Occurrence of Cirrhosis-Related Complications is a Time-Dependent Prognostic Pre

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From Liver International
Occurrence of Cirrhosis-Related Complications is a Time-Dependent Prognostic Predictor Independent of Baseline Model for End-Stage Liver Disease Score
Posted 01/20/2006
Teh-la Huo; Han-Chieh Lin; Fa-Yauh Lee; Ming-Chih Hou; Pui-Ching Lee; Jaw-Ching Wu; Full-Young Chang; Shou-Dong Lee
Abstract and Introduction
Abstract

Background: The model for end-stage liver disease (MELD) is used to prioritize cirrhotic patients awaiting liver transplantation. Many cirrhosis-related complications are indications for transplantation but are not included in MELD. This study investigated the impact of these complications on survival and association with MELD.
Methods: The mortality risk of cirrhosis-related complications, including bleeding esophageal varices, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome and hepatic decompensation, was analyzed using a time-dependent Cox regression model in 227 cirrhotic patients.
Results: A total of 281 episodes of complications occurred in 142 (63%) patients. Patients who died had a significantly higher baseline MELD score compared with those who survived (14.5±4.5 vs 12.8±3.9, P=0.004). There was no significant difference in the MELD score between patients with and without the occurrence of complications (13.6±4.3 vs 12.9±4.0, P=0.093). Patients with a higher baseline MELD score tended to develop early complications (ρ=−0.598, P< 0.001). Using the Cox regression model, the risk ratio of mortality was 4.9 (95% confidence interval: 3.9–6.3, P< 0.0001) for each additional episode of complication.
Conclusions: The mortality risk increases as the number of complication episodes increases. While patients with repeated complications have a poor outcome, they do not necessarily have a higher baseline MELD score and could be down-staged in the MELD era.
Introduction

While liver transplantation is the only definite treatment modality for patients with decompensated liver cirrhosis, patients on the waiting list for transplantation far outnumber the potential liver donors. As a result, the number of patients dying while on the waiting list or removed as a result of becoming very ill is progressively increasing in the US, Europe and other countries that use the MELD score.[1] Donor livers are allocated to the recipients according to the severity of underlying disease, and the United Network of Organ Sharing (UNOS) has switched from the Child–Pugh-based algorithm to the model for end-stage liver disease (MELD) to prioritize adult patients on the waiting list for transplantation.[2, 3] The MELD scoring system has been shown to predict 3-month mortality more accurately than the Child–Pugh system in a multicenter study in the United States.[4] Its accuracy for outcome prediction in patients with decompensated cirrhosis has also been confirmed in Europe.[5, 6]

Patients with end-stage cirrhosis may frequently develop a variety of complications, including hepatic encephalopathy, bleeding esophageal varices (EV), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome and progressive decompensation. These are common cirrhosis-related adverse complications and have been considered as major indications for liver transplantation. Importantly, these complications may occur repeatedly and may eventually lead to mortality. Although patients with any of these complications are usually recommended for transplantation, many of them are not included in the MELD. In fact, these transplant recipient candidates could be potentially overlooked missed in the waiting list of organ allocation if they are prioritized solely based on the MELD score. In this study, we have determined the impact of cirrhosis-related complications on patient survival. As these complications may not be initially present at the time of diagnosis, they are treated as a time-dependent variable in the longitudinal survival analysis to determine its prognostic ability. We also investigated the correlation of baseline MELD in patients with and without complications to assess the feasibility of MELD as a prognostic predictor in these patients. We found that while the risk of mortality greatly increased in patients with repeated episodes of complications, they did not necessarily have a higher baseline MELD score, which is necessary to prioritize them on the transplantation waiting list.

