- Email: [email protected]
m2: Would It Be a Poor Prognosis Predictive Factor?
Complications Associated With Liver Transplantation in Recipients With Body Mass Index >35 kg/m2: Would It Be a Poor Prognosis Predictive Factor? J. Trigueroa,*, A. Garcíab, A. Molinaa, C. San Miguela, P. Notarioa, T. Villegasa, A. Becerraa, M. Expósitob, K. Muffaka, M.J. Álvareza, and Y. Fundoraa a
General, Digestive Surgery, and Liver Transplantation Department, Virgen de las Nieves University Hospital (University Hospital Centre of Granada), Granada, Spain; and bBiostatistical and Epidemiological Support Department, Virgen de las Nieves University Hospital (University Hospital Centre of Granada), Granada, Spain
ABSTRACT Background. Obesity is a global epidemic that continues to increase in a great number of countries, and it has become a major public health problem in Spain. Unfortunately, the impact of obesity on survival in liver transplantation (LT) recipients is underestimated and controversial. The aim of this study was to determine if obesity is a risk factor for morbidity and mortality after LT. Methods. In a retrospective cohort study of the records of 180 consecutive patients who had undergone to LT from 2007 to 2013, 11 obese patients with body mass index (BMI) >35 kg/m2 were identified. Their data have been compared with recipients with BMI 20e25 kg/m2. Results. There were no differences in demographic data, Child-Pugh score, Model for End-Stage Liver Disease score, or cause of liver failure. BMI >35 kg/m2 recipients had a significantly higher rate of portal vein thrombosis before LT, compared with the BMI 20e25 kg/m2 group (36.5% vs 13.9%; P ¼ .041). There were also no differences in development of post-reperfusion syndrome. The groups were also comparable concerning morbidity rate after LT, stay in the intensive care unit, and global hospital stay. However, the mortality rate was significantly higher in the obese group compared with the nonobese group (72.7% vs 38.9%; P ¼ .032). Conclusions. The results of the study clearly demonstrate higher mortality rates in obese patients undergoing LT; thus, it is fair to consider obesity as a poor prognosis predictive factor concerning mortality rate.
O
BESITY is a global epidemic that continues to increase in a great number of countries. Obesity has become a major public health problem in Spain, with an increasing incidence. The last National Health Survey, performed by National Statistic Institute of Spain in 2013, disclosed that 1 in 6 adults was obese, with a prevalence of 17%. In the same way, the rising prevalence of obesity has been translated into a growing number of obese patients with liver disease who are on a waiting list for liver transplantation (LT). On the basis of the increasing prevalence of obesity, nonalcoholic liver disease, a common complication of obesity, is likely to affect more population, with an
increasing number to progress to cirrhosis also end-stage liver disease [1]. Currently, many studies have evaluated the outcomes after elective surgery in obese patients. It is common knowledge that obesity increases the risk of most postoperative complications, such as cardiac and respiratory *Address correspondence to Jennifer Triguero Cabrera, General, Digestive Surgery and Liver Transplantation Department, Virgen de las Nieves University Hospital (University Hospital Centre of Granada), Avenida Fuerzas Armadas s/n, 18014, Granada, Spain. E-mail: [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.10.015
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2650
Transplantation Proceedings, 47, 2650e2652 (2015)
LIVER TRANSPLANTATION IN RECIPIENTS WITH BMI >35 kg/m2
