- Email: [email protected]
Model for End-Stage Liver Disease (MELD) Score Does Not Predict Outcomes of Hepatitis B–Induced Acute-on-Chronic Liver Failure in Transplant Recipients
Model for End-Stage Liver Disease (MELD) Score Does Not Predict Outcomes of Hepatitis BeInduced Acute-on-Chronic Liver Failure in Transplant Recipients B.-W. Duana, S.-C. Lub,*, J.-S. Wua, Q.-L. Guoa, D.-B. Zenga, T. Jianga, D.-G. Konga, and J. Dinga a
Department of Hepatobiliary Surgery and You-An Liver Transplant Center, Beijing You-An Hospital, Capital Medical University, Beijing, People’s Republic of China; and bInstitute and Hospital of Hepatobiliary Surgery, Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLA, Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, People’s Republic of China
ABSTRACT Background. Acute-on-chronic liver failure (ACLF) is a severe clinical entity and liver transplantation is the only definitive therapy to salvage these patients. However, the timing of liver transplant for these patients remains unclear. Methods. Seventy-eight patients undergoing liver transplantation because of hepatitis B ACLF were retrospectively analyzed from June 2004 to December 2010. The areas under the receiver operating characteristic curve (AUC) of Model for End-Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (CTP) score for the post-transplantation outcomes were calculated. Results. The median age was 44 years (range, 25e64 years), serum bilirubin 418.53 mmol/L (range, 112.90e971.40 mmol/L), INR 3.177 (range, 1.470e9.850), and creatinine 70.84 mmol/L (range, 12.39e844.1 mmol/L); the median MELD score was 32 (range, 21e53) and CTP score 12 (8e15). The AUCs of MELD and CTP scores for 3-month mortality were 0.581 (95% confidence interval [CI], 0.421e0.742; sensitivity, 87.5%; specificity, 32.8%) and 0.547 (95% CI, 0.401e0.693; sensitivity, 75%; specificity, 41%), respectively. Meanwhile, there were no significant differences in hospital mortality (P ¼ .252) or morbidity (P ¼ .338) between the patients with MELD score 30 and those <30. Conclusions. MELD score had no predictive ability for the outcomes of patients with hepatitis B ACLF after orthotopic liver transplantation.
A
CUTE-ON-CHRONIC LIVER FAILURE (ACLF) is a severe clinical syndrome with the definition of acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease [1]. This serious condition with varied etiologies and manifestations has a mortality of 50%e90% when the patients develop multiple organ failure [2e6]. ACLF has been considered to be a good indication for orthotopic liver transplantation (LT) [7] and is the best procedure to save patients suffering from ACLF [8]. The outcome following LT for patients with ACLF has been satisfactory [9e14], and the overall 1-, 3-, and 5-year survival rates were similar to those for acute liver failure [15]. However, it is critical to quickly and accurately identify those patients most likely to benefit from LT, because of the
higher short-term mortality of ACLF and graft shortage. The Model for End-Stage Liver Disease (MELD) score was originally developed and validated to evaluate the shortterm outcomes of patients with cirrhosis undergoing a transjugular intrahepatic portosystemic shunt procedure [16] and has been used extensively to allocate donor livers worldwide [17]. MELD score is also an objective and efficient system for predicting survival in chronic hepatitis B (CHB) patients with ACLF [18,19]. Moreover, some reports
Funding: Capital Health Research and Development of Special (grant 2011-2018-03) and Education Committee of Beijing Science and Technology Development Plan (grant KM201110025026). *Address correspondence to Shi-Chun Lu, MD, PhD, 28 Fuxing Road, Beijing. E-mail: [email protected]
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.07.075
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3502
Transplantation Proceedings, 46, 3502e3506 (2014)
MELD SCORE DOES NOT PREDICT OUTCOMES
suggested that MELD score could accurately predict the 3-month survival of patients with ACLF undergoing LT [14,20]. In China, ACLF is the most common type of liver failure [21], and the most common reason is CHB [22,23]. The prognosis of ACLF in CHB is extremely poor, with 3-month mortality rates without LT reported to be >50% [18,19]. In the present study, we retrospectively summarized LT for hepatitis B ACLF and evaluated whether the MELD score can predict postoperative morbidity and mortality. PATIENTS AND METHODS From June 2004 to December 2010, 427 patients underwent LT in Beijing You-An Hospital, Capital Medical University. All of the liver explants were examined histologically. Inclusion criteria included pathology reports of “chronic severe hepatitis” or “submassive hepatocyte necrosis” combined with preexisting chronic liver disease and age 18 years. Medical records were used to ascertain that their clinical presentations fulfilled the ACLF definition [1]. Exclusion criteria were pathologic diagnosis with “fulminant hepatic failure” or “acute liver failure” and age <18 years. The serum total bilirubin, creatinine, and international normalized ratio (INR) were acquired immediately before LT. Before the study, the protocol was approved by the Institutional Review Board of Beijing You-An Hospital according to the principles expressed in the 1975 Declaration of Helsinki, and written informed consent was obtained from each of the study patients. All organ donations were approved by the Institutional Review Board of Beijing You-An Hospital under the guidelines of the Ethics Committee of the hospital and the current regulations of the Chinese Government. All statistical analysis was undertaken with the use of SPSS version 18.0 for Windows (SPSS, Chicago, Illinois). The discriminative power of MELD score and Child-Turcotte-Pugh (CTP) score were evaluated for 3-month mortality and early morbidity following transplantation with the use of the area under the receiver operating characteristic (ROC) curve (AUC). Survival was calculated with the use of the Kaplan-Meier method. A P value of <.05 was considered to be statistically significant.