Teh-la Huo,1,2 Han-Chieh Lin,1,2 Fa-Yauh Lee,1,2 Ming-Chih Hou,1,2 Pui-Ching Lee,2 Jaw-Ching Wu,1,3 Full-Young Chang,1,2 and Shou-Dong Lee,1,2

1National Yang-Ming University School of Medicine, Taipei, Taiwan, China, Departments of 2Medicine and 3Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan, China

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Patients and Methods
Patients

From March 2002 to November 2004, patients who had liver cirrhosis and visited our hospital were prospectively evaluated, and their medial profiles were retrospectively analyzed in this study. The following criteria were used to select patients:[1] an initial Child–Pugh score of 7 or more (equivalent to class B or C) to fulfill the minimal listing criteria for liver transplantation,[7, 2] no coexisting hepatocellular carcinoma or human immunodeficiency virus infection at presentation,[3] known initial MELD score and survival status with a minimal follow-up of 3 months. Two hundred and twenty seven patients fulfilled these criteria and were included. Among them, eight patients who underwent liver transplantation during the follow-up period were not excluded, and their survival was censored at the time of transplantation. This study complies with the standards of the Declaration of Helsinki and 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), and attributed to hepatitis C virus (HCV) infection if patients were seropositive for antibody against HCV by a second-generation enzyme immunoassay (Abbott Laboratories).

The diagnosis of liver cirrhosis was based on 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 detection of EV by endoscopy.
Definitions

The presence and treatment of EV bleeding have been reported in detail in our previous studies.[8, 9] EV bleeding was diagnosed by (1) clinical signs of hematemesis or coffee ground vomitus and (2) endoscopic signs of active bleeding or adherent clot on EV. The diagnosis and treatment of SBP are in line with the recommendations by the International Ascites Club.[10] SBP was suspected when the clinical signs of peritonitis and infection were present, and was diagnosed when (1) the ascites polymorphonuclear leukocyte (PMN) count was >250/mm3 with or without positive ascites bacterial culture or (2) when the ascites PMN count was <250/mm3 but with positive ascites bacterial culture.[10] The definition of porto-systemic encephalopathy (PSE) was according to the West Haven criteria.[11] The management of PSE included correction of underlying precipitating factors, administration of enema and oral lactulose and other supportive treatment as needed. Hepatorenal syndrome (HRS) was diagnosed according to the criteria proposed by the International Ascites Club.[12] Hepatic decompensation was defined as an increase of the Child–Pugh score of 2 points or more because of any causes, and was treated by reversal or correction of the predisposing factors.
MELD Score

The MELD equation used to calculate the severity score was as follows: 9.6 × loge (creatinine, mg/dl)+3.8 × loge (bilirubin, mg/dl)+11.2 × loge (INR)+6.4 (constant for liver disease etiology).[4] Minimal values were set to 1.0 for calculation purposes. The maximal serum creatinine level considered within the MELD score equation was 4.0 mg/dl. The measurement of the MELD score was performed at the time of transplantation referral, and when any cirrhosis-related complication occurred in the follow-up period. Patients with cirrhosis-related complications at initial presentation or later during follow-up were compared with patients without complications for their baseline MELD scores to determine the association.
Statistical Methods

The Mann–Whitney ranked sum test was used for continuous data. Spearman's correlation analysis was used to estimate the correlation between MELD score and categorical variables. The potential prognostic predictors, including age, sex, etiology of cirrhosis, serum biochemistries, Child–Pugh score, MELD score and the occurrence of complications (PSE, EV bleeding, SBP, HRS and hepatic decompensation), were analyzed in the survival analysis to determine the significance for outcome prediction. As the occurrence of complications may not be foreseeable in advance and most cases developed complications some time during the follow-up period, it was treated as a time-dependent variable in the Cox regression model using the following equation:[13, 14]
Equation 1.

The model states that at a given time t, the prognostic index (PI(t)) of a patient with the q variables z1(t)–zq(t) at that time is a function of these variables weighted by the corresponding regression coefficients b1–bq. The time interval for the occurrence of complication was recorded as the time lapsed from enrollment. For example, the time interval for patients who developed complications at 4 months of enrollment was coded as 4, and the time interval for patients who had complication at the initial presentation was coded as 0.

