Graft Regeneration in Pediatric Living Donor Liver Transplantation W.-X. Lim, Y.-F. Cheng, T.-L. Huang, T.-Y. Chen, L.L.-C. Tsang, H.-Y. Ou, C.-Y. Yu, H.-W. Hsu, and C.-L. Chen ABSTRACT Objective. Due to the shortage of cadaver liver grafts in Asia, more than 90% of biliary atresia (BA) patients require living donor liver transplantation (LDLT), but the factors that influence liver graft regeneration in pediatric patients are still unclear. The aim of this study was to evaluate the potential predisposing factors that encourage liver graft regeneration in pediatric liver transplantation (LT). Methods. Case notes and Doppler ultrasound and computed tomography studies performed before and 6 months after transplantation of 103 BA patients who underwent LDLT were reviewed. The predisposing factors that triggered liver regeneration were compiled from statistical analyses and included the following: age, gender, body weight and height, spleen size, graft weightetoerecipient weight ratio (GRWR), post-transplantation total portal flow, and vascular complications. Results. Seventy-two pediatric recipients were enrolled in this study. The liver graft regeneration rate was 29.633 36.61% (range, 29.53e126.27%). The size of the spleen (P ¼ .001), post-transplantation portal flow (P ¼ .004), and age (P ¼ .04) were correlated lineally with the regeneration rate. The GRWR was negatively correlated with the regeneration rate (P ¼ .001) and was the only independent factor that affected the regeneration rate. When the GRWR was >3.4, patients tended to have poor and negative graft regeneration (P ¼ .01). Conclusion. Large-for-size grafts have negative effect on regeneration rates because liver grafts that are too large can compromise total portal flow and increase vascular complications, especially when the GRWR is >3.4. Thus, optimal graft size is more essential than other factors in a pediatric LDLT patient.
B
ILIARY atresia (BA) is the most common indication for liver transplantation (LT) in children [1]. Due to the shortage of cadaver liver grafts in Asia, more than 90% of BA patients required living donor liver transplantation (LDLT). Size of the graft, portal hypertension, and graft congestion are thought to be the causes of post-transplantation graft dysfunction and hold back the graft regeneration [2]. Thus, adequate graft size, control of sufficient portal flow, and adequate hepatic outflow are crucial in adult LDLT patients, but the factors that influence liver graft regeneration in pediatric patients are still unclear. The aim of this study was to evaluate any predisposing factors that encourage liver graft regeneration and optimal graft size for the pediatric patient.
PATIENTS AND METHODS This retrospective study was approved by the ethics committee of Chang Gung Memorial Hospital (102-2456B). Between March 2002 and September 2010, a total of 103 BA patients underwent LDLT. Thirty-one patients were excluded from this study due to lost in
From the Liver Transplantation Program and Departments of Diagnostic Radiology (W.-X.L., Y.-F.C., T.-L.H., T.-Y.C., L.L.-C.T., H.-Y.O., C.-Y.Y., H.-W.H.) and Surgery (C.-L.C.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. Address reprint requests to Dr Chun-Yen Yu, Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-Sung, Kaohsiung, Taiwan. E-mail: [email protected]
Crown Copyright ª 2014 Published by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 767e769 (2014)
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.10.048 767
768 follow-up (n ¼ 21), death (n ¼ 5), and age older than 10 years (n ¼ 5). The data was collected from a prospectively maintained database and analyzed retrospectively.
LIM, CHENG, HUANG ET AL
Relationship Between Graft Factors and Graft Regeneration
The recipients’ preoperative and 6-month postoperative liver and spleen volumes were estimated by using multislice computed tomography (CT). The CT volume was calculated from 10-mm cut slices. The absolute graft weight was assumed to be the actual graft volume because the liver and the spleen have nearly the same density as water and this gives an accurate volume with an error of 10% [3].