RESULTS
Seventy-eight adult patients of ACLF caused by hepatitis B were enrolled to the present study according to pathologic diagnosis and the definition of ACLF. The median age was 44 years (range, 25e64 years), and the ratio of male to female was 61:17. The median total bilirubin level was 418.53 mmol/L (range, 112.90e971.40 mmol/L), the median INR 3.177 (range, 1.470e9.850), and the median creatinine 70.84 mmol/L (range, 12.39e844.1 mmol/L). The median MELD score was 32 (range, 21e53) and the median CTP score 12 (8e15). Thirty-nine patients (50%) had complications with hepatic encephalopathy of which 15 (19.2%) were grade I, 11 (14.1%) grade II, 6 (7.7%) grade III, and 7 (9.0%) grade IV. Five patients (6.4%) needed endotracheal intubation owing to respiratory dysfunction/failure before surgery (Table 1). Sixty-three patients (80.8%) underwent cadaveric-donor LT (DDLT), 34.6% had piggyback LT (PBLT), and 46.1% had classic orthotopic LT (CLT) in which 34.6% had
3503 Table 1. Characteristics of the Study Population (n [ 78) Variable
Age, y Male:female, n Mean CTP score Mean MELD score Serum bilirubin, mmol/L Serum creatinine, mmol/L INR Hepatic encephalopathy, n (%) Grade 1 Grade 2 Grade 3 Grade 4 Endotracheal intubation, n (%)
44 (25e64) 61:17 12 (8e15) 32 (21e53) 418.53 (112.90e971.40) 70.84 (12.39e844.1) 3.177 (1.470e9.850) 39 (50%) 15 (19.2%) 11 (14.1%) 6 (7.7%) 7 (9.0%) 5 (6.4%)
Note. Values are presented as median (range). Abbreviations: CTP, Child-Turcotte-Pugh; MELD, Model for End-Stage Liver Disease; INR, international normalized ratio.
venovenous bypass. Fifteen patients (19.2%) received LDLT, of whom 2 underwent auxiliary partial orthotopic living-donor LT. The median volume of blood loss was 2,750 mL (range, 200e10,000 mL), the median operation duration was 627.5 minutes (range, 405e1,340 min). There was a significant difference in blood loss between LDLT and CLT with venovenous bypass (P ¼ .041). Moreover, there were significant differences in operation duration between PBLT and CLT with venovenous bypass (P ¼ .030) and between PBLT and LDLT (P ¼ .002). The immunosuppressive protocol included tacrolimus, steroids, and mycophenolate mofetil. Early complications (<30 d) occurred in 30 patients (38.5%) including pulmonary infection (n ¼ 13), acute renal failure (n ¼ 5), acute rejection (n ¼ 3), graft failure (n ¼ 1), bile leak (n ¼ 3), hepatic vein occlusion (n ¼ 1), hepatic artery rupture (n ¼ 1), cardiac complication (n ¼ 1), abdominal hemorrhage (n ¼ 1), and cytomegalovirus infection (n ¼ 1). There was no significant difference in the incidence of complication among the surgical procedures. The overall hospital mortality was 21.8% (17/78); the early causes of death included surgical complications (n ¼ 4), and medical complications consisted of multiorgan failure (n ¼ 5), respiratory complications (n ¼ 3), cardiac complications (n ¼ 3), and graft failure (n ¼ 2). Hepatocellular carcinoma was found in liver explants of 8 patients (10.1%), one of which was incidentally found in the explant after surgery. Five patients (6.4%) underwent retransplantation because of bile duct complication. The follow-up ended on September 30, 2012, and the median follow-up duration was 58.01 months (range, 0.10e96.23 mo). There were 2 patients lost to follow-up. The overall 1-, 3-, and 5-year cumulative survival rates were 78.2%, 74.2%, and 72.6%, respectively, and the graft 1-, 3-, and 5-year cumulative survival rates were 76.9%, 70.3%, and 68.6%, respectively; there was no significant difference between DDLT and LDLT (P ¼ .327). Comparing the MELD score, CTP score, bilirubin, and INR between the survivor group and nonsurvivor group, there was no significant difference; however, there was a
3504
DUAN, LU, WU ET AL
Table 2. Clinical Data in Survivor and Nonsurvivor Groups Variable
Survivor Group
Age, y Male:female, n Serum bilirubin, mmol/L Serum creatinine, mmol/L INR MELD score CTP score
43.35 9.40 50:12 429.58 208.22 76.11 36.86* 3.379 1.499 33.53 7.15 11.92 1.54
Nonsurvivor Group P Value
47.13 8.56 11:5 435.81 106.66 99.56 35.64 3.910 1.623 35.14 8.07 12.19 1.22
.150 .304 .908 .025 .218 .438 .521
Note. Values are presented as mean SD. Abbreviations as in Table 1. *One case was excluded from the analysis owing to an extreme value.