events, infections, and wound complications, in addition to overall mortality [2]. Despite these outcomes after general surgical procedures, the impact of obesity on long-term results after LT is unsettled and controversial [3e7]. In addition, a body mass index (BMI) upper limit value at a higher risk for complications and mortality has not yet been established. Most studies have not been comparable with each other because they do not coincide in BMI upper-limit value. On the other hand, few studies have suggested BMI >35 kg/m2 as the upper limit value at which complications are more common [2]. Owing to divergent outcomes from studies to date, we describe a retrospective study to evaluate short-term and long-term survival and morbidity in obese patients (BMI >35 kg/m2) undergoing LT compared with normalweight patients (BMI 20e25 kg/m2). METHODS A retrospective cohort study was performed to compare the results into 2 groups of recipients undergoing LT in the Virgen de las Nieves University Hospital, from January 2007 to December 2013. The cohort was then divided into 2 groups, based on recipient BMI: the obese recipients group (BMI >35 kg/m2) and the normal-weight recipients group (BMI 20e25 kg/m2). We included recipients with BMI measured before LT and corrected by ascites. We excluded those who had undergone LT with the use of grafts from donors after cardiac death. Preoperative data were sex, age, and BMI. Comorbidity, Child-Pugh score, and Model for End-Stage Liver Disease (MELD) score were registered to estimate the patient’s preoperative status. We also recorded the cause of liver failure and the presence of portal vein thrombosis before LT. Perioperatively, development of post-reperfusion syndrome was registered. Postoperatively, we recorded morbidity such as biliary and vascular complications, ischemic cholangiopathy, graft rejection, and other clinical events, including acute respiratory events (ARE), cytomegalovirus (CMV) infection, and wound infections. We also registered the need of re-operation and liver re-transplantation. Duration of stay in intensive care unit (ICU) and global hospital stay were collected. Mortality and survival were specifically reviewed. Minimum follow-up was 24 months. Quantitative variables are expressed as medians and ranges. Qualitative variables are expressed as percentages. Bivariate analysis was used to estimate the differences between the 2 groups with the use of the Mann-Whitney rank test for quantitative variables; the Fisher test and c2 test were used for qualitative variables. Finally, data for survival were analyzed with the use of a KaplanMeier plot and log-rank test. A value of P < .05 was considered statistically significant. Data were analyzed with the use of IBM SPSS Statistics 19 software.
RESULTS
During the study period, 180 patients had LT. We included 11 (6.1%) recipients in the obese group and 36 (20%) in the nonobese group. The demographic and preoperative data are shown in Table 1. There were no significant differences in sex, median age, and preoperative Child-Pugh and MELD scores between the groups. Only median BMI was significantly higher in the obese group. Alcoholic cirrhosis
2651 Table 1. Demographic and Preoperative Data and Perioperative and Postoperative Events for Obese Patients and the Nonobese Group BMI >35 kg/m2 Group n ¼ 11 (6.1%)
BMI 20e25 kg/m2 Group n ¼ 36 (20%)
Demographic and preoperative data Sex Male 9 (81.8%) 28 Female 2 (18.2%) 8 Age, years 53 (45e64) 54.5 BMI, kg/m2 37 (35.1e40.1) 23.9 Child-Pugh score 7 (6e9) 8 MELD score 15 (14e18) 15 Portal vein thrombosis 4 (36.5%) 5 before LT Perioperative events Post-reperfusion 2 (18.2%) 8 syndrome Postoperative events (morbidity and mortality) Vascular complications 3 (27.3%) 12 Biliary complications 2 (18.2%) 7 Ischemic 2 (18.2%) 3 cholangiopathy Graft rejection 4 (36.4%) 10 Re-operation rate 4 (36.4%) 10 Re-transplantation rate 2 (18.2%) 3 Wound infection 4 (36.4%) 6 ARE 5 (45.5%) 8 CMV infection 2 (18.2%) 3 ICU stay 5 (3e6) 3 Global hospital stay 26 (16e33) 30.5 Overall mortality 8 (72.7%) 14
P*
1 (77.8%) (22.2%) (48.25e63.75) .543 (22.7e24.75) >.001 (6.25e9) .268 (15e18) .737 (13.9%) .041
(22.9%)
1
(33.3%) (19.4%) (8.3%)
1 1 .578
(28.6%) (28.6%) (8.3%) (16.7%) (22.2%) (8.3%) (3e5) (16.7e48.5) (38.9%)
.713 .713 .578 .213 .246 .578 .348 .490 .032
Quantitative data are expressed as median and ranges. Qualitative data are expressed as percentages. Abbreviations: BMI, body mass index; MELD, Model for End-Stage Liver Disease; LT, liver transplantation; ARE, acute respiratory events; CMV, cytomegalovirus; ICU, intensive care unit. *P < .05 (Mann-Whitney rank test, Fisher test, and c2 test) was statistically significant.
