HPB
http://dx.doi.org/10.1016/j.hpb.2015.08.006
ORIGINAL ARTICLE
Serial volumetric assessment of large for size liver grafts after whole cadaveric liver transplant in adults: do large liver grafts shrink in size? Mohamed Bekheit1,2, Muthukumarassamy Rajakannu1,2, Petru Bucur1,2, Rene Adam1,3,4, Antonio SaCunha1,2,3, Denis Castaing1,2,3, Daniel Cherqui1,2,3 & Eric Vibert1,2,3 1
Centre Hépato-Biliaire, Paul Brousse Hospital, AP-HP, 2INSERM, Unit 1193, 3University of Paris-Sud, and 4INSERM, Unit UMRS776, Villejuif, F-94800, France
Abstract Background: After whole graft orthotopic liver transplantation (OLT), adaptation of the large grafts’ volume to recipient weight is widely accepted despite the paucity of evidence on this subject. Methods: Thirty nine patients with GRWR > 2.5% were included in this study and subsequently divided into two groups with 3 GRWR > 3%. Patients had CT scans at three predetermined time points after OLT used for measuring the liver volume. The objective of this study is to evaluate the volumetric changes of whole large liver grafts after adult OLT. Results: At LT, the mean graft recipient body weight ratio (GRWR) was 3.1 ± 0.4%. The mean liver weight was 1881 ± 68 g at LT, 2014 ± 99 ml at one week, 1725 ± 126 ml at 3 months, and 1632 ± 117 (ml) at >6 months. There is an initial increase at 1 week after LT and a subsequent decrease of liver volume on later measurements. None of the late volume measurements were significantly different from the initial graft volume at liver transplant in pair wise comparisons ANOVA repeated measures (p > 0.05). Similarly, the mean GRWR did not change significantly between the initial calculation at transplantation date and the subsequent measurements during the different study time points (F = 0.04, p = 0.96) with a mean of 3.1% (95% CI = 2.2–4.2). AUC ROC discriminated a cutoff of 3% for the initial GRWR above which grafts tend to decrease in size over time (c statistics = 0.74, p = 0.036). In a Clustered ANOVA repeated measures, there was no significant difference in the changes of liver volume between both groups. However, patients with GRWR > 3 showed a trend towards a latent reduction in volume over the tracing period. There was a tendency, but none significant; towards a higher bilirubin, AST, ALT levels over the first postoperative days in recipients with GRWR > 3. Conclusion: Large grafts do not significantly decrease in size. Nonetheless, grafts weighing >3% of the GRWR show a different trend towards decrease in size over time. Received 20 August 2015; accepted 20 August 2015
Correspondence Eric Vibert, Hôpital Paul Brousse, Centre Hépato-Biliaire, 12 avenue Paul-Vaillant-Couturier, 94804 Villejuif, France. Tel: +33 145593000. Fax: +33 145593857. E-mail: [email protected]
Introduction Graft weight recipient weight relationship (GRWR) has been a subject of extensive research in liver transplant. The largest sector of research focused on the regeneration occurring after partial liver transplant. Regeneration of transplanted small for size partial liver to match the metabolic requirement of the recipient is well documented in the literature.1 In western countries, whole liver graft transplant is more common than partial liver transplant.2 The continuous expansion of the donation criteria due to
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organ shortage;3 made the size of the graft one of the variables that frequently mismatched. Recipients of whole liver grafts are commonly debilitated and wasted4 that makes large for size transplantation a more common clinical scenario than small for size one. Both small and large for size grafts are source of complications in the postoperative course. Grafts smaller than 0.8% GRWR are frequently associated with significant dysfunction.5 Large for size definition is not uniform in the literature6,7 We previously reported that using large grafts (>2.5% GRWR)
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did not impair either graft or patient survival but increased postoperative respiratory morbidity,7 nonetheless; we did not assess the volumetric evolution of these liver grafts. Human studies, assessing the changes in liver volume after transplantation of large for size orthotopic whole liver grafts are scarce. However, the notion of adaptation of the grafts to body size is widely accepted. The aim of this study is to investigate the validity of this hypothesis and whether the whole large liver grafts adapt to smaller recipients’ weight. Patients and methods Study population We studied the volume evolution of full liver grafts after orthotopic transplantation in patients who received grafts with more than 2.5% GRWR.7 The study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. Out of 602 OLT performed between January 2008 and May 