significant difference in creatinine between the 2 groups (P ¼ .025; Table 2). ROC analysis showed that the AUCs of the MELD score and CTP score for 3-month mortality were 0.581 (95% confidence interval [CI], 0.421e0.742; sensitivity, 87.5%; specificity, 32.8%) and 0.547 (95% CI, 0.401e0.693; sensitivity, 75%; specificity, 41%), respectively, both of which were <0.7 and had no clinically utility (Fig 1). Moreover, the AUCs of the MELD and CTP scores for early morbidity were 0.608 (95% CI, 0.478e0.738; sensitivity, 77.4%; specificity, 39.1%) and 0.521 (95% CI, 0.389e0.653; sensitivity, 67.7%; specificity, 41.3%), respectively (Fig 2). The stratified analysis of DDLT suggested that the AUC of MELD score for 3-month mortality was 0.547 (95% CI, 0.367e0.727; sensitivity, 84.6%; specificity, 36%) and for morbidity was 0.582 (95% CI, 0.437e0.727; sensitivity, 73.1%; specificity, 43.2%). For further analysis, the patients were divided into 2 groups according to MELD score: group 1, score <30 (n ¼ 26); and group 2, 30 (n ¼ 56); however, there were no significant differences in the 3-month mortality (4/26 for the <30 group and 12/52 for the 30 group; P ¼ .428) and early complications (8/26 for <30 group and 23/52 for the 30 group; P ¼ .252)
Fig 1. Area under the receiver operating characteristic (ROC) curve (AUC) of Model for End-Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (Child) score for 3-month mortality.
Fig 2. AUC of MELD score and Child score for early complications. Abbreviations as in Fig 1.
between the 2 groups. Survival analysis also showed no significant differences in overall survival rates (P ¼ .317; Fig 3) and graft survival rates (P ¼ .338; Fig 4).
DISCUSSION
Acute-on-chronic liver failure is an increasingly recognized entity encompassing an acute deterioration of liver function in patients with cirrhosis, either secondary to superimposed liver injury or due to extrahepatic precipitating factors such as infection culminating in end-organ dysfunction [24]. ACLF in CHB includes acute severe exacerbation of CHB, a disease presentation distinct from other types of chronic liver diseases by its sudden virologic surge followed by biochemical flares. Its pathophysiology and management
Fig 3. The overall cumulative survival rate for Model for EndStage Liver Disease scores 30 and <30.
MELD SCORE DOES NOT PREDICT OUTCOMES
Fig 4. The graft cumulative survival rate for Model for EndStage Liver Disease scores 30 and <30.
also are very different from other causes of acute liver failure [15]. The prognosis is dismal when it progresses to multiorgan dysfunction, such as hepatorenal syndrome and hepatic encephalopathy, and LT is the only definitive therapy to salvage these patients [1]. However, it is generally thought that patients with more severe liver diseases at the time of transplantation have higher perioperative mortality and more complications [25,26]. Therefore, it is of clinical significance to find the optimal timing of LT for patients with ACLF. The CTP score was originally devised for the assessment of the severity of liver disease in predicting the outcome of patients with cirrhosis in whom surgical therapy for portal hypertension was planned [27], and it has been the reference for many years for assessing the prognosis of cirrhosis [28]. However, CTP score has important limitations among which is subjective interpretation of some of its variables, making it difficult to categorize patients according to their own disease severity [29,30]. The MELD score has been confirmed as an excellent predictor of waiting list mortality, but its relationship with post-transplantation outcome was less consistent [31]. A systematic review disclosed that MELD score did not perform better than the CTP score for patients with cirrhosis on the waiting list and can not predict post-LT mortality [32]; the long-term prediction of mortality or removal from waiting list in patients awaiting LT might be better assessed by CTP score than by MELD score [33]. However, some reports implied that MELD score might be a good prognostic model for patients with ACLF to predict the post-transplantation mortality and morbidity as well as long-term survival. Wang et al [14] reported that MELD score was superior to CTP score to predict postoperative short-term survival and 3-month morbidity among patients with hepatitis B ACLF undergoing orthotopic LT; ROC analysis identified the best MELD cutoff score to be 25.67 to predict postoperative morbidity (AUC, 0.841; sensitivity,
3505