The GRWR was inversely proportional to graft regeneration, which meant the larger the graft, the less the regeneration rate of the graft (P ¼ .00). The receiver operating characteristic (ROC) curve revealed a cut point of GRWR at 3.4 with a sensitivity of 71.43% and specificity of 72.55%. Further analysis was done by using chi-square test and simple t test. The result of the analysis was that patients with GRWR >3.4 had a much lower regeneration rate. Fifteen cases (51.7%; n ¼ 29) had a negative regeneration rate, compared with 6 cases (13.9%; n ¼ 43) who had GRWR 3.4 were more likely to have lesser or negative regeneration rates despite the spleen size. The patient age at LDLT was also directly proportional to the regeneration rate (P ¼ .04), which means younger patients were associated with relatively poor graft regeneration rates. The age ROC curve showed a cutoff point at 15 months old with sensitivity of 51% and specificity of 81%. Multivariable Regression Analysis
Using multivariate analysis, GRWR was found to be the only independent significant factor that influenced graft regeneration (P ¼ .00). DISCUSSION
RESULTS
A total of 72 recipients was included and evaluated for liver regeneration in this study with a follow-up rate of 69.9%. Mean patient age at LDLT was 24.79 27.7 months (range, 6e121 months). Thirty-seven patients (51.38%) were younger than 1 year old. Mean patient body weight at LDLT was 11.2 7.39 kg (range, 5.90e51.4 kg). The mean body height was 79.14 19.77 cm (range, 61.0 to 149.7 cm). Mean graft weight was 298.98 89.60 g (range, 175e832 g). Mean GRWR was 3.09 0.98 (range, 0.91e5.28). The mean size of the recipient’s preoperative spleen was 171.41 149.21 cm3 (range, 33e830 cm3). Regeneration of the Graft
Overall, the mean regeneration rate was 29.633 36.61% (range, 29.53e126.27%). There were 21 patients (29.16%) with a negative regeneration rate and 51 patients with a positive regeneration rate. During the 6-month follow-up period after transplantation early portal vein (PV) occlusion occurred in 6 cases, and later after transplantation PV stenosis occurred in 5 cases. These were managed by redo portal anastomosis and PV stent.
Cheng et al reported that the size of the spleen, total portal flow, and GRWR were linearly correlated with the regeneration rate in adult LDLT patients [2]. Few series have focused on the results of pediatric LDLT for BA and graft regeneration data are also lacking. In this study we tried to find out the potential predisposing factors that encourage liver graft regeneration in this group of patients. The marked difference between adult and pediatric recipients in liver regeneration rates was that the hyperkinetic portal hemodynamic condition is much more important in the former. Portal hyperperfusion in a small-for-size volume liver graft is thought to be one of the main causes of posttransplantation graft dysfunction in adult LDLT patients. In contrast, the biggest problem in LT for small infants results from large-for-size grafts. This situation occurs when the smallest anatomic graft, the left lateral segment, is >4 GRWR. This large-for-size situation is characterized by the discrepancy between a small abdominal cavity and a large graft that can lead to a diminished blood supply to the liver graft. Severe vascular problems, early graft losses, and graft necrosis because of direct pressure on the liver parenchyma using large grafts have been reported [4e8]. The GRWR is well accepted as an important predictor of the adequacy of
GRAFT REGENERATION IN PEDIATRIC LDLT
post-transplantation liver function with a safety ratio range of 3.4 was found to be a cutoff point that had significant negative impact on regeneration rate and induced negative graft regeneration. Although the result also showed us that increased spleen size is linearly correlated to portal flow and increased portal flow favors regeneration, this advantage is countered by the increased GRWR because a large graft can lead to a diminished blood supply of the liver graft. To prevent large-for-size situations, some centers choose to reduce the graft into a monosegmental or “hyperreduced” graft. This may allow for an easier abdominal wall closure and avoid an insufficient blood supply to the graft. A 2005 published meta-analysis showed an advantage in favor of the use of monosegmental grafts among pediatric patients, where complication rates were comparable between mono-segmental and other grafts [9]. On the other hand, Schulze et al claim that the use of mono-segmental grafts is unnecessary if the transplant of left lateral grafts is performed by an experienced multidisciplinary team. The ventroedorsal diameter of the graft appears to be more relevant to potential graft necrosis than the actual graft size [10]. Our result demonstrated higher PV complications (early PV occlusion occurred in 6 cases and PV stenosis later after the transplantation in 5 case) in patients whose GRWR was >3.4, although the difference was not statistically significant (P ¼ .105). In general, small patients with BA demonstrate a greater risk at LT because of infection or vascular complications [11,12]. According to our analysis, BA patients who were younger than 15 months old have less graft regeneration and tend to have a negative regeneration rate. Mizuta et al described a poor post-transplantation survival rate in small patients [13]. They concluded that LDLT should be considered when patient body weight is 8 to 20 kg, corresponding to age 2 to 4 years.