2013 at the Centre Hepato-Biliaire (Hospital Paul Brousse, Assistance Publique des Hôpitaux de Paris [APHP], Université Paris 11, Villejuif, France); 39 patients (6.5% of the whole cohort) received full liver grafts that weighed more than the chosen threshold (GRWR > 2.5%) for their body weight at the date of LT. GRWR was calculated from the following equation (graft weight or volume in gram or ml/recipient weight in kg × 10).The included patients had consecutive abdominal CT scans that matched the study protocol, hence their data were analyzed. Formal consent is not a requirement for this type of study. For the sake of tracing the changes in liver volume, CT scans were searched for at three different intervals. The routine 7th day abdominal CT scan and at least one later CT were required for inclusion. Later CT scans were identified as being performed at an interval of 2–3 months (first interval) and at more than 6 months (late interval). While 36 patients had an available CT scan at two different time points, 16 patients had their CT scans available from the whole 3 predefined time points of the study. Every included patient had a record on the transplanted graft weight. Demographic data Donors’ graft weight was measured in grams by an automatic weighing machine after the rapid procurement technique developed by Starzl et al.8; and IGL-1® preservative solution (Institute George Lopez-1, Lyon, France) was used in the majority of cases. Analyzed data Measurement of grafts’ volume was performed in the hepatic venous phase of the patients’ CT scans, except in two cases in group-1 in their 7th day scans where dye has not been injected; using Myrian XP-Liver 1.14.1 software (Intrasense, Montpellier, France). Analysis of volume was automated in all cases except where the manual correction was necessary; due to inaccuracy of
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the automated region of interest (ROI) selection, as well as in the two cases with non-contrast CT scans. The automated volume measurement of the liver excluded the majority of large vessels. Biological and clinical outcomes of this cohort were previously reported.7 Statistical analysis All data were tabulated and the analysis was conducted via MedCalc for Windows, version 14.8.1 (MedCalc Software, Ostend, Belgium). Base line descriptive analysis of the data was conducted. Repeated measures analysis was performed to evaluate the volume changes (ANOVA). The repeated measures analysis was performed on several iterations involved inclusion and subsequent consecutive exclusion of time point measurement to avoid underestimation of the change in liver volume. To ensure the robustness of the analysis; whenever the assumption of sphericity of the general linear model is violated, we use the corrected degree of freedom test value of GreenhouseGeisser to interpret the test significance. We used a post-hoc Bonferroni’s correction for the post-hoc pair wise comparison. The observed trend was then analyzed using multiple regression analysis with the mean difference in liver volume between the transplant time and the late interval measurement as an outcome and the initial GRWR, portal ischemia time and transaminases as predictors. A ROC curve analysis was subsequently conducted to define a discriminative level to the GRWR at transplant associated with a late reduction of volume. The factor variable was defined in categories based on whether the difference between the late interval volume is lower (category 1) or greater (category 0) than the initial graft weight at transplant. A time series analysis was then conducted to estimate the time to reach the minimum volume in the two subgroups. Paired and student t-tests were used accordingly to describe the significance of the differences between quantitative variables. Chi-square tests were used when appropriate to describe the difference in qualitative data. Quantitative data summary was reported in means ± standard error of the mean and/or 95% CI. Numeric output data were approximated to the nearest integer value.
Results The included group of patients (n = 36) had a mean age of 50 ± 13 year-old. Their mean height and weight just before the intervention were 167 ± 9 cm and 64 ± 11 kg respectively. Males constituted 59% of the study population, while females constituted 41%. HCC was the most frequent indication for OLT among this group (30%) followed by re-transplantation (20.5%). End stage liver disease (15.4%), whether alcoholic or viral; acute fulminant hepatitis (10.3%), polycystic liver disease (5.1%) and metabolic and miscellaneous disorders composed the rest of indications in this series. Their 5% trimmed mean MELD score was 18.5 (range 5–43). The mean portal ischemia time was 525 ± 18 min, while the arterial ischemia time was 685 ± 44 min.
