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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 13  |  Issue : 3  |  Page : 210-215

Incidence and risk factors for mortality in patients with cirrhosis awaiting liver transplantation


Department of Gastroenterology and Hepatology, Gleneagles Global Health City, Chennai, Tamil Nadu, India

Date of Submission16-Jul-2019
Date of Decision28-Aug-2019
Date of Acceptance03-Sep-2019
Date of Web Publication17-Sep-2019

Correspondence Address:
Dr. Mayank Jain
Department of Gastroenterology and Hepatology, Gleneagles Global Hospital, Chennai, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_27_19

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  Abstract 


Aim: This study aimed to determine the mortality in Indian patients awaiting liver transplantation and to assess the impact of cirrhosis-related complications (CRCs) on mortality. Materials and Methods: This was a prospective study on patients of Indian origin, aged >18 years, with cirrhosis liver (confirmed by imaging and/or liver biopsy), and registered for liver transplant (LTx) between November 2015 and May 2016. Patients were followed up for at least a year. Any admission or day-care procedure for complications after registration was recorded as an event, and outcome was noted as recovered, deterioration, or death. The primary end point of the study was LTx, survival, or death. Patients undergoing transplantation were grouped with survivors for analysis of factors predicting waitlist mortality. Statistics: t-test, Chi-square test, Mann–Whitney U-test, and univariate and logistic regression analyses were used for statistical analysis. P < 0.05 was considered statistically significant. Results: A total of 227 (72.3%) registered patients survived. Waitlist mortality at 1 year was 27.7%, and the waitlist mortality rate was 33.8 deaths/100 patient-years. A significant proportion of nonsurvivors belonged to the Child–Turcotte–Pugh C score (P = 0.031), with higher Model for End Stage Liver Disease (P = 0.002) and greater frequency of CRC (P < 0.001). Hepatic encephalopathy (HE), renal dysfunction (RD), infection, and variceal bleeding were significantly associated with death. A higher proportion of nonsurvivors had combination of more than two CRCs. Conclusion: The waitlist mortality was 27.7%. Complications such as variceal bleed, spontaneous bacterial peritonitis, HE, and RD were significantly high in nonsurvivors.

Keywords: Cirrhosis, liver transplantation, mortality


How to cite this article:
Jain M, Varghese J, Kedarishetty CK, Srinivasan V, Venkataraman J. Incidence and risk factors for mortality in patients with cirrhosis awaiting liver transplantation. Indian J Transplant 2019;13:210-5

How to cite this URL:
Jain M, Varghese J, Kedarishetty CK, Srinivasan V, Venkataraman J. Incidence and risk factors for mortality in patients with cirrhosis awaiting liver transplantation. Indian J Transplant [serial online] 2019 [cited 2019 Oct 19];13:210-5. Available from: http://www.ijtonline.in/text.asp?2019/13/3/210/266945




  Introduction Top


Patients with liver cirrhosis progress over a period of time to end-stage liver disease (ESLD), liver failure, multiorgan failure, and death.[1],[2],[3] This progression is attributed to recurrent cirrhosis-related complications (CRCs) including bacterial infection. The only definitive modality for treating these patients is liver transplantation (LT). In the United States of America, approximately 5%–10% of patients listed for LT die without receiving an organ.[4]

The present prospective study was intended to determine the mortality rate in cirrhotic patients followed up for a year and to assess the impact of CRCs on mortality.


  Materials and Methods Top


Patients of Indian origin, aged >18 years, with a diagnosis of cirrhosis liver (confirmed by radiological imaging and/or liver biopsy), and registered in the liver clinic between November 2015 and May 2016 were included in the study. Patient information including date of registration; age; gender; comorbidity; Child–Turcotte–Pugh (CTP) score; baseline and end-of-study Model for ESLD (MELD) score; and complications such as variceal bleed, hepatic encephalopathy (HE), refractory ascites, spontaneous bacterial infection (spontaneous bacterial peritonitis [SBP]), and renal dysfunction (RD) was recorded.

The patients were subsequently followed up to May 2017. Any admission or a day-care procedure after registration for complications such as variceal bleed, SBP, renal insufficiency, HE, and fever was recorded as an event, and outcome was recorded as recovered, deterioration, or death. The patients were managed as per the standard of care for CRCs, both during inpatient stay and day care.

The primary end point of the study was liver transplant (LTx), survival, or death within a year of registration. For analysis of risk factors predicting mortality, patients undergoing transplantation were grouped with survivors and terminally ill patients were clubbed with nonsurvivors.

Standard definitions used in the study

  1. Ascites was either overt or detected during ultrasound screening. Diagnostic paracentesis was performed in all patients during each of the admission with an intention to detect SBP
  2. SBP was defined by ascitic fluid's polymorphonuclear cell count >250 cells/mm and/or ascitic fluid culture positivity
  3. RD included hepatorenal syndrome (HRS)–acute kidney injury (AKI)[5],[6]
  4. Refractory ascites was diagnosed as per the International Ascites Club criteria[6]
  5. Variceal bleed was graded as per the Baveno guidelines[7],[8]
  6. HE was defined as an episode of neurological and neuropsychiatric abnormality revertible after an effective ammonia-lowering treatment and graded according to the West Haven grading[9]
  7. Sepsis was considered when skin, urine, sputum, bronchial secretions, or blood culture was positive. When culture was negative, fever, leukocytosis, and/or raised procalcitonin were considered as surrogate markers for septicemia.