769
In conclusion, factors that influence the graft regeneration rate of pediatric patients are different from adults. Portal hemodynamics are important but the graft size is more essential. Large size grafts can compromise the total portal flow and, when the GRWR is >3.4, there are significant negative effects on graft regeneration and increased PV complications, and these may induce graft regression. REFERENCES [1] Migliazza L, López SantamarÍa M, Murcia J, et al. Long-term survival expectancy after liver transplantation in children. J Pediatr Surg 2000;35:5. [2] Cheng YF, Huang TL, Chen TY, et al. Liver graft regeneration in right lobe adult living donor liver transplantation. Am J Transplant 2009;9:1382. [3] Breiman RS, Beck JW, Korobkin M, et al. Volume determinations using computed tomography. AJR Am J Roentgenol 1982;138:329. [4] Colombani PM, Cigarroa FG, Schwarz K, et al. Liver transplantation in infants younger than 1 year of age. Ann Surg 1996;223: 658. [5] Cacciarelli TV, Esquivel CO, Moore DH, et al. Factors affecting survival after orthotopic liver transplantation in infants. Transplantation 1997;64:242. [6] Saing H, Fan ST, Chan KL, et al. Liver transplantation in infants. J Pediatr Surg 1999;34:172. [7] Iglesias J, López JA, Ortega J, et al. Liver transplantation in infants weighing under 7 kilograms: management and out-come of PICU. Pediatr Transplant 2004;8:228. [8] Kiuchi T, Kasahara M, Uryuhara K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation 1999;67:321. [9] Enne M, Pacheo-Moreira L, Balbi E, et al. Liver transplantation with monosegments. Technical aspects and outcome: a meta-analysis. Liver Transplant 2005;11:564. [10] Schulze M, Dresske B, Deinzer J, et al. Implications for the usage of the left lateral liver graft for infants
B
ILIARY atresia (BA) is the most common indication for liver transplantation (LT) in children [1]. Due to the shortage of cadaver liver grafts in Asia, more than 90% of BA patients required living donor liver transplantation (LDLT). Size of the graft, portal hypertension, and graft congestion are thought to be the causes of post-transplantation graft dysfunction and hold back the graft regeneration [2]. Thus, adequate graft size, control of sufficient portal flow, and adequate hepatic outflow are crucial in adult LDLT patients, but the factors that influence liver graft regeneration in pediatric patients are still unclear. The aim of this study was to evaluate any predisposing factors that encourage liver graft regeneration and optimal graft size for the pediatric patient.