was the most common indication for LT in both groups (45.5% in the obese group vs 50.0% in the nonobese group). Overall outcomes of perioperative and postoperative events are included in Table 1. BMI >35 kg/m2 recipients had a significantly higher rate of portal vein thrombosis before LT. We found no statistically significant differences in analysis of vascular (hepatic artery thrombosis or stenosis and portal vein thrombosis or stenosis) and biliary complications in the obese group compared with the nonobese group. Ischemic cholangiopathy, re-transplantation, reoperation rates, and clinical complications were higher in the obese group than in the nonobese group, with no significant differences. The groups were comparable concerning graft rejection rate, ICU stay, and global hospital stay. Finally, the obese group had a significantly higher rate of overall mortality compared with the nonobese group. The main cause of death in BMI >35 kg/m2 recipients was associated with complications after LT (hepatic artery and portal vein thrombosis). A Kaplan-Meier plot showed the differences in survival in the 2 groups. There was a
2652
statistically significant difference between the 2 curves, determined by means of a log-rank test. DISCUSSION
The increasing global prevalence of obesity is ineluctable. The transplant world is progressively being challenged with more obese donors and recipients. The mortality rate among obese LT recipients with elevated BMI has ranged from 0% to 65% [1]. Moreover, it has been controversial whether obese LT recipients have worse outcomes than did normal-weight recipients. Many multicenters and database review studies have shown that obesity should be a relative contraindication to LT, since they have suggested higher mortality and postoperative complications after LT in the obese group than in the nonobese group. A Denmark study with 20 recipients with BMI >30 kg/m2 showed increased postoperative complications and mortality in this group as compared with recipients with BMI <30 kg/m2 [4]. In a retrospective cohort review of the United Network for Organ Sharing database from 1988 to 1996, Nair et al. [7] found lower recipient survival associated with LT in patients with obesity. Only few studies found no differences in morbidity and mortality in obese patients compared with control patients. In a retrospective cohort study from 2007 to 2011, Ashish et al. [2] showed that recipient and graft survival was similar between a BMI >40 kg/m2 group and a BMI <40 kg/m2 group. In a single-center study from the University of Wisconsin, Mattina et al. [4] found similar complication and mortality rates in obese and nonobese recipients. The results of the present study demonstrate an increased mortality rate in obese patients (BMI >35 kg/2) operated in our LT program in recent years compared with nonobese control patients (BMI 20e25 kg/m2). These findings are in accordance with some studies published to date. Besides, the higher prevalence of portal vein thrombosis before LT in the obese group should be noted. That fact could be associated with a greater probability of portal vein
TRIGUERO, GARCÍA, MOLINA ET AL
thrombosis after LT, which is one of the main causes of death in obese patients undergoing LT. On the other hand, there were no significant differences regarding complications after LT, stay in the ICU, and global hospital stay between both groups in our series. Also, ischemic cholangiopathy, re-transplantation, and re-operation rate were higher in the obese group than in the normal-weight group, with no significant differences but with a slight significance tendency. We may need an increasing number of samples to obtain more reliable outcomes. In view of the results, we cannot establish that obesity is an absolute contraindication for LT. However, we can conclude that obesity can be a poor prognosis predictive factor concerning mortality rate. ACKNOWLEDGMENTS The authors wish to thank Daniel Garrote for assistance in the preparation of the manuscript.
REFERENCES [1] Saab S, Lalezari D, Pruthi P. The impact of obesity on patient survival in liver transplant recipients: a meta-analysis. Liver Int 2015;35:164e70. [2] Singhal A, Wilson G, Wima K, et al. Impact of recipient morbid obesity on outcomes after liver transplantation. Transpl Int 2014;28:148e55. [3] Hakeem AR, Cockbain AJ, Raza SS, et al. Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom. Liver Transpl 2013;19:551e62. [4] La Mattina JC, Foley DP, Fernandez LA, et al. Complications associated with liver transplantation in the obese recipient. Clin Transplant 2012;26:910e8. [5] Hillingsø JC, Wettergren A, Hyoudo M, et al. Obesity increases mortality in liver transplantation: the Danish experience. Transpl Int 2005;18:1231e5. [6] Braunfeld MY, Chan S, Pregler J, et al. Liver transplantation in the morbidly obese. J Clin Anesth 1996;8:585e90. [7] Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002;35:105e9.