85.7%; specificity, 60.0%), and the best CTP cutoff point was 11.5 (AUC, 0.747; sensitivity, 85.7%; specificity, 54.3%). Cai et al [20] found that the 1-year survival rate of the MELD score <30 group was higher than that of the 30 group (77.8% and 33.3%; P ¼ .007), and the rate of complications in the <30 group was lower (P ¼ .012); MELD score <30 may be the optimal time to perform LT for patients with severe hepatitis. Another report suggested that downgrading MELD for liver transplant candidates with MELD score 30 was effective in improving patient prognosis after LT and the incidence of post-transplantation morbidity and mortality of these patients were higher than those with MELD score <30 [23]. In the present study, all of the patients suffered ACLF due to CHB and had the severe clinical condition before surgery. The hospital mortality and morbidity were similar to those for patients with acute liver failure; meanwhile, the overall survival rate and graft survival rate were satisfactory. However, we did not find that both MELD score and CTP score had the predictive value for postoperative 3-month mortality and early morbidity in the study. Moreover, the ACLF patients with high MELD score (30) also had a good post-transplantation outcome compared with those patients with score <30 after LT, which was consistent with other reports [9e11]. Therefore, MELD score was not a good prognostic scoring system for patients with ACLF caused by CHB undergoing LT according to our results [32]. Furthermore, ACLF is a severe systemic disease usually complicated with multiorgan dysfunction (eg, hepatorenal syndrome, hepatic encephalopathy, systemic inflammatory response), so liver function is not the main determinant of the outcome of patients with decompensated cirrhosis, and liver-specific scoring systems have limitations to accurately predict the outcome of patients with ACLF [34]. In conclusion, LT is the definite curative therapy for patients with CHB ACLF, and the post-transplantation outcomes are similar to other indications. MELD score can not predict the postoperative mortality and morbidity for patients with ACLF, and the patients with high MELD score (30) also have an excellent prognosis. It is important for these patients to find a new scoring system to determine which patients can benefit from LT and which LTs are futile.
REFERENCES [1] Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, et al. Acute-on-chronic liver failure: Consensus recommendations of the asian pacific association for the study of the liver (apasl). Hepatol Int 2009;3:269. [2] Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif 2002;20:252. [3] Laleman W, Wilmer A, Evenepoel P, Verslype C, Fevery J, Sevens F. Review article: non-biological liver support in liver failure. Aliment Pharmacol Ther 2006;23:351. [4] Kim W, Brown RJ, Terrault N, El-Serag H. Burden of liver disease in the United States: summary of a workshop. Hepatology 2002;36:227. [5] Leon D, McCambridge J. Liver cirrhosis mortality rates in Britain from 1950 to 2002: an analysis of routine data. Lancet 2006;367:52.
3506 [6] Roberts S, Goldacre M, Yeates D. Trends in mortality after hospital admission for liver cirrhosis in an English population from 1968 to 1999. Gut 2005;54:1615. [7] Bahirwani R, Shaked O, Bewtra M, Forde K, Reddy KR. Acute-on-chronic liver failure before liver transplantation: Impact on posttransplant outcomes. Transplantation 2011;92: 952. [8] Ostapowicz G, Lee WM. Acute hepatic failure: a Western perspective. J Gastroenterol Hepatol 2000;15:480. [9] Chan AC, Fan ST, Lo CM, Liu CL, Chan SC, et al. Liver transplantation for acute-on-chronic liver failure. Hepatol Int 2009;3:571e81. [10] Chen Z, Wen T, Zeng Y, Wang L, Lu JJ, et al. A single institution experience with living donor liver transplantation for acute-on-chronic hepatitis B liver failure. Hepatogastroenterology 2011;58:1267. [11] Liu CL, Fan ST, Lo CM, Wei WI, Yong BH, Lai CL, et al. Live-donor liver transplantation for acute-on-chronic hepatitis B liver failure. Transplantation 2003;76:1174. [12] Shi-Chun L, Meng-Long W, Ning L, Wei L, Ping C, et al. Emergent right lobe adult-to-adult living donor liver transplantation for high model for end-stage liver disease score severe hepatitis. Transpl Int 2010;23:23. [13] Chen Z, Zeng Y, Wen TF, Gong S, Zhao JC, et al. Dual grafts live donor liver transplantation for acute-on-chronic hepatitis B liver failure. Transplant Proc 2010;42:4552. [14] Wang ZX, Yan LN, Wang WT, Xu MQ, Yang JY. Impact of pretransplant meld score on posttransplant outcome in orthotopic liver transplantation for patients with acute-on-chronic hepatitis b liver failure. Transplant Proc 2007;39:1501. [15] William M, Lee M, Larson AM, Stravitz RT. AASLD position paper: the management of acute liver failure: update. Hepatology 2012;55:965. [16] Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864. [17] Wiesner R, Edwards E, Freeman R, Harper A, Kim R, et al. Model for end-stage liver disease (meld) and allocation of donor livers. Gastroenterology 2003;124:91. [18] Sun QF, Ding JG, Xu DZ, Chen YP, Hong L, et al. Prediction of the prognosis of patients with acute-on-chronic hepatitis b liver failure using the model for end-stage liver disease scoring system and a novel logistic regression model. J Viral Hepat 2009;16: 464. [19] Yu JW, Sun LJ, Zhao YH, Li SC. Prediction value of model for end-stage liver disease scoring system on prognosis in patients