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The 5% trimmed mean weight of their original liver was 1302 g (625–3535). They received grafts with a mean weight of 1926 ± 41 ml according to the estimate of density [1 g is equivalent to I milliliter]9 and their mean graft body weight ratio (GRWR) was 3.1 ± 0.4%, at transplant time. The mean liver volume measured in the routine first postoperative CT scan (n = 38) was 1992 ± 70 ml. On the first interval CT scan (between 2 and 6 months); the mean liver volume (n = 26) was 1724 ± 87 ml. On the late interval CT scan (n = 25); the mean liver volume was 1586 ± 88 ml. Changes in the liver volume were estimated to be significant in the repeated measures multivariate model (Iteration 1; including the 4 time points) (F = 7.8, p = 3. A mixed repeated measures ANOVA model was then reproduced using the GRWR of 3% as a between subjects factor. There was no significant difference in the change in liver volume based on the group membership (F = 0.27, p = 0.6) using the 4 time points in the model. However, there was a visual trend (Fig. 3) towards a decrease in the liver volume when the GRWR is >3 after the initial increase at one week. Nonetheless, the mean GRWR did not change significantly between the initial calculation at transplantation date and the subsequent measurements during the different study time points (F = 0.04, p = 0.96) with a mean of 3.1% (95% CI = 2.2–4.2). The time to reach the minimum volume was 87 (95% CI = 50–123) days in recipients with GRWR at transplant lower
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Figure 4 Time series analysis presented in multiple line graph showing
the trend of volume evolution based on the GRWR at transplant. X axis defines the time in relation to the transplant and Y axis defines the estimated liver volume at different time points after transplant for each Figure 2 ROC for the GRWR at transplant as a discriminate variable
patient in each subgroup
for the mean difference between the liver weight at transplant and its volume after more than 6 months. The AUC was 0.74, p = 0.036
than 3% and 138 (95% CI = 106–170) days in recipients with GRWR higher than 3% (Fig. 4) (t = 2.14, p = 0.04). Patients’ weight at corresponding time points was recorded and analyzed (Fig. 5). The mean preoperative weight was 63.7 ± 11 kg, 57.9 ± 12 kg at the 7th day, 56.4 ± 11 kg between 2 and 3 months and 58.3 ± 12.6 kg at more than 6 months. Both groups showed weight reduction following transplantation, and a later weight regain.
There was no significant difference in the pattern of change of the ALT and AST over the earliest 10 days after transplant between recipients with GRWR higher or lower than 3 (F = 0.42, p = 0.5 and F = 1.46, p = 0.24 respectively). Nonetheless, their values tended to be higher in the group with GRWR > 3. Similarly, the postoperative bilirubin and creatinine levels tended to be at higher levels in recipients with GRWR > 3. Unlike the INR levels which was equal in both groups. The consecutive transaminases and bilirubin levels were summarized in graph (Fig. 6). The portal ischemia time was 550 ± 28 min in recipients with GRWR 3 versus 498 ± 23 min in recipients with GRWR > 3, however this was not significant (t = −1.4, p = 0.16). There was a
Figure 3 Clustered multiple variable line graph showing the evolution
of liver volume after liver transplant based on the subgroup category. X axis defines the time in relation to the transplant and Y axis defines the mean and 95% CI for the liver volume at the corresponding time
Figure 5 Line graph summarizing the recipients’ weight changes over
points for each subgroup
the time period of the study in both groups (GRWR < 3 and >3)
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Figure 6 Summary of the biological data after liver transplantation in multiple clustered multiple line graphs; X axis represents the time in relation
to transplant and Y axis represents the mean and 95% CI; showing: a) the relatively higher ALT levels at day 2,3 in recipients with GRWR > 3, b) the AST levels follows the same pattern as the ALT, c) the relatively higher direct bilirubin levels in recipients with GRWR > 3 over the first 10 day after transplant, d) the INR levels follow a symmetric pattern in both groups, and e) showing a slight increase in creatinine levels in recipients with GRWR > 3 compared to the minimal reduction in its level in recipients with GRWR < 3
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non-significant difference between groups as regards the preoperative MELD scores (17 ± 2.9 versus 21 ± 2.6 respectively and t = 1, p = 0.29).
