) Age (years), mean (range) 67G11 (36 80) Male (%) 268 (76) Underlying liver disease (%) Hepatitis B 242 (69) Hepatitis C 46 (13) Hepatitis BCC 19 (5) Alcohol 21 (6) Cryptogenic 14 (4) Others 9 (3) Median initial/ second serum level Bilirubin (mg/dl) (range) 1.8 ( )/2.5 ( ) Creatinine (mg/dl) (range) 1.2 ( )/1.5 ( ) INR of prothrobmin time (range) 1.1 ( )/1.2 ( ) Initial MELD score Median (range) 11.8 ( ) DMELD/month Median (range) 2.0 (K1.9 to 6.7) Initial CTP score Median (range) 8 (7 12)

4 T.-I. Huo et al. / Journal of Hepatology 42 (2005) Table 3 Comparison of the 6-month and 12-month mortality among DMELD/ month, initial MELD and CTP scoring systems Parameters 6-month (nz351) 12-month (nz319) No. of patients Mortality (%) No. of patients Mortality (%) DMELD/month! O MELD score! O CTP score or R DMELD/month was estimated as the rate of change in MELD score per month. O2. None of the patients with a negative direction of DMELD died at 12 months. The correlation of DMELD/month with initial MELD and CTP score was shown in Fig. 1. There was a statistically significant yet weak association between DMELD/month and initial MELD score (rzk0.217, P!0.001). A similar relationship was also found to exist between DMELD/ month and initial CTP score (rz0.136, PZ0.01). Using the c-statistic and mortality taken as the end point, the area under the ROC curve for DMELD/month was (95% CI: ), compared with (95% CI: ) for the initial MELD score (PZ0.130), and (95% CI: ) for CTP score (P!0.001) at 6 months (Fig. 2(A)). At 12 months, the area under the ROC curve for DMELD/month was (95% CI: ), compared with (95% CI: ) for the initial MELD score (PZ0.018) and (95% CI: ) for CTP score (P!0.001) (Fig. 2(B)). The difference for area under the ROC curve between initial MELD and CTP score was significant at both 6 months (PZ0.004) and 12 months (P!0.001). By selecting the cut-off value that best predicted the outcome from the ROC curve, we compared the predictive risk of death at 6 and 12 months for DMELD/month, initial MELD and CTP score, respectively (Table 4). In univariate analysis, both DMELD/month O2.5 (P!0.001) and MELD O12.8 (PZ0.043) significantly predicted a high risk of death at 6 months, whereas CTPR9 and other parameters did not show significant predictive value. Multivariate analysis showed DMELD/month O2.5 (OR: 9.8, 95% CI: , P!0.001) was the only significant prognostic predictor. At 12 months, both DMELD/month O2.5 (P!0.001) and MELD O12.8 (PZ0.047) significantly predicted a high risk of death, whereas CTPR9 and others did not show significant predictive value. Fig. 1. Correlation of DMELD with initial MELD (panel A) and CTP score (panel B). Multivariate analysis showed DMELD/month O2.5 (OR: 16.3, 95% CI: , P!0.001) was the only significant prognostic predictor in this group. One hundred (28%) patients died during a follow-up period of 17G8 months. When MELD and DMELD/month were treated as continuous numerical variables in the multivariate Cox model with time-dependent covariate along with other parameters, both were independent prognostic predictors with a risk ratio of 1.18 and 1.88, respectively per unit increase of the score (Table 5), whereas other parameters were not significantly associated with mortality. There was no significant interaction between MELD and DMELD/month (PZ0.335).

5 830 T.-I. Huo et al. / Journal of Hepatology 42 (2005) Table 4 Comparison of DMELD/month, initial MELD and CTP score with the cut-off values that best predict the risk of mortality Cut-offs a Odds ratio 95% confidence interval 6-month mortality DMELD/month O !0.001 MELD O CTPR month mortality DMELD/month O !0.001 MELD O CTPR a The cut-offs with the best predictive accuracy were determined from the ROC curve. P Fig. 2. Comparison of the area under the receiver operating characteristic curve (AUC) among DMELD/month, initial MELD and CTP score in predicting 6-month (panel A) and 12-month (panel B) mortality. DMELD/month was significantly better than the CTP score to predict 6-month mortality (P!0.001), and was significantly better than the MELD (PZ0.018) and CTP score (P!0.001) to predict 12- month mortality. 4. Discussion The MELD scoring system has become the prevailing criteria for donor liver allocation [14,15]. It possesses the advantage of minimal variability and wide-range continuous scale to assess underlying disease severity compared to the traditional CTP scoring system [14]. In addition, MELD has been shown to correlate with residual liver function and predict mortality across a broad spectrum of liver disease [5,16]. More importantly, the utilization of MELD was demonstrated to have an equal or better ability than the CTP system for short or intermediate term outcome prediction [4 7,17 19]. Consistently our data indicate that the MELD system is better than the CTP system in predicting both 6- and 12-month mortality by using the ROC curve. The utilization of MELD system has been further extended, because the MELD score in combination with the staging (CLIP) system for HCC may enhance the prognostic power and more accurately predict the survival for HCC patients undergoing arterial chemoembolization [20]. DMELD measures the dynamic change of residual liver function over time. Although the increase of MELD is anticipated in patients with decompensated cirrhosis, the factors associated with the changes were unknown. Our study, which was performed in an area endemic for hepatitis B, was the first to prospectively address this question and found that the increase of DMELD at 3 months was substantially high (mean, 3.6 points). Risk factor analysis showed that patients with ascites had an increased risk of increasing DMELD. The formation of ascites in cirrhotic patients suggests the development of clinically relevant portal hypertension. Since advanced cirrhosis is characterized by peripheral vasodilatation associated with decreased renal perfusion due to the activation of vasoconstrictor systems [21 23], overt or aggressive diuresis without appropriate volume expansion may further compromise the renal function and lead to increasing MELD score. Moreover, the existence of ascites, as a nontumoral parameter, was implicated as a prognostic factor in HCC patients undergoing percutaneous ablation therapy [24,25]. Table 5 Prognostic predictors and their risk ratio by the Cox proportional hazard model with time-dependent covariate DMELD/ month Initial MELD Regression coefficient Standard error Relative risk a 95% Confidence interval ! !0.001 a The risk ratio was expressed as the risk of mortality per unit score increase of the variables. P