DUAN, LU, WU ET AL with acute-on-chronic hepatitis b liver failure after plasma exchange and lamivudine treatment. J Gastroenterol Hepatol 2008;23:1242. [20] Cai QC, Jiang Y, Lv LZ, Hu HZ, Zhang XJ, et al. Operative timing of liver transplantation for patients with severe hepatitis. Hepatobiliary Pancreat Dis Int 2009;8:479. [21] Du WB, Li LJ, Huang JR, Yang Q, Liu XL, et al. Effects of artificial liver support system on patients with acute or chronic liver failure. Transplant Proc 2005;37:4359. [22] Liu C, Wang YM, Fan K. Epidemiological and clinical features of hepatitis B virus related liver failure in China. World J Gastroenterol 2011;17:3054. [23] Ling Q, Xu X, Wei Q, Liu X, Guo H, et al. Downgrading meld improves the outcomes after liver transplantation in patients with acute-on-chronic hepatitis b liver failure. PLoS One 2012;7: e30322. [24] Jalan R, Gines P, Olson JC, Mookerjee RP, Moreau R, et al. Acute-on chronic liver failure. J Hepatol 2012;57:1336. [25] Pacheco-Moreira LF, Balbi E, Enne M, Roma J, Paulino dos Santos K, et al. Liver transplantation for acute liver failure: Trying to define when transplantation is futile. Transplant Proc 2007;39:3178. [26] Ghobrial RM, Gornbein J, Steadman R, Danino N, Markmann JF, et al. Pretransplant model to predict posttransplant survival in liver transplant patients. Ann Surg 2002;236:315. [27] Pugh RN, Murray-Lyon IM, Dawson JL. Transsection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646. [28] Infante-Rivard C, Esnaola S, Villeneuve JP. Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhotics. Hepatology 1987;7:660. [29] Christensen E. Prognostic models including the Child-Pugh, MELD and Mayo risk scoresdwhere are we and where should we go? J Hepatol 2004;41:344. [30] Durand F, Valla D. Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol 2005;42:S100. [31] Martin AP, Bartels M, Hauss J, Fangmann J. Overview of the meld score and the unos adult liver allocation system. Transplant Proc 2007;39:3169. [32] Cholongitas E, Marelli L, Shusang V, Senzolo M, Rolles K, Patch D, et al. A systematic review of the performance of the model for end-stage liver disease (meld) in the setting of liver transplantation. Liver Transpl 2006;12:1049. [33] Gotthardt D, Weiss KH, Baumgartner M, Zahn A, Stremmel W, et al. Limitations of the meld score in predicting mortality or need for removal from waiting list in patients awaiting liver transplantation. BMC Gastroenterol 2009;9:72. [34] Durand F, Valla D. Assessment of prognosis of cirrhosis. Semin Liver Dis 2008;28:110.
Department of Hepatobiliary Surgery and You-An Liver Transplant Center, Beijing You-An Hospital, Capital Medical University, Beijing, People’s Republic of China; and bInstitute and Hospital of Hepatobiliary Surgery, Key Laboratory of Digital Hepatobiliary Surgery of Chinese PLA, Chinese PLA Medical School, Chinese PLA General Hospital, Beijing, People’s Republic of China
ABSTRACT Background. Acute-on-chronic liver failure (ACLF) is a severe clinical entity and liver transplantation is the only definitive therapy to salvage these patients. However, the timing of liver transplant for these patients remains unclear. Methods. Seventy-eight patients undergoing liver transplantation because of hepatitis B ACLF were retrospectively analyzed from June 2004 to December 2010. The areas under the receiver operating characteristic curve (AUC) of Model for End-Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (CTP) score for the post-transplantation outcomes were calculated. Results. The median age was 44 years (range, 25e64 years), serum bilirubin 418.53 mmol/L (range, 112.90e971.40 mmol/L), INR 3.177 (range, 1.470e9.850), and creatinine 70.84 mmol/L (range, 12.39e844.1 mmol/L); the median MELD score was 32 (range, 21e53) and CTP score 12 (8e15). The AUCs of MELD and CTP scores for 3-month mortality were 0.581 (95% confidence interval [CI], 0.421e0.742; sensitivity, 87.5%; specificity, 32.8%) and 0.547 (95% CI, 0.401e0.693; sensitivity, 75%; specificity, 41%), respectively. Meanwhile, there were no significant differences in hospital mortality (P ¼ .252) or morbidity (P ¼ .338) between the patients with MELD score 30 and those <30. Conclusions. MELD score had no predictive ability for the outcomes of patients with hepatitis B ACLF after orthotopic liver transplantation.