All statistical analyses were conducted using SPSS for Windows version 12 (SPSS Inc., Chicago, IL). For all tests, a P-value less than 0.05 was considered statistically significant.

Results
Patient Characteristics, Occurrence and Types of Cirrhosis-Related Complications

The details of patient characteristics are shown in Table 1. Of the 227 patients (mean age: 66±13 years; 74% male), the etiology of cirrhosis was chronic hepatitis B in 69% and hepatitis C in 18% of patients. The baseline MELD and Child–Turcotte–Pugh (CTP) score was 13.3±4.2 and 8.4±1.2, respectively. In all, 142 (63%) patients developed 281 episodes of cirrhosis-related complications during the follow-up period of 15±8 months.

The distribution of the types and cumulative number of cirrhosis-related complications are given inTable 2. Among the 142 patients who had complications, there were 49 (35%), 58 (41%), 25 (18%) and 10 (7%) patients who had one, two, three and four or more episodes of complications, respectively, during the follow-up period.
Association of MELD Score and Occurrence of Cirrhosis-Related Complications

Patients who died had a significantly higher baseline MELD score compared with those who survived (14.5±4.5 vs 12.8±3.9, P=0.004). However, there was no significant difference in the baseline MELD score between patients with and without the occurrence of complications (13.6±4.3 vs 12.9±4.0, P=0.093). The MELD scores at the time of each cumulative episode of complication are given in Table 2. There was a significant trend of increasing MELD score in patients with more episodes of complications (P<0.0001). Patients with a higher baseline MELD score tended to have cirrhosis-related complications that developed early during the follow-up period (ρ=−0.598, P< 0.001; Fig. 1), but a higher MELD score was not significantly associated with the number of episodes of complications (P=0.332, Fig. 2). Among patients who had complications, non-survivors had a significantly higher baseline MELD score compared with survivors for patients with either one episode only (15.7±4.4 vs 12.9±3.5, P=0.023) or two or more complications (14.4±4.5 vs 12.4±4.2, P=0.029) (Fig. 3).

     
Click to zoom   
Figure 1.  (click image to zoom) http://images.medscape.com/images/521/458/thumb-liv521458.fig1.gif

Correlation between baseline model for end-stage liver disease (MELD) score and time to the first episode of cirrhosis-related complications.

     
Click to zoom   
Figure 2.  (click image to zoom) http://images.medscape.com/images/521/458/thumb-liv521458.fig2.gif

Correlation between baseline model for end-stage liver disease (MELD) score and number of episodes of complications. Black dots indicate mortality cases.

     
Click to zoom   
Figure 3.  (click image to zoom) http://images.medscape.com/images/521/458/thumb-liv521458.fig3.gif

Comparison of the baseline model for end-stage liver disease (MELD) score between survivors and non-survivors in patients with and without occurrence of cirrhosis-related complications.

Risk of Cirrhosis-Related Complication as a Time-Dependent Prognostic Predictor

The occurrence of cirrhosis-related complication was treated as a time-dependent covariate, and the risk of mortality was estimated by using the Cox regression model. The risk ratio was 4.9 (95% confidence interval [CI]: 3.9–6.3, P<0.0001) for each additional episode of complication in the longitudinal survival analysis. Baseline CTP score ≥9 (relative risk [RR]: 2.0, 95% CI: 1.2–3.3, P=0.008) and MELD score>18 (RR: 2.7, 95% CI: 1.6–4.5, P=0.001) were also independent predictors associated with an increased risk of mortality. Otherwise, other parameters were not significant in terms of outcome prediction in the Cox model.
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Discussion