General, Digestive Surgery, and Liver Transplantation Department, Virgen de las Nieves University Hospital (University Hospital Centre of Granada), Granada, Spain; and bBiostatistical and Epidemiological Support Department, Virgen de las Nieves University Hospital (University Hospital Centre of Granada), Granada, Spain
ABSTRACT Background. Obesity is a global epidemic that continues to increase in a great number of countries, and it has become a major public health problem in Spain. Unfortunately, the impact of obesity on survival in liver transplantation (LT) recipients is underestimated and controversial. The aim of this study was to determine if obesity is a risk factor for morbidity and mortality after LT. Methods. In a retrospective cohort study of the records of 180 consecutive patients who had undergone to LT from 2007 to 2013, 11 obese patients with body mass index (BMI) >35 kg/m2 were identified. Their data have been compared with recipients with BMI 20e25 kg/m2. Results. There were no differences in demographic data, Child-Pugh score, Model for End-Stage Liver Disease score, or cause of liver failure. BMI >35 kg/m2 recipients had a significantly higher rate of portal vein thrombosis before LT, compared with the BMI 20e25 kg/m2 group (36.5% vs 13.9%; P ¼ .041). There were also no differences in development of post-reperfusion syndrome. The groups were also comparable concerning morbidity rate after LT, stay in the intensive care unit, and global hospital stay. However, the mortality rate was significantly higher in the obese group compared with the nonobese group (72.7% vs 38.9%; P ¼ .032). Conclusions. The results of the study clearly demonstrate higher mortality rates in obese patients undergoing LT; thus, it is fair to consider obesity as a poor prognosis predictive factor concerning mortality rate.
O
BESITY is a global epidemic that continues to increase in a great number of countries. Obesity has become a major public health problem in Spain, with an increasing incidence. The last National Health Survey, performed by National Statistic Institute of Spain in 2013, disclosed that 1 in 6 adults was obese, with a prevalence of 17%. In the same way, the rising prevalence of obesity has been translated into a growing number of obese patients with liver disease who are on a waiting list for liver transplantation (LT). On the basis of the increasing prevalence of obesity, nonalcoholic liver disease, a common complication of obesity, is likely to affect more population, with an
increasing number to progress to cirrhosis also end-stage liver disease [1]. Currently, many studies have evaluated the outcomes after elective surgery in obese patients. It is common knowledge that obesity increases the risk of most postoperative complications, such as cardiac and respiratory *Address correspondence to Jennifer Triguero Cabrera, General, Digestive Surgery and Liver Transplantation Department, Virgen de las Nieves University Hospital (University Hospital Centre of Granada), Avenida Fuerzas Armadas s/n, 18014, Granada, Spain. E-mail: [email protected]
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.10.015
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2650
Transplantation Proceedings, 47, 2650e2652 (2015)
LIVER TRANSPLANTATION IN RECIPIENTS WITH BMI >35 kg/m2
events, infections, and wound complications, in addition to overall mortality [2]. Despite these outcomes after general surgical procedures, the impact of obesity on long-term results after LT is unsettled and controversial [3e7]. In addition, a body mass index (BMI) upper limit value at a higher risk for complications and mortality has not yet been established. Most studies have not been comparable with each other because they do not coincide in BMI upper-limit value. On the other hand, few studies have suggested BMI >35 kg/m2 as the upper limit value at which complications are more common [2]. Owing to divergent outcomes from studies to date, we describe a retrospective study to evaluate