A
CUTE-ON-CHRONIC LIVER FAILURE (ACLF) is a severe clinical syndrome with the definition of acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease [1]. This serious condition with varied etiologies and manifestations has a mortality of 50%e90% when the patients develop multiple organ failure [2e6]. ACLF has been considered to be a good indication for orthotopic liver transplantation (LT) [7] and is the best procedure to save patients suffering from ACLF [8]. The outcome following LT for patients with ACLF has been satisfactory [9e14], and the overall 1-, 3-, and 5-year survival rates were similar to those for acute liver failure [15]. However, it is critical to quickly and accurately identify those patients most likely to benefit from LT, because of the
higher short-term mortality of ACLF and graft shortage. The Model for End-Stage Liver Disease (MELD) score was originally developed and validated to evaluate the shortterm outcomes of patients with cirrhosis undergoing a transjugular intrahepatic portosystemic shunt procedure [16] and has been used extensively to allocate donor livers worldwide [17]. MELD score is also an objective and efficient system for predicting survival in chronic hepatitis B (CHB) patients with ACLF [18,19]. Moreover, some reports
Funding: Capital Health Research and Development of Special (grant 2011-2018-03) and Education Committee of Beijing Science and Technology Development Plan (grant KM201110025026). *Address correspondence to Shi-Chun Lu, MD, PhD, 28 Fuxing Road, Beijing. E-mail: [email protected]
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.07.075
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3502
Transplantation Proceedings, 46, 3502e3506 (2014)
MELD SCORE DOES NOT PREDICT OUTCOMES
suggested that MELD score could accurately predict the 3-month survival of patients with ACLF undergoing LT [14,20]. In China, ACLF is the most common type of liver failure [21], and the most common reason is CHB [22,23]. The prognosis of ACLF in CHB is extremely poor, with 3-month mortality rates without LT reported to be >50% [18,19]. In the present study, we retrospectively summarized LT for hepatitis B ACLF and evaluated whether the MELD score can predict postoperative morbidity and mortality. PATIENTS AND METHODS From June 2004 to December 2010, 427 patients underwent LT in Beijing You-An Hospital, Capital Medical University. All of the liver explants were examined histologically. Inclusion criteria included pathology reports of “chronic severe hepatitis” or “submassive hepatocyte necrosis” combined with preexisting chronic liver disease and age 18 years. Medical records were used to ascertain that their clinical presentations fulfilled the ACLF definition [1]. Exclusion criteria were pathologic diagnosis with “fulminant hepatic failure” or “acute liver failure” and age <18 years. The serum total bilirubin, creatinine, and international normalized ratio (INR) were acquired immediately before LT. Before the study, the protocol was approved by the Institutional Review Board of Beijing You-An Hospital according to the principles expressed in the 1975 Declaration of Helsinki, and written informed consent was obtained from each of the study patients. All organ donations were approved by the Institutional Review Board of Beijing You-An Hospital under the guidelines of the Ethics Committee of the hospital and the current regulations of the Chinese Government. All statistical analysis was undertaken with the use of SPSS version 18.0 for Windows (SPSS, Chicago, Illinois). The discriminative power of MELD score and Child-Turcotte-Pugh (CTP) score were evaluated for 3-month mortality and early morbidity following transplantation with the use of the area under the receiver operating characteristic (ROC) curve (AUC). Survival was calculated with the use of the Kaplan-Meier method. A P value of <.05 was considered to be statistically significant.
RESULTS
Seventy-eight adult patients of ACLF caused by hepatitis B were enrolled to the present study according to pathologic diagnosis and the definition of ACLF. The median age was 44 years (range, 25e64 years), and the ratio of male to female was 61:17. The median total bilirubin level was 418.53 mmol/L (range, 112.90e971.40 mmol/L), the median INR 3.177 (range, 1.470e9.850), and the median creatinine 70.84 mmol/L (range, 12.39e844.1 mmol/L). The median MELD score was 32 (range, 21e53) and the median CTP score 12 (8e15). Thirty-nine patients (50%) had complications with hepatic encephalopathy of which 15 (19.2%) were grade I, 11 (14.1%) grade II, 6 (7.7%) grade III, and 7 (9.0%) grade IV. Five patients (6.4%) needed endotracheal intubation owing to respiratory dysfunction/failure before surgery (Table 1). Sixty-three patients (80.8%) underwent cadaveric-donor LT (DDLT), 34.6% had piggyback LT (PBLT), and 46.1% had classic orthotopic LT (CLT) in which 34.6% had
3503 Table 1. Characteristics of the Study Population (n [ 78) Variable
Age, y Male:female, n Mean CTP score Mean MELD score Serum bilirubin, mmol/L Serum creatinine, mmol/L INR Hepatic encephalopathy, n (%) Grade 1 Grade 2 Grade 3 Grade 4 Endotracheal intubation, n (%)
44 (25e64) 61:17 12 (8e15) 32 (21e53) 418.53 (112.90e971.40) 70.84 (12.39e844.1) 3.177 (1.470e9.850) 39 (50%) 15 (19.2%) 11 (14.1%) 6 (7.7%) 7 (9.0%) 5 (6.4%)
Note. Values are presented as median (range). Abbreviations: CTP, Child-Turcotte-Pugh; MELD, Model for End-Stage Liver Disease; INR, international normalized ratio.