Discussion This study is the largest reported series on serial volume assessment of whole large liver grafts with relatively long term follow up. Our results suggest that large for size whole grafts do not adapt to recipient size, yet grafts weighing more than 3% of the recipients’ weight might show tendency to decrease in size. This trend takes place over several months post transplantation. The current contention that the transplanted whole liver grafts’ volume adapt to the recipients’ weight is based on few studies that included very little number of subjects without long enough follow up to ascertain the behavior of the initially observed changes.10,11 Interestingly; both of these studies examined the small for size grafts not the large grafts. Van Theil et al., reported that intact small for size livers do enlarge in size to adapt for patients size but they reported only two cases.11 The follow up of their patients was 10 days in one case and 12 days in the second cases in which a plateau was observed after the 10th day. With this short follow up, it could not be possible to exclude the possible influence of early graft edema on the measured volume, particularly since both grafts received relatively high portal flow since it is reported that a suboptimal GRWR is associated with increased portal flow12 which might lead to a more pronounced augmentation of the early recorded volume. Similarly, Kam et al., reported an increase of the liver volume to adapt to the recipient size.10 In that study, the follow up period was up to 30 days in only two of the seven studied dogs, which could be criticized as the previous study. Evolution of large graft’s volume was not, to our knowledge; reported before. In our study, despite that the grafts are large for size; we observed an initial increase in the graft volume during the 7th day, similar to what was observed in studies on small for size livers. This initial increase could be attributed to a possible tissue edema as a result of ischemia reperfusion injury;13 as well as to restoration of the blood flow which adds to the measured volume. An estimated 2–13% difference is reported between the CT volume and the explanted liver weight is attributed the loss of intrahepatic blood volume loss after explantation.14 The intrahepatic blood volume could be subdivided into two compartments; one is the intra-sinusoidal representing around 60% of the intrahepatic blood volume and the other is the blood contained in the large hepatic vessels representing around 40% of the intrahepatic blood volume.15 During graft weighing, in our study; sinusoids were filled with preservative solution. Therefore, one might argue that the potential difference between the direct graft weight and its CT measured volume could be insignificant and that assuming that 1 g liver equals 1 ml liver volume is acceptable, which is particularly valid since the automated and
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semi-automated ROI detector excludes large vessels from the volume calculation. Despite that GRWR did not change over time, perhaps grafts with initial GRWR > 3 are more close to the definition of large for size compared to grafts with initial GRWR between 2.5 and 3% since the trend to decrease in size is only manifested in the former group. In adult transplantation, only minor complications were reported after transplant when GRWR is >3,6 and the main consequence of a large-for-size graft is pulmonary complication as was demonstrated by Levesque et al., in 2013.7 On the other hand, significant complications were reported to occur only after transplantation of grafts larger than 4% of body weight in one of the largest pediatric series ever reported.16 In our study, the biological impact of the larger grafts is trivial implying the possible safety of transplanting large liver grafts within the range of 3–4% of the recipient’s weight. As a consequence; the donor recipient matching criteria might expand to accommodate GRWR between 3 and 4%. In our study the ischemia time was slightly lower in the larger grafts group, which does not explain why the AST, ALT were relatively higher in the larger grafts. Yet this might be explained by the vulnerability of the large grafts for more profound ischemia reperfusion injury as demonstrated by Moreira et al.17 Despite that these differences were not significant, it highlights that there could be more cellular damage associated with larger grafts,18 which could be involved in the mechanistic process of volume reduction. The slightly higher bilirubin levels in the group with larger GRWR, along with the difference in the hepatic transaminases might be attributed to the higher preoperative MELD score in this group,19 or to the tendency that those patients receive nonstandard grafts.20 The higher creatinine levels could be a result of increased intra-abdominal pressure due to larger grafts.21 The majority of our recipients had hyper dynamic portal circulation due to cirrhosis.22 Perhaps this contributed to the latent decrease in size during the course of the follow up. Henderson reported that patients with portal hyper dynamic circulation do not have their circulation normalized early after transplantation.22 In spite of the effort done to reduce bias, our study is limited by the small number of included patients, which could introduce type II error to our conclusions. Therefore, further studies would be recommended to further explore this interesting issue.
Conclusion Large grafts do not significantly decrease in size. Nonetheless, grafts weighing >3% of the GRWR show a different trend towards decrease in size over time. Authors’ contribution Mohamed Bekheit wrote the manuscript draft and performed the volume measurements and data analysis. Muthukumarassamy Rajakannu participated in data collection. Petru Bucur participated in study design, and
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revision of the draft. Rene Adam, Antonio SaCunha, Denis Castaing and
11. Van Thiel DH, Gavaler JS, Kam I, Francavilla A, Polimeno L, Schade RR
Daniel Cherqui critically revised the manuscript. Eric Vibert designed the
et al. (1987) Rapid growth of an intact human liver transplanted into a
study, participated in the manuscript writing and critically revised the
recipient larger than the donor. Gastroenterology 93:1414–1419. 12. Troisi R, Cammu G, Militerno G, De Baerdemaeker L, Decruyenaere J,
manuscript.
Hoste E et al. (2003) Modulation of portal graft inflow: a necessity in Conflict of interest None declared.
adult living-donor liver transplantation? Ann Surg 237:429–436. 13. Klune JR, Tsung A. (2010) Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent advancements. Surg
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Stockmann M. (2010) Liver volume measurement: reason of the differ-
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783–787. 2. Adam R, McMaster P, O’Grady JG, Castaing D, Klempnauer JL, Jamieson N et al. (2003) Evolution of liver transplantation in Europe: report of the European liver transplant registry. Liver Transplant 9:
15. Greenway CV, Stark RD. (1971) Hepatic vascular bed. Physiol Rev 51: 23–65. 16. Kasahara M, Sakamoto S, Umeshita K, Uemoto S. (2014) Effect of graft size matching on pediatric living-donor liver transplantation in Japan.