PATIENTS AND METHODS This retrospective study was approved by the ethics committee of Chang Gung Memorial Hospital (102-2456B). Between March 2002 and September 2010, a total of 103 BA patients underwent LDLT. Thirty-one patients were excluded from this study due to lost in
From the Liver Transplantation Program and Departments of Diagnostic Radiology (W.-X.L., Y.-F.C., T.-L.H., T.-Y.C., L.L.-C.T., H.-Y.O., C.-Y.Y., H.-W.H.) and Surgery (C.-L.C.), Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. Address reprint requests to Dr Chun-Yen Yu, Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital, 123 Ta-Pei Road, Niao-Sung, Kaohsiung, Taiwan. E-mail: [email protected]
Crown Copyright ª 2014 Published by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 767e769 (2014)
0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.10.048 767
768 follow-up (n ¼ 21), death (n ¼ 5), and age older than 10 years (n ¼ 5). The data was collected from a prospectively maintained database and analyzed retrospectively.
LIM, CHENG, HUANG ET AL
Relationship Between Graft Factors and Graft Regeneration
The recipients’ preoperative and 6-month postoperative liver and spleen volumes were estimated by using multislice computed tomography (CT). The CT volume was calculated from 10-mm cut slices. The absolute graft weight was assumed to be the actual graft volume because the liver and the spleen have nearly the same density as water and this gives an accurate volume with an error of 10% [3].
The GRWR was inversely proportional to graft regeneration, which meant the larger the graft, the less the regeneration rate of the graft (P ¼ .00). The receiver operating characteristic (ROC) curve revealed a cut point of GRWR at 3.4 with a sensitivity of 71.43% and specificity of 72.55%. Further analysis was done by using chi-square test and simple t test. The result of the analysis was that patients with GRWR >3.4 had a much lower regeneration rate. Fifteen cases (51.7%; n ¼ 29) had a negative regeneration rate, compared with 6 cases (13.9%; n ¼ 43) who had GRWR 3.4 were more likely to have lesser or negative regeneration rates despite the spleen size. The patient age at LDLT was also directly proportional to the regeneration rate (P ¼ .04), which means younger patients were associated with relatively poor graft regeneration rates. The age ROC curve showed a cutoff point at 15 months old with sensitivity of 51% and specificity of 81%. Multivariable Regression Analysis
Using multivariate analysis, GRWR was found to be the only independent significant factor that influenced graft regeneration (P ¼ .00). DISCUSSION
RESULTS
A total of 72 recipients was included and evaluated for liver regeneration in this study with a follow-up rate of 69.9%. Mean patient age at LDLT was 24.79 27.7 months (range, 6e121 months). Thirty-seven patients (51.38%) were younger than 1 year old. Mean patient body weight at LDLT was 11.2 7.39 kg (range, 5.90e51.4 kg). The mean body height was 79.14 19.77 cm (range, 61.0 to 149.7 cm). Mean graft weight was 298.98 89.60 g (range, 175e832 g). Mean GRWR was 3.09 0.98 (range, 0.91e5.28). The mean size of the recipient’s preoperative spleen was 171.41 149.21 cm3 (range, 33e830 cm3). Regeneration of the Graft
Overall, the mean regeneration rate was 29.633 36.61% (range, 29.53e126.27%). There were 21 patients (29.16%) with a negative regeneration rate and 51 patients with a positive regeneration rate. During the 6-month follow-up period after transplantation early portal vein (PV) occlusion occurred in 6 cases, and later after transplantation PV stenosis occurred in 5 cases. These were managed by redo portal anastomosis and PV stent.