venovenous bypass. Fifteen patients (19.2%) received LDLT, of whom 2 underwent auxiliary partial orthotopic living-donor LT. The median volume of blood loss was 2,750 mL (range, 200e10,000 mL), the median operation duration was 627.5 minutes (range, 405e1,340 min). There was a significant difference in blood loss between LDLT and CLT with venovenous bypass (P ¼ .041). Moreover, there were significant differences in operation duration between PBLT and CLT with venovenous bypass (P ¼ .030) and between PBLT and LDLT (P ¼ .002). The immunosuppressive protocol included tacrolimus, steroids, and mycophenolate mofetil. Early complications (<30 d) occurred in 30 patients (38.5%) including pulmonary infection (n ¼ 13), acute renal failure (n ¼ 5), acute rejection (n ¼ 3), graft failure (n ¼ 1), bile leak (n ¼ 3), hepatic vein occlusion (n ¼ 1), hepatic artery rupture (n ¼ 1), cardiac complication (n ¼ 1), abdominal hemorrhage (n ¼ 1), and cytomegalovirus infection (n ¼ 1). There was no significant difference in the incidence of complication among the surgical procedures. The overall hospital mortality was 21.8% (17/78); the early causes of death included surgical complications (n ¼ 4), and medical complications consisted of multiorgan failure (n ¼ 5), respiratory complications (n ¼ 3), cardiac complications (n ¼ 3), and graft failure (n ¼ 2). Hepatocellular carcinoma was found in liver explants of 8 patients (10.1%), one of which was incidentally found in the explant after surgery. Five patients (6.4%) underwent retransplantation because of bile duct complication. The follow-up ended on September 30, 2012, and the median follow-up duration was 58.01 months (range, 0.10e96.23 mo). There were 2 patients lost to follow-up. The overall 1-, 3-, and 5-year cumulative survival rates were 78.2%, 74.2%, and 72.6%, respectively, and the graft 1-, 3-, and 5-year cumulative survival rates were 76.9%, 70.3%, and 68.6%, respectively; there was no significant difference between DDLT and LDLT (P ¼ .327). Comparing the MELD score, CTP score, bilirubin, and INR between the survivor group and nonsurvivor group, there was no significant difference; however, there was a
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Table 2. Clinical Data in Survivor and Nonsurvivor Groups Variable
Survivor Group
Age, y Male:female, n Serum bilirubin, mmol/L Serum creatinine, mmol/L INR MELD score CTP score
43.35 9.40 50:12 429.58 208.22 76.11 36.86* 3.379 1.499 33.53 7.15 11.92 1.54
Nonsurvivor Group P Value
47.13 8.56 11:5 435.81 106.66 99.56 35.64 3.910 1.623 35.14 8.07 12.19 1.22
.150 .304 .908 .025 .218 .438 .521
Note. Values are presented as mean SD. Abbreviations as in Table 1. *One case was excluded from the analysis owing to an extreme value.
significant difference in creatinine between the 2 groups (P ¼ .025; Table 2). ROC analysis showed that the AUCs of the MELD score and CTP score for 3-month mortality were 0.581 (95% confidence interval [CI], 0.421e0.742; sensitivity, 87.5%; specificity, 32.8%) and 0.547 (95% CI, 0.401e0.693; sensitivity, 75%; specificity, 41%), respectively, both of which were <0.7 and had no clinically utility (Fig 1). Moreover, the AUCs of the MELD and CTP scores for early morbidity were 0.608 (95% CI, 0.478e0.738; sensitivity, 77.4%; specificity, 39.1%) and 0.521 (95% CI, 0.389e0.653; sensitivity, 67.7%; specificity, 41.3%), respectively (Fig 2). The stratified analysis of DDLT suggested that the AUC of MELD score for 3-month mortality was 0.547 (95% CI, 0.367e0.727; sensitivity, 84.6%; specificity, 36%) and for morbidity was 0.582 (95% CI, 0.437e0.727; sensitivity, 73.1%; specificity, 43.2%). For further analysis, the patients were divided into 2 groups according to MELD score: group 1, score <30 (n ¼ 26); and group 2, 30 (n ¼ 56); however, there were no significant differences in the 3-month mortality (4/26 for the <30 group and 12/52 for the 30 group; P ¼ .428) and early complications (8/26 for <30 group and 23/52 for the 30 group; P ¼ .252)
Fig 1. Area under the receiver operating characteristic (ROC) curve (AUC) of Model for End-Stage Liver Disease (MELD) score and Child-Turcotte-Pugh (Child) score for 3-month mortality.