short-term and long-term survival and morbidity in obese patients (BMI >35 kg/m2) undergoing LT compared with normalweight patients (BMI 20e25 kg/m2). METHODS A retrospective cohort study was performed to compare the results into 2 groups of recipients undergoing LT in the Virgen de las Nieves University Hospital, from January 2007 to December 2013. The cohort was then divided into 2 groups, based on recipient BMI: the obese recipients group (BMI >35 kg/m2) and the normal-weight recipients group (BMI 20e25 kg/m2). We included recipients with BMI measured before LT and corrected by ascites. We excluded those who had undergone LT with the use of grafts from donors after cardiac death. Preoperative data were sex, age, and BMI. Comorbidity, Child-Pugh score, and Model for End-Stage Liver Disease (MELD) score were registered to estimate the patient’s preoperative status. We also recorded the cause of liver failure and the presence of portal vein thrombosis before LT. Perioperatively, development of post-reperfusion syndrome was registered. Postoperatively, we recorded morbidity such as biliary and vascular complications, ischemic cholangiopathy, graft rejection, and other clinical events, including acute respiratory events (ARE), cytomegalovirus (CMV) infection, and wound infections. We also registered the need of re-operation and liver re-transplantation. Duration of stay in intensive care unit (ICU) and global hospital stay were collected. Mortality and survival were specifically reviewed. Minimum follow-up was 24 months. Quantitative variables are expressed as medians and ranges. Qualitative variables are expressed as percentages. Bivariate analysis was used to estimate the differences between the 2 groups with the use of the Mann-Whitney rank test for quantitative variables; the Fisher test and c2 test were used for qualitative variables. Finally, data for survival were analyzed with the use of a KaplanMeier plot and log-rank test. A value of P < .05 was considered statistically significant. Data were analyzed with the use of IBM SPSS Statistics 19 software.
RESULTS
During the study period, 180 patients had LT. We included 11 (6.1%) recipients in the obese group and 36 (20%) in the nonobese group. The demographic and preoperative data are shown in Table 1. There were no significant differences in sex, median age, and preoperative Child-Pugh and MELD scores between the groups. Only median BMI was significantly higher in the obese group. Alcoholic cirrhosis
2651 Table 1. Demographic and Preoperative Data and Perioperative and Postoperative Events for Obese Patients and the Nonobese Group BMI >35 kg/m2 Group n ¼ 11 (6.1%)
BMI 20e25 kg/m2 Group n ¼ 36 (20%)
Demographic and preoperative data Sex Male 9 (81.8%) 28 Female 2 (18.2%) 8 Age, years 53 (45e64) 54.5 BMI, kg/m2 37 (35.1e40.1) 23.9 Child-Pugh score 7 (6e9) 8 MELD score 15 (14e18) 15 Portal vein thrombosis 4 (36.5%) 5 before LT Perioperative events Post-reperfusion 2 (18.2%) 8 syndrome Postoperative events (morbidity and mortality) Vascular complications 3 (27.3%) 12 Biliary complications 2 (18.2%) 7 Ischemic 2 (18.2%) 3 cholangiopathy Graft rejection 4 (36.4%) 10 Re-operation rate 4 (36.4%) 10 Re-transplantation rate 2 (18.2%) 3 Wound infection 4 (36.4%) 6 ARE 5 (45.5%) 8 CMV infection 2 (18.2%) 3 ICU stay 5 (3e6) 3 Global hospital stay 26 (16e33) 30.5 Overall mortality 8 (72.7%) 14
P*
1 (77.8%) (22.2%) (48.25e63.75) .543 (22.7e24.75) >.001 (6.25e9) .268 (15e18) .737 (13.9%) .041
(22.9%)
1
(33.3%) (19.4%) (8.3%)
1 1 .578
(28.6%) (28.6%) (8.3%) (16.7%) (22.2%) (8.3%) (3e5) (16.7e48.5) (38.9%)
.713 .713 .578 .213 .246 .578 .348 .490 .032
Quantitative data are expressed as median and ranges. Qualitative data are expressed as percentages. Abbreviations: BMI, body mass index; MELD, Model for End-Stage Liver Disease; LT, liver transplantation; ARE, acute respiratory events; CMV, cytomegalovirus; ICU, intensive care unit. *P < .05 (Mann-Whitney rank test, Fisher test, and c2 test) was statistically significant.