1231–1243. 3. Renz JF, Kin C, Kinkhabwala M, Jan D, Varadarajan R, Goldstein M et al. (2005) Utilization of extended donor criteria liver allografts maximizes donor use and patient access to liver transplantation. Ann Surg 242:556.
Exp Clin Transplant Off J Middle East Soc Organ Transplant 12(Suppl. 1):1–4. 17. Rangel Moreira DdA, Aoun Tannuri AC, Belon AR, Mendonça
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18. Leal AJ, Tannuri AC, Belon AR, Guimaraes RR, Coelho MC, Oliveira Goncalves J et al. (2013) A simplified experimental model of large-for-
Opin Crit Care 11:150–155. 6. Kiuchi T, Kasahara M, Uryuhara K, Inomata Y, Uemoto S, Asonuma K et al. (1999) Impact of graft size mismatching on graft prognosis in liver transplantation from living donors. Transplantation 67:321–327. 7. Levesque E, Duclos J, Ciacio O, Adam R, Castaing D, Vibert E. (2013) Influence of larger graft weight to recipient weight on the post-liver
size liver transplantation in pigs. Clin (Sao Paulo) 68:1152–1156. 19. Chokshi A, Cheema FH, Schaefle KJ, Jiang J, Collado E, Shahzad K et al. (2012) Hepatic dysfunction and survival after orthotopic heart transplantation: application of the MELD scoring system for outcome prediction. J Heart Lung Transplant 31:591–600. 20. Avolio AW, Agnes S, Gasbarrini A, Barbarino R, Nure E, Siciliano M et al.
transplantation course. Clin Transpl 27:239–247. 8. Starzl TE, Miller C, Broznick B, Makowka L. (1987) An improved tech-
(2006) Allocation of nonstandard livers to transplant candidates with
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21. Shu M, Peng C, Chen H, Shen B, Zhou G, Shen C et al. (2007) Intra-
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233:221–226. 10. Kam I, Lynch S, Svanas G, Todo S, Polimeno L, Francavilla A et al.
22. Henderson JM, Mackay GJ, Kutner MH, Noe B. (1993) Volumetric and
(1987) Evidence that host size determines liver size: studies in dogs
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HPB 2016, 18, 200–206
© 2015 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
http://dx.doi.org/10.1016/j.hpb.2015.08.006
ORIGINAL ARTICLE
Serial volumetric assessment of large for size liver grafts after whole cadaveric liver transplant in adults: do large liver grafts shrink in size? Mohamed Bekheit1,2, Muthukumarassamy Rajakannu1,2, Petru Bucur1,2, Rene Adam1,3,4, Antonio SaCunha1,2,3, Denis Castaing1,2,3, Daniel Cherqui1,2,3 & Eric Vibert1,2,3 1
Centre Hépato-Biliaire, Paul Brousse Hospital, AP-HP, 2INSERM, Unit 1193, 3University of Paris-Sud, and 4INSERM, Unit UMRS776, Villejuif, F-94800, France
Abstract Background: After whole graft orthotopic liver transplantation (OLT), adaptation of the large grafts’ volume to recipient weight is widely accepted despite the paucity of evidence on this subject. Methods: Thirty nine patients with GRWR > 2.5% were included in this study and subsequently divided into two groups with 3 GRWR > 3%. Patients had CT scans at three predetermined time points after OLT used for measuring the liver volume. The objective of this study is to evaluate the volumetric changes of whole large liver grafts after adult OLT. Results: At LT, the mean graft recipient body weight ratio (GRWR) was 3.1 ± 0.4%. The mean liver weight was 1881 ± 68 g at LT, 2014 ± 99 ml at one week, 1725 ± 126 ml at 3 months, and 1632 ± 117 (ml) at >6 months. There is an initial increase at 1 week after LT and a subsequent decrease of liver volume on later measurements. None of the late volume measurements were significantly different from the initial graft volume at liver transplant in pair wise comparisons ANOVA repeated measures (p > 0.05). Similarly, the mean GRWR did not change significantly between the initial calculation at transplantation date and the subsequent measurements during the different study time points (F = 0.04, p = 0.96) with a mean of 3.1% (95% CI = 2.2–4.2). AUC ROC discriminated a cutoff of 3% for the initial GRWR above which grafts tend to decrease in size over time (c statistics = 0.74, p = 0.036). In a Clustered ANOVA repeated measures, there was no significant difference in the changes of liver volume between both groups. However, patients with GRWR > 3 showed a trend towards a latent reduction in volume over the tracing period. There was a tendency, but none significant; towards a higher bilirubin, AST, ALT levels over the first postoperative days in recipients with GRWR > 3. Conclusion: Large grafts do not significantly decrease in size. Nonetheless, grafts weighing >3% of the GRWR show a different trend towards decrease in size over time. Received 20 August 2015; accepted 20 August 2015
Correspondence Eric Vibert, Hôpital Paul Brousse, Centre Hépato-Biliaire, 12 avenue Paul-Vaillant-Couturier, 94804 Villejuif, France. Tel: +33 145593000. Fax: +33 145593857. E-mail: [email protected]
Introduction Graft weight recipient weight relationship (GRWR) has been a subject of extensive research in liver transplant. The largest sector of research focused on the regeneration occurring after partial liver transplant. Regeneration of transplanted small for size partial liver to match the metabolic requirement of the recipient is well documented in the literature.1 In western countries, whole liver graft transplant is more common than partial liver transplant.2 The continuous expansion of the donation criteria due to
HPB 2016, 18, 200–206