The MELD scoring system has become the prevailing criterion for donor liver allocation.[15–17] It is characterized by a wide-range continuous scale to assess underlying disease severity and has the advantage of minimal variability compared with the traditional Child–Pugh scoring system. In addition, MELD has been shown to correlate with residual liver function and predict mortality across a broad spectrum of chronic liver diseases.[18] More importantly, the utilization of MELD was demonstrated to have a better predictive ability than the Child–Pugh system for outcome prediction,[4–6, 19, 20] and was useful for cirrhotic patients undergoing major surgical procedures.[21] The MELD has been suggested to extend to patients with hepatocellular carcinoma (HCC) to further enhance the prognostic power for HCC patients undergoing loco-regional therapy.[22]

Abundant studies have shown that the development of hepatic encephalopathy, SBP, EV bleeding or hepatorenal syndrome indicates ongoing deterioration of residual liver function that precedes the development of eventual hepatic failure.[10–12, 23–26] Patients with the occurrence of any of these complications have long been considered candidates for liver transplantation. However, there has been no clear designation for the priority of organ allocation for these patients in the MELD era. Our study, which was performed in an area endemic for hepatitis B, suggests that patients with cirrhosis-related complications do not have a higher baseline MELD score, which is necessary to prioritize these patients on the waiting list. A recent study from the US, where HCV infection and alcoholism are common etiologies of cirrhosis, consistently showed that the existence of ascites and encephalopathy did not correlate with the MELD score.[27] In our study, we found that there was no significant association between MELD score and number of episodes of complications (Fig. 2). These results indicate a potential limitation of the currently used MELD system because patients at a high mortality risk may not be readily identified by solely calculating their baseline MELD score.[28]

Given that cirrhotic patients tend to have worsening liver functions during the longitudinal follow-up period, there has been no study to address the impact of cirrhosis-related complication as a time-dependent covariate on the survival. We have specifically assessed the risk of mortality among patients with cirrhosis-related complications using a time-dependent Cox regression model in this study. This model is useful in providing updated information for cirrhotic patients awaiting liver transplantation. Our results showed that the occurrence of complications was an independent prognostic predictor associated with a decreased survival; the risk ratio was 4.9-fold with each additional episode of complication. This finding highlights the crucial role that these complications might play for outcome prediction in cirrhotic patients on the transplant waiting list.

Although patients with the occurrence of complication did not have a significantly increased baseline MELD score, a higher MELD score per se was indeed an independent prognostic predictor. In addition, we found that non-survivors with either one or more complications had a higher baseline MELD score compared with the survivors. Moreover, patients with a higher baseline MELD score tended to have complications that developed early in their lifetime. While these data confirm the prognostic value and indicate an intrinsic characteristic of MELD, our findings convey an important message that the development of complication is strongly associated with a poor survival. We propose that the occurrence of cirrhosis-related complications, in addition to MELD, may serve as an important prognostic marker. This strategy may compensate for the potential defect of the MELD system and identify patients with utmost need for liver transplantation.

In addition to the use of cirrhosis-related complications that may occur in the timeline as a prognostic predictor, there have been studies to indicate that the change of MELD score over time (ΔMELD) may more accurately predict the survival compared with single-point MELD determination in cirrhotic patients awaiting liver transplantation.[28–30] Consistently, in this study, we found that there was a significant trend of increasing MELD score for patients at the time of cumulative episode of complication (P<0.0001; Table 2), suggesting a close association between repeated episodes of complication and increasing MELD scores. Nevertheless, the prognostic value of ΔMELD has not been fully confirmed in another study, and may require further investigations for confirmation.[31]

A major limitation of this study is that the impact of a specific type of cirrhosis-related complications on survival was unclear because the complications were analyzed as a whole series. However, it would be difficult to assess a specific complication separately and individually because different types of complications may well occur in the same patient. Alternatively, the same complication may also occur repeatedly in the same patient. Therefore, it may not be appropriate to consider only one complication and ignore others because certain complications (e.g. hepatic encephalopathy) may occur as a consequence of another complication (e.g. EV bleeding) that could act synergistically to affect the outcome.