was the most common indication for LT in both groups (45.5% in the obese group vs 50.0% in the nonobese group). Overall outcomes of perioperative and postoperative events are included in Table 1. BMI >35 kg/m2 recipients had a significantly higher rate of portal vein thrombosis before LT. We found no statistically significant differences in analysis of vascular (hepatic artery thrombosis or stenosis and portal vein thrombosis or stenosis) and biliary complications in the obese group compared with the nonobese group. Ischemic cholangiopathy, re-transplantation, reoperation rates, and clinical complications were higher in the obese group than in the nonobese group, with no significant differences. The groups were comparable concerning graft rejection rate, ICU stay, and global hospital stay. Finally, the obese group had a significantly higher rate of overall mortality compared with the nonobese group. The main cause of death in BMI >35 kg/m2 recipients was associated with complications after LT (hepatic artery and portal vein thrombosis). A Kaplan-Meier plot showed the differences in survival in the 2 groups. There was a
2652
statistically significant difference between the 2 curves, determined by means of a log-rank test. DISCUSSION
The increasing global prevalence of obesity is ineluctable. The transplant world is progressively being challenged with more obese donors and recipients. The mortality rate among obese LT recipients with elevated BMI has ranged from 0% to 65% [1]. Moreover, it has been controversial whether obese LT recipients have worse outcomes than did normal-weight recipients. Many multicenters and database review studies have shown that obesity should be a relative contraindication to LT, since they have suggested higher mortality and postoperative complications after LT in the obese group than in the nonobese group. A Denmark study with 20 recipients with BMI >30 kg/m2 showed increased postoperative complications and mortality in this group as compared with recipients with BMI <30 kg/m2 [4]. In a retrospective cohort review of the United Network for Organ Sharing database from 1988 to 1996, Nair et al. [7] found lower recipient survival associated with LT in patients with obesity. Only few studies found no differences in morbidity and mortality in obese patients compared with control patients. In a retrospective cohort study from 2007 to 2011, Ashish et al. [2] showed that recipient and graft survival was similar between a BMI >40 kg/m2 group and a BMI <40 kg/m2 group. In a single-center study from the University of Wisconsin, Mattina et al. [4] found similar complication and mortality rates in obese and nonobese recipients. The results of the present study demonstrate an increased mortality rate in obese patients (BMI >35 kg/2) operated in our LT program in recent years compared with nonobese control patients (BMI 20e25 kg/m2). These findings are in accordance with some studies published to date. Besides, the higher prevalence of portal vein thrombosis before LT in the obese group should be noted. That fact could be associated with a greater probability of portal vein
TRIGUERO, GARCÍA, MOLINA ET AL
thrombosis after LT, which is one of the main causes of death in obese patients undergoing LT. On the other hand, there were no significant differences regarding complications after LT, stay in the ICU, and global hospital stay between both groups in our series. Also, ischemic cholangiopathy, re-transplantation, and re-operation rate were higher in the obese group than in the normal-weight group, with no significant differences but with a slight significance tendency. We may need an increasing number of samples to obtain more reliable outcomes. In view of the results, we cannot establish that obesity is an absolute contraindication for LT. However, we can conclude that obesity can be a poor prognosis predictive factor concerning mortality rate. ACKNOWLEDGMENTS The authors wish to thank Daniel Garrote for assistance in the preparation of the manuscript.
REFERENCES [1] Saab S, Lalezari D, Pruthi P. The impact of obesity on patient survival in liver transplant recipients: a meta-analysis. Liver Int 2015;35:164e70. [2] Singhal A, Wilson G, Wima K, et al. Impact of recipient morbid obesity on outcomes after liver transplantation. Transpl Int 2014;28:148e55. [3] Hakeem AR, Cockbain AJ, Raza SS, et al. Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom. Liver Transpl 2013;19:551e62. [4] La Mattina JC, Foley DP, Fernandez LA, et al. Complications associated with liver transplantation in the obese recipient. Clin Transplant 2012;26:910e8. [5] Hillingsø JC, Wettergren A, Hyoudo M, et al. Obesity increases mortality in liver transplantation: the Danish experience. Transpl Int 2005;18:1231e5. [6] Braunfeld MY, Chan S, Pregler J, et al. Liver transplantation in the morbidly obese. J Clin Anesth 1996;8:585e90. [7] Nair S, Verma S, Thuluvath PJ. Obesity and its effect on survival in patients undergoing orthotopic liver transplantation in the United States. Hepatology 2002;35:105e9.