Exclusion criteria

Exclusion criteria were patients with extrahepatic portal vein obstruction, those with noncirrhotic portal fibrosis, those with acute liver failure, noncirrhotics with hepatocellular carcinoma, defaulters to treatment, those lost to follow-up, or those with incomplete data. Overseas patients were excluded as they were direct referrals for LTx workup. Others excluded were patients who were lost to follow-up after initial registration or were not reachable through telephonic calls.

The consort chart of the study is shown in [Figure 1].
Figure 1: Consort flow diagram

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Statistical analysis

Mortality was considered as the primary outcome variable. Waitlist mortality was calculated for those listed for LTx. It was defined as the number of deaths on the waiting list divided by the sum of the number of patients on the waiting list at the start of the period and the number of patients activated over the period, expressed as a percentage.

For comparative analysis, the cohort was divided into the following two groups: survivors and nonsurvivors.

Descriptive analysis was done using mean and standard deviation for quantitative variables and frequency and percentages for categorical variables. The ordinal variables were compared by median and interquartile range. Independent sample t-test, Chi-square test, and Mann–Whitney U-test were used to test the statistical significance of the differences between the two groups. For analyses of risk factors that were associated with mortality, univariate logistic regression analysis was followed by multivariate forward step-wise logistic regression analysis for variables that were statistically significant in univariate analysis. P < 0.05 was considered statistically significant.

The ethics committee of the institution approved the study.


  Results Top


Baseline characteristics

There were 227 survivors and 87 nonsurvivors. The two groups were similar in terms of age and gender. The mean age was just above 50 years, and men outnumbered women by approximately six times in both the groups. The etiology and comorbidity between the two groups were comparable [Table 1].
Table 1: Comparison of baseline parameters between survivors and nonsurvivors

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Among 75 (23.9%) patients, 45 received living donor LTx and 30 received diseased donor LT.

Mortality during waiting period

At the end of 1-year follow-up, there were 227 (72.3%) survivors. The mortality rate at 1 year was 27.7%, and the waitlist LTx mortality rate was 33.8 deaths/100 patient-years.

Comparison of survivors and nonsurvivors

Compared to survivors, significant proportion of nonsurvivors belonged to CTP C score (P = 0.031), with higher median MELD at first admission (16 vs. 20, P < 0.001) and at last follow-up (18 vs. 26, P < 0.0001) and more frequent CRCs (4 vs. 1; P < 0.001). Sixty-seven (29.5%) survivors and 6 (6.9%) nonsurvivors had no CRC; the remaining had at least one CRC [Table 1].

Comparative morbidity

A total of 684 CRCs were noted during the follow-up period. There were 401 episodes of CRC in survivors (1.76 episodes/patient) and 283 episodes among nonsurvivors (3.25 episodes/patient). The difference in the average number of CRC encountered was significantly higher in nonsurvivors (ANOVA P < 0.01). Overall, HE, RD, infection, and variceal bleeding were the CRCs significantly associated with death [Figure 2], [Figure 3], [Figure 4], [Figure 5]. Moreover, significantly higher proportion of nonsurvivors had a combination of two or more CRCs during follow-up [Table 2].
Figure 2: Kaplan–Meier curve for survival analysis in the presence and absence of cirrhosis-related complications. Cum survival stands for cumulative survival

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Figure 3: Kaplan–Meier curve for survival analysis in variceal bleed. Cum survival stands for cumulative survival

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Figure 4: Kaplan–Meier curve for survival analysis in spontaneous bacterial peritonitis

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Figure 5: Kaplan–Meier curve for survival analysis in hepatic encephalopathy

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Table 2: Comparison of cirrhosis-related complications between survivors and nonsurvivors

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Cirrhosis-related complications during successive admissions

In the first admission, variceal bleed (17.2% vs. 4%), SBP (11.5% vs. 4.4%), HE (34.5% vs. 15.4%), and RD (29.9% vs. 11.9%) were statistically significant in nonsurvivors (P = 0.05). In subsequent admissions, the number of complications was comparable in the two groups but with a proportional reduction in individuals (death, transplanted) [Figure 6]. RD (P < 0.001) in the second and third admissions, P = 0.001, was statistically significant among nonsurvivors.
Figure 6: Frequency of complication at different admissions

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On univariate logistic regression analysis [Table 3]a, variceal bleed, SBP, HE, and RD in the first admission; variceal bleed and RD in the second admission; and sepsis and RD in the third admission were associated with significant mortality. On multivariate logistic regression analysis [Table 3]b, variceal bleed (odds ratio [OR]: 5.6 and 8, 2.23–14.42, P < 0.001) and RD at the first admission (OR: 2.9, 1.46–5.74, P = 0.002) and RD in the second admission (OR: 3.74, 1.5–9.3, P = 0.004) had the strongest association to mortality.