Cheng et al reported that the size of the spleen, total portal flow, and GRWR were linearly correlated with the regeneration rate in adult LDLT patients [2]. Few series have focused on the results of pediatric LDLT for BA and graft regeneration data are also lacking. In this study we tried to find out the potential predisposing factors that encourage liver graft regeneration in this group of patients. The marked difference between adult and pediatric recipients in liver regeneration rates was that the hyperkinetic portal hemodynamic condition is much more important in the former. Portal hyperperfusion in a small-for-size volume liver graft is thought to be one of the main causes of posttransplantation graft dysfunction in adult LDLT patients. In contrast, the biggest problem in LT for small infants results from large-for-size grafts. This situation occurs when the smallest anatomic graft, the left lateral segment, is >4 GRWR. This large-for-size situation is characterized by the discrepancy between a small abdominal cavity and a large graft that can lead to a diminished blood supply to the liver graft. Severe vascular problems, early graft losses, and graft necrosis because of direct pressure on the liver parenchyma using large grafts have been reported [4e8]. The GRWR is well accepted as an important predictor of the adequacy of
GRAFT REGENERATION IN PEDIATRIC LDLT
post-transplantation liver function with a safety ratio range of 3.4 was found to be a cutoff point that had significant negative impact on regeneration rate and induced negative graft regeneration. Although the result also showed us that increased spleen size is linearly correlated to portal flow and increased portal flow favors regeneration, this advantage is countered by the increased GRWR because a large graft can lead to a diminished blood supply of the liver graft. To prevent large-for-size situations, some centers choose to reduce the graft into a monosegmental or “hyperreduced” graft. This may allow for an easier abdominal wall closure and avoid an insufficient blood supply to the graft. A 2005 published meta-analysis showed an advantage in favor of the use of monosegmental grafts among pediatric patients, where complication rates were comparable between mono-segmental and other grafts [9]. On the other hand, Schulze et al claim that the use of mono-segmental grafts is unnecessary if the transplant of left lateral grafts is performed by an experienced multidisciplinary team. The ventroedorsal diameter of the graft appears to be more relevant to potential graft necrosis than the actual graft size [10]. Our result demonstrated higher PV complications (early PV occlusion occurred in 6 cases and PV stenosis later after the transplantation in 5 case) in patients whose GRWR was >3.4, although the difference was not statistically significant (P ¼ .105). In general, small patients with BA demonstrate a greater risk at LT because of infection or vascular complications [11,12]. According to our analysis, BA patients who were younger than 15 months old have less graft regeneration and tend to have a negative regeneration rate. Mizuta et al described a poor post-transplantation survival rate in small patients [13]. They concluded that LDLT should be considered when patient body weight is 8 to 20 kg, corresponding to age 2 to 4 years.
769
In conclusion, factors that influence the graft regeneration rate of pediatric patients are different from adults. Portal hemodynamics are important but the graft size is more essential. Large size grafts can compromise the total portal flow and, when the GRWR is >3.4, there are significant negative effects on graft regeneration and increased PV complications, and these may induce graft regression. REFERENCES [1] Migliazza L, López SantamarÍa M, Murcia J, et al. Long-term survival expectancy after liver transplantation in children. J Pediatr Surg 2000;35:5. [2] Cheng YF, Huang TL, Chen TY, et al. Liver graft regeneration in right lobe adult living donor liver transplantation. Am J Transplant 2009;9:1382. [3] Breiman RS, Beck JW, Korobkin M, et al. Volume determinations using computed tomography. AJR Am J Roentgenol 1982;138:329. [4] Colombani PM, Cigarroa FG, Schwarz K, et al. Liver transplantation in infants younger than 1 year of age. Ann Surg 1996;223: 658. [5] Cacciarelli TV, Esquivel CO, Moore DH, et al. Factors affecting survival after orthotopic liver transplantation in infants. Transplantation 1997;64:242. [6] Saing H, Fan ST, Chan KL, et al. Liver transplantation in infants. J Pediatr Surg 1999;34:172. [7] Iglesias J, López JA, Ortega J, et al. Liver transplantation in infants weighing under 7 kilograms: management and out-come of PICU. Pediatr Transplant 2004;8:228. [8] Kiuchi T, Kasahara M, Uryuhara K, et al. Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation 1999;67:321. [9] Enne M, Pacheo-Moreira L, Balbi E, et al. Liver transplantation with monosegments. Technical aspects and outcome: a meta-analysis. Liver Transplant 2005;11:564. [10] Schulze M, Dresske B, Deinzer J, et al. Implications for the usage of the left lateral liver graft for infants