Fig 2. AUC of MELD score and Child score for early complications. Abbreviations as in Fig 1.
between the 2 groups. Survival analysis also showed no significant differences in overall survival rates (P ¼ .317; Fig 3) and graft survival rates (P ¼ .338; Fig 4).
DISCUSSION
Acute-on-chronic liver failure is an increasingly recognized entity encompassing an acute deterioration of liver function in patients with cirrhosis, either secondary to superimposed liver injury or due to extrahepatic precipitating factors such as infection culminating in end-organ dysfunction [24]. ACLF in CHB includes acute severe exacerbation of CHB, a disease presentation distinct from other types of chronic liver diseases by its sudden virologic surge followed by biochemical flares. Its pathophysiology and management
Fig 3. The overall cumulative survival rate for Model for EndStage Liver Disease scores 30 and <30.
MELD SCORE DOES NOT PREDICT OUTCOMES
Fig 4. The graft cumulative survival rate for Model for EndStage Liver Disease scores 30 and <30.
also are very different from other causes of acute liver failure [15]. The prognosis is dismal when it progresses to multiorgan dysfunction, such as hepatorenal syndrome and hepatic encephalopathy, and LT is the only definitive therapy to salvage these patients [1]. However, it is generally thought that patients with more severe liver diseases at the time of transplantation have higher perioperative mortality and more complications [25,26]. Therefore, it is of clinical significance to find the optimal timing of LT for patients with ACLF. The CTP score was originally devised for the assessment of the severity of liver disease in predicting the outcome of patients with cirrhosis in whom surgical therapy for portal hypertension was planned [27], and it has been the reference for many years for assessing the prognosis of cirrhosis [28]. However, CTP score has important limitations among which is subjective interpretation of some of its variables, making it difficult to categorize patients according to their own disease severity [29,30]. The MELD score has been confirmed as an excellent predictor of waiting list mortality, but its relationship with post-transplantation outcome was less consistent [31]. A systematic review disclosed that MELD score did not perform better than the CTP score for patients with cirrhosis on the waiting list and can not predict post-LT mortality [32]; the long-term prediction of mortality or removal from waiting list in patients awaiting LT might be better assessed by CTP score than by MELD score [33]. However, some reports implied that MELD score might be a good prognostic model for patients with ACLF to predict the post-transplantation mortality and morbidity as well as long-term survival. Wang et al [14] reported that MELD score was superior to CTP score to predict postoperative short-term survival and 3-month morbidity among patients with hepatitis B ACLF undergoing orthotopic LT; ROC analysis identified the best MELD cutoff score to be 25.67 to predict postoperative morbidity (AUC, 0.841; sensitivity,
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85.7%; specificity, 60.0%), and the best CTP cutoff point was 11.5 (AUC, 0.747; sensitivity, 85.7%; specificity, 54.3%). Cai et al [20] found that the 1-year survival rate of the MELD score <30 group was higher than that of the 30 group (77.8% and 33.3%; P ¼ .007), and the rate of complications in the <30 group was lower (P ¼ .012); MELD score <30 may be the optimal time to perform LT for patients with severe hepatitis. Another report suggested that downgrading MELD for liver transplant candidates with MELD score 30 was effective in improving patient prognosis after LT and the incidence of post-transplantation morbidity and mortality of these patients were higher than those with MELD score <30 [23]. In the present study, all of the patients suffered ACLF due to CHB and had the severe clinical condition before surgery. The hospital mortality and morbidity were similar to those for patients with acute liver failure; meanwhile, the overall survival rate and graft survival rate were satisfactory. However, we did not find that both MELD score and CTP score had the predictive value for postoperative 3-month mortality and early morbidity in the study. Moreover, the ACLF patients with high MELD score (30) also had a good post-transplantation outcome compared with those patients with score <30 after LT, which was consistent with other reports [9e11]. Therefore, MELD score was not a good prognostic scoring system for patients with ACLF caused by CHB undergoing LT according to our results [32]. Furthermore, ACLF is a severe systemic disease usually complicated with multiorgan dysfunction (eg, hepatorenal syndrome, hepatic encephalopathy, systemic inflammatory response), so liver function is not the main determinant of the outcome of patients with decompensated cirrhosis, and liver-specific scoring systems have limitations to accurately predict the outcome of patients with ACLF [34]. In conclusion, LT is the definite curative therapy for patients with CHB ACLF, and the post-transplantation outcomes are similar to other indications. MELD score can not predict the postoperative mortality and morbidity for patients with ACLF, and the patients with high MELD score (30) also have an excellent prognosis. It is important for these patients to find a new scoring system to determine which patients can benefit from LT and which LTs are futile.
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