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Model for End Stage Liver Disease dynamics

There was a wide range of interval between successive admissions, ranging from 2 days to 11 months with significant change in the MELD with each admission that was largely influenced by the CRCs during each admission. Comparing baseline MELD and at last follow-up, MELD was significantly high among nonsurvivors [Table 1].


  Discussion Top


Liver disease burden in India is enormous with 22.2 deaths/100,000 population attributed to cirrhosis by the Global Health Observatory data from the World Health Organization.[10]

According to the present study, the 1-year mortality rate in patients with cirrhosis of liver was 27.7%. It was higher in patients with advanced liver disease as evidenced by higher MELD score and higher frequency of CRC at registration. Those with RD had poor rates of survival. Those with variceal bleed during the first admission had worse survival. Beyond the fourth admission, nearly all CRCs were associated with worse outcomes. These observations indicate that patients with more advanced liver disease and RD at the time of registration need to be prioritized for diseased donor LT or even an early living donor transplant.

CRC correlated with the severity of liver disease and the degree of portal hypertension. The recurrence of CRC has a significant impact on the morbidity and mortality in ESLD patients.[11],[12] In our study, nonsurvivors compared to survivors had major complications such as refractory ascites (25.3%), HE (7.2%), RD (6.4%), SBP (3%), and variceal bleed (2.64%) at the time of registration and at follow-up (Mann–Whitney P < 0.05 and P < 0.0001, respectively). This is similar to the observations by Huo et al. who reported that patients who died had higher baseline MELD levels than survivors and their mortality risk increased as the frequency of complication episodes increased.[13] RD in our series was 17.3% (39 patients) in survivors and 50% (44 patients) in nonsurvivors (P < 0.001), and this in our study, we strongly believe, is the significant “hit” in predicting mortality.

RD is an important prognostic factor in ESLD. Hypovolemia and infection are the most frequent causes of renal failure in these patients. Mortality is higher in patients with HRS and infection.[14] The incidence of mortality, infections, and CRC is higher with worsening severity of AKI. Progression is significantly more common in nonsurvivors than survivors.[15] A combination of HE and RD is associated with worse prognosis and on most occasions, they are the terminal events occurring secondary to other complications such as variceal bleed, SBP, ascites, and bacterial infection.[16]

Summarizing, the waitlist mortality at the end of 1 year in those listed for LTx was 27.7%, and the waitlist mortality rate was 33.8 deaths/100 patient-years. The nonsurvivors had higher frequency of CRCs and often in combinations. For the future, prioritizing the patients for LT should be based on the presence and type of CRCs with better management strategies for RD.

Acknowledgment

We thank Dr. Sukanya Lakshmi, Junior Registrar for data collection, and Mr. Tom Michael, Junior Research Fellow, for computing the data.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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2.
Arvaniti V, D'Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010;139:1246-56, 1256.e1-5.  Back to cited text no. 2
    
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Foreman MG, Mannino DM, Moss M. Cirrhosis as a risk factor for sepsis and death: Analysis of the national hospital discharge survey. Chest 2003;124:1016-20.  Back to cited text no. 3
    
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Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310-8.  Back to cited text no. 6
    
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de Franchis R, Baveno VI Faculty. Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743-52.  Back to cited text no. 7
    
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Garcia-Tsao G, Bosch J, Groszmann RJ. Portal hypertension and variceal bleeding – Unresolved issues. Summary of an American association for the study of liver diseases and European association for the study of the liver single-topic conference. Hepatology 2008;47:1764-72.  Back to cited text no. 8
    
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Butterworth RF. Complications of cirrhosis III. Hepatic encephalopathy. J Hepatol 2000;32:171-80.  Back to cited text no. 9
    
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World Health Organization. Global Health Observatory Data Repository. Available from: http://apps.who.int/gho/data/view.main.GHECTRYASDRGHE123v?lang5en. [Last accessed on 2015 Dec 21].  Back to cited text no. 10
    
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Ferreira LG, Anastácio LR, Lima AS, Touslon Davisson Correia MI. Predictors of mortality in patients on the waiting list for liver transplantation. Nutr Hosp 2013;28:914-9.  Back to cited text no. 11
    
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D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. J Hepatol 2006;44:217-31.  Back to cited text no. 12
    
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Huo TI, Lin HC, Lee FY, Hou MC, Lee PC, Wu JC, et al. Occurrence of cirrhosis-related complications is a time-dependent prognostic predictor independent of baseline model for end-stage liver disease score. Liver Int 2006;26:55-61.  Back to cited text no. 13
    
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Qureshi MO, Shafqat F, Dar FS, Salih M, Khokhar N. Renal failure in patients with end stage liver disease and its impact on clinical outcome. J Coll Physicians Surg Pak 2014;24:628-31.  Back to cited text no. 14
    
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Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, et al. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013;57:753-62.  Back to cited text no. 15
    
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Mandayam S, Jamal MM, Morgan TR. Epidemiology of alcoholic liver disease. Semin Liver Dis 2004;24:217-32.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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