6 T.-I. Huo et al. / Journal of Hepatology 42 (2005) Hepatic encephalopathy, which represents a status of profound portosystemic shunting, was also a significant factor in connection with increasing MELD score in our series. The existence of hepatic encephalopathy possibly reflects ongoing deterioration of residual liver function that precedes the development of eventual hepatic failure. It has been shown a strong predictor of mortality in cirrhotic patients [26,27], and inclusion of this factor was suggested to add additional prognostic value to the MELD score [16]. In this study, we have examined the association between DMELD and initial MELD and CTP score and their prognostic significance. The regression coefficient obtained in the regression analysis was very low, suggesting DMELD had no apparent clinical relevance with MELD or CTP score. However, increasing DMELD had a high predictive accuracy and may be superior to initial MELD in assessing the outcome. Serial determination of MELD score provides updated information of disease severity that could alter the ranking status in patients awaiting transplantation. A negative direction of DMELD probably indicates correction of a reversible factor and is likely to predict a subsequent lower risk of mortality. Therefore, DMELD conveys important clinical information and should be considered as an additional predictive factor in addition to the determination of one-time MELD score, especially when patients initial MELD scores are low but are progressively increasing during the follow-up period. As shown in Table 3, a higher DMELD score was associated with a rapidly increasing mortality rate as compared to the MELD and CTP score. In multivariate analysis, DMELD per month O2.5 independently predicted a high mortality risk, with a risk ratio up to 9.8- and 16.3-fold at 6- and 12-month, respectively. Consistently this result was confirmed in the Cox model. We found that there was 88% and 18% increased risk of death per unit score increment for DMELD/month and MELD, respectively. Identification of these high-risk patients would allow organ allocation more accurate and benefit those who are in utmost need for transplantation, and this strategy may in turn contribute to the decrease of mortality rate on the waiting list. Given the advantages of DMELD as a prognostic factor in cirrhotic patients, there are a number of concerns for the application DMELD in outcome prediction. First, it does not necessarily exclude the predictive value of MELD score to assess the short term survival because patients who had an already high initial MELD or CTP score may have a very limited survival and did not undergo a second MELD determination. This may partly explain why the performance of initial CTP score was less satisfactory in this study. Secondly, The determination of DMELD is dependent on both frequency and interval of serial MELD estimation, and the optimal model to generate DMELD that can accurately predict the outcome may need further fine-tuning in the prospectively collected data set. Thirdly, de novo development of HCC in cirrhotic patients awaiting liver transplantation may occur [28 30], the reported incidence being up to 20% of the cases [31]. Indeed, the occurrence of HCC can be a significant confounding factor to impair the prognostic power of DMELD. Further studies are needed to define the optimal equivalent DMELD score for these patients. Lastly, since DMELD is a continuous variable, it is not known whether a certain DMELD score could be used as a cut-off to avoid unnecessary or futile transplantation. In conclusion, increasing MELD score is associated with the onset of ascites and encephalopathy. Determination of DMELD score over time is superior to single MELD or CTP score estimation in predicting the intermediate term outcome, and should be considered as an additional prognostic predictor for patients with advanced cirrhosis. The optimal model to generate DMELD may require further investigation for refinement. Acknowledgements This study was supported by a grant from the National Science Council (NSC B ), Executive Yuan, Taiwan. References [1] Annual Report of the US Scientific Registry for Organ Transplantation and the Organ Procurement and Transplantation Network. Transplant Data UNOS, Richmond, VA, and the Division of Transplantation, Bureau of Health Resources and Services Administration, US Department of Health and Human Services, Rockville, MD; [2] Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with endstage liver disease. 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