organ shortage;3 made the size of the graft one of the variables that frequently mismatched. Recipients of whole liver grafts are commonly debilitated and wasted4 that makes large for size transplantation a more common clinical scenario than small for size one. Both small and large for size grafts are source of complications in the postoperative course. Grafts smaller than 0.8% GRWR are frequently associated with significant dysfunction.5 Large for size definition is not uniform in the literature6,7 We previously reported that using large grafts (>2.5% GRWR)
© 2015 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
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did not impair either graft or patient survival but increased postoperative respiratory morbidity,7 nonetheless; we did not assess the volumetric evolution of these liver grafts. Human studies, assessing the changes in liver volume after transplantation of large for size orthotopic whole liver grafts are scarce. However, the notion of adaptation of the grafts to body size is widely accepted. The aim of this study is to investigate the validity of this hypothesis and whether the whole large liver grafts adapt to smaller recipients’ weight. Patients and methods Study population We studied the volume evolution of full liver grafts after orthotopic transplantation in patients who received grafts with more than 2.5% GRWR.7 The study was conducted in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. Out of 602 OLT performed between January 2008 and May 2013 at the Centre Hepato-Biliaire (Hospital Paul Brousse, Assistance Publique des Hôpitaux de Paris [APHP], Université Paris 11, Villejuif, France); 39 patients (6.5% of the whole cohort) received full liver grafts that weighed more than the chosen threshold (GRWR > 2.5%) for their body weight at the date of LT. GRWR was calculated from the following equation (graft weight or volume in gram or ml/recipient weight in kg × 10).The included patients had consecutive abdominal CT scans that matched the study protocol, hence their data were analyzed. Formal consent is not a requirement for this type of study. For the sake of tracing the changes in liver volume, CT scans were searched for at three different intervals. The routine 7th day abdominal CT scan and at least one later CT were required for inclusion. Later CT scans were identified as being performed at an interval of 2–3 months (first interval) and at more than 6 months (late interval). While 36 patients had an available CT scan at two different time points, 16 patients had their CT scans available from the whole 3 predefined time points of the study. Every included patient had a record on the transplanted graft weight. Demographic data Donors’ graft weight was measured in grams by an automatic weighing machine after the rapid procurement technique developed by Starzl et al.8; and IGL-1® preservative solution (Institute George Lopez-1, Lyon, France) was used in the majority of cases. Analyzed data Measurement of grafts’ volume was performed in the hepatic venous phase of the patients’ CT scans, except in two cases in group-1 in their 7th day scans where dye has not been injected; using Myrian XP-Liver 1.14.1 software (Intrasense, Montpellier, France). Analysis of volume was automated in all cases except where the manual correction was necessary; due to inaccuracy of
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the automated region of interest (ROI) selection, as well as in the two cases with non-contrast CT scans. The automated volume measurement of the liver excluded the majority of large vessels. Biological and clinical outcomes of this cohort were previously reported.7 Statistical analysis All data were tabulated and the analysis was conducted via MedCalc for Windows, version 14.8.1 (MedCalc Software, Ostend, Belgium). Base line descriptive analysis of the data was conducted. Repeated measures analysis was performed to evaluate the volume changes (ANOVA). The repeated measures analysis was performed on several iterations involved inclusion and subsequent consecutive exclusion of time point measurement to avoid underestimation of the change in liver volume. To ensure the robustness of the analysis; whenever the assumption of sphericity of the general linear model is violated, we use the corrected degree of freedom test value of GreenhouseGeisser to interpret the test significance. We used a post-hoc Bonferroni’s correction for the post-hoc pair wise comparison. The observed trend was then analyzed using multiple regression analysis with the mean difference in liver volume between the transplant time and the late interval measurement as an outcome and the initial GRWR, portal ischemia time and transaminases as predictors. A ROC curve analysis was subsequently conducted to define a discriminative level to the GRWR at transplant associated with a late reduction of volume. The factor variable was defined in categories based on whether the difference between the late interval volume is lower (category 1) or greater (category 0) than the initial graft weight at transplant. A time series analysis was then conducted to estimate the time to reach the minimum volume in the two subgroups. Paired and student t-tests were used accordingly to describe the significance of the differences between quantitative variables. Chi-square tests were used when appropriate to describe the difference in qualitative data. Quantitative data summary was reported in means ± standard error of the mean and/or 95% CI. Numeric output data were approximated to the nearest integer value.