In conclusion, our results suggest that the occurrence of cirrhosis-related complications is a time-dependent prognostic predictor. While these patients have a poor prognosis and early transplantation referral is recommended, they do not necessarily have a higher MELD score and could be potentially overlooked during the process of organ allocation in the MELD era. Early identification of these high-risk patients may contribute to the decrease of mortality rate on the waiting list.

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Figures for:
Occurrence of Cirrhosis-Related Complications is a Time-Dependent Prognostic Predictor Independent of Baseline Model for End-Stage Liver Disease Score

[Liver Int.  2006;26(1):55-61.  ©2006 Blackwell Publishing]

    Figure 1.Correlation between baseline model for end-stage liver disease (MELD) score and time to the first episode of cirrhosis-related complications.http://images.medscape.com/images/521/458/art-liv521458.fig1.gif

    Figure 2.Correlation between baseline model for end-stage liver disease (MELD) score and number of episodes of complications. Black dots indicate mortality cases.http://images.medscape.com/images/521/458/art-liv521458.fig2.gif

    Figure 3.Comparison of the baseline model for end-stage liver disease (MELD) score between survivors and non-survivors in patients with and without occurrence of cirrhosis-related complications.
http://images.medscape.com/images/521/458/art-liv521458.fig3.gif

 Tables for:
Occurrence of Cirrhosis-Related Complications is a Time-Dependent Prognostic Predictor Independent of Baseline Model for End-Stage Liver Disease Score

[Liver Int.  2006;26(1):55-61.  ©2006 Blackwell Publishing]

Table 1. Patient characteristics


    Total number of patients   227
    Age (years)   66±13
    Male (%)   168 (74)
    Etiology of cirrhosis
      HBsAg-positive (%)   157 (69)
      Anti-HCV-positive (%)   47 (18)
      Alcoholic (%)   15 (7)
      Cryptogenic (%)   8 (6)
    Baseline serum levels
      Bilirubin (mg/dl)   2.6±1.8
      Creatinine (mg/dl)   1.3±0.3
      INR of prothrombin time   1.2±0.2
    Baseline Child–Pugh score   8.4±1.2
    Baseline MELD score   13.3±4.2
    Follow-up period (months)   15±8
    Number of patients with occurrence of complications during follow-up   142
    Number of cumulative episodes of complications during follow-up   281

    HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; INR, international normalized ratio; MELD, model for end-stage liver disease.


Table 2. Distribution, type and MELD score in cumulative episodes of cirrhosis-related complications


        One episode   Two episodes   Three episodes   Four episodes   Five episodes   Total (%)
    No. of patients (%)   49 (35)   58 (41)   25 (18)   9 (6)   1 (1)   142 (100)
    Number of episodes (%)   49 (17)   116 (41)   75 (27)   36 (13)   5 (2)   281 (100)
    Increase of CTP score ≥ 2   10   59   36   11   2   118
    SBP   9   15   12   7   1   44
    EV bleeding   15   22   15   7   1   60
    Encephalopathy   15   16   8   9   1   49
    Hepatorenal syndrome   0   4   4   2   0   10
    MELD at the time of each cumulative complication (no. of patients)   14.3±3.6*(n=142)   15.6±3.7*(n=93)   17.6±2.6*(n=35)   21.2±3.0*(n=10)   22.2 (n=1)   

    *P< 0.0001 (one-way ANOVA test). CTP, Child–Turcotte–Pugh; SBP, spontaneous bacterial peritonitis; EV, esophageal varices; MELD, model for end-stage liver disease.

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Occurrence of Cirrhosis-Related Complications is a Time-Dependent Prognostic Predictor Independent of Baseline Model for End-Stage Liver Disease Score

[Liver Int.  2006;26(1):55-61.  ©2006 Blackwell Publishing]

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