Results The included group of patients (n = 36) had a mean age of 50 ± 13 year-old. Their mean height and weight just before the intervention were 167 ± 9 cm and 64 ± 11 kg respectively. Males constituted 59% of the study population, while females constituted 41%. HCC was the most frequent indication for OLT among this group (30%) followed by re-transplantation (20.5%). End stage liver disease (15.4%), whether alcoholic or viral; acute fulminant hepatitis (10.3%), polycystic liver disease (5.1%) and metabolic and miscellaneous disorders composed the rest of indications in this series. Their 5% trimmed mean MELD score was 18.5 (range 5–43). The mean portal ischemia time was 525 ± 18 min, while the arterial ischemia time was 685 ± 44 min.
© 2015 Published by Elsevier Ltd on behalf of International Hepato-Pancreato-Biliary Association Inc.
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The 5% trimmed mean weight of their original liver was 1302 g (625–3535). They received grafts with a mean weight of 1926 ± 41 ml according to the estimate of density [1 g is equivalent to I milliliter]9 and their mean graft body weight ratio (GRWR) was 3.1 ± 0.4%, at transplant time. The mean liver volume measured in the routine first postoperative CT scan (n = 38) was 1992 ± 70 ml. On the first interval CT scan (between 2 and 6 months); the mean liver volume (n = 26) was 1724 ± 87 ml. On the late interval CT scan (n = 25); the mean liver volume was 1586 ± 88 ml. Changes in the liver volume were estimated to be significant in the repeated measures multivariate model (Iteration 1; including the 4 time points) (F = 7.8, p = 3. A mixed repeated measures ANOVA model was then reproduced using the GRWR of 3% as a between subjects factor. There was no significant difference in the change in liver volume based on the group membership (F = 0.27, p = 0.6) using the 4 time points in the model. However, there was a visual trend (Fig. 3) towards a decrease in the liver volume when the GRWR is >3 after the initial increase at one week. Nonetheless, the mean GRWR did not change significantly between the initial calculation at transplantation date and the subsequent measurements during the different study time points (F = 0.04, p = 0.96) with a mean of 3.1% (95% CI = 2.2–4.2). The time to reach the minimum volume was 87 (95% CI = 50–123) days in recipients with GRWR at transplant lower
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Figure 4 Time series analysis presented in multiple line graph showing
the trend of volume evolution based on the GRWR at transplant. X axis defines the time in relation to the transplant and Y axis defines the estimated liver volume at different time points after transplant for each Figure 2 ROC for the GRWR at transplant as a discriminate variable
patient in each subgroup
for the mean difference between the liver weight at transplant and its volume after more than 6 months. The AUC was 0.74, p = 0.036
than 3% and 138 (95% CI = 106–170) days in recipients with GRWR higher than 3% (Fig. 4) (t = 2.14, p = 0.04). Patients’ weight at corresponding time points was recorded and analyzed (Fig. 5). The mean preoperative weight was 63.7 ± 11 kg, 57.9 ± 12 kg at the 7th day, 56.4 ± 11 kg between 2 and 3 months and 58.3 ± 12.6 kg at more than 6 months. Both groups showed weight reduction following transplantation, and a later weight regain.
There was no significant difference in the pattern of change of the ALT and AST over the earliest 10 days after transplant between recipients with GRWR higher or lower than 3 (F = 0.42, p = 0.5 and F = 1.46, p = 0.24 respectively). Nonetheless, their values tended to be higher in the group with GRWR > 3. Similarly, the postoperative bilirubin and creatinine levels tended to be at higher levels in recipients with GRWR > 3. Unlike the INR levels which was equal in both groups. The consecutive transaminases and bilirubin levels were summarized in graph (Fig. 6). The portal ischemia time was 550 ± 28 min in recipients with GRWR 3 versus 498 ± 23 min in recipients with GRWR > 3, however this was not significant (t = −1.4, p = 0.16). There was a
Figure 3 Clustered multiple variable line graph showing the evolution
of liver volume after liver transplant based on the subgroup category. X axis defines the time in relation to the transplant and Y axis defines the mean and 95% CI for the liver volume at the corresponding time
Figure 5 Line graph summarizing the recipients’ weight changes over
points for each subgroup
the time period of the study in both groups (GRWR < 3 and >3)
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Figure 6 Summary of the biological data after liver transplantation in multiple clustered multiple line graphs; X axis represents the time in relation
to transplant and Y axis represents the mean and 95% CI; showing: a) the relatively higher ALT levels at day 2,3 in recipients with GRWR > 3, b) the AST levels follows the same pattern as the ALT, c) the relatively higher direct bilirubin levels in recipients with GRWR > 3 over the first 10 day after transplant, d) the INR levels follow a symmetric pattern in both groups, and e) showing a slight increase in creatinine levels in recipients with GRWR > 3 compared to the minimal reduction in its level in recipients with GRWR < 3
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non-significant difference between groups as regards the preoperative MELD scores (17 ± 2.9 versus 21 ± 2.6 respectively and t = 1, p = 0.29).
Discussion This study is the largest reported series on serial volume assessment of whole large liver grafts with relatively long term follow up. Our results suggest that large for size whole grafts do not adapt to recipient size, yet grafts weighing more than 3% of the recipients’ weight might show tendency to decrease in size. This trend takes place over several months post transplantation. The current contention that the transplanted whole liver grafts’ volume adapt to the recipients’ weight is based on few studies that included very little number of subjects without long enough follow up to ascertain the behavior of the initially observed changes.10,11 Interestingly; both of these studies examined the small for size grafts not the large grafts. Van Theil et al., reported that intact small for size livers do enlarge in size to adapt for patients size but they reported only two cases.11 The follow up of their patients was 10 days in one case and 12 days in the second cases in which a plateau was observed after the 10th day. With this short follow up, it could not be possible to exclude the possible influence of early graft edema on the measured volume, particularly since both grafts received relatively high portal flow since it is reported that a suboptimal GRWR is associated with increased portal flow12 which might lead to a more pronounced augmentation of the early recorded volume. Similarly, Kam et al., reported an increase of the liver volume to adapt to the recipient size.10 In that study, the follow up period was up to 30 days in only two of the seven studied dogs, which could be criticized as the previous study. Evolution of large graft’s volume was not, to our knowledge; reported before. In our study, despite that the grafts are large for size; we observed an initial increase in the graft volume during the 7th day, similar to what was observed in studies on small for size livers. This initial increase could be attributed to a possible tissue edema as a result of ischemia reperfusion injury;13 as well as to restoration of the blood flow which adds to the measured volume. An estimated 2–13% difference is reported between the CT volume and the explanted liver weight is attributed the loss of intrahepatic blood volume loss after explantation.14 The intrahepatic blood volume could be subdivided into two compartments; one is the intra-sinusoidal representing around 60% of the intrahepatic blood volume and the other is the blood contained in the large hepatic vessels representing around 40% of the intrahepatic blood volume.15 During graft weighing, in our study; sinusoids were filled with preservative solution. Therefore, one might argue that the potential difference between the direct graft weight and its CT measured volume could be insignificant and that assuming that 1 g liver equals 1 ml liver volume is acceptable, which is particularly valid since the automated and
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semi-automated ROI detector excludes large vessels from the volume calculation. Despite that GRWR did not change over time, perhaps grafts with initial GRWR > 3 are more close to the definition of large for size compared to grafts with initial GRWR between 2.5 and 3% since the trend to decrease in size is only manifested in the former group. In adult transplantation, only minor complications were reported after transplant when GRWR is >3,6 and the main consequence of a large-for-size graft is pulmonary complication as was demonstrated by Levesque et al., in 2013.7 On the other hand, significant complications were reported to occur only after transplantation of grafts larger than 4% of body weight in one of the largest pediatric series ever reported.16 In our study, the biological impact of the larger grafts is trivial implying the possible safety of transplanting large liver grafts within the range of 3–4% of the recipient’s weight. As a consequence; the donor recipient matching criteria might expand to accommodate GRWR between 3 and 4%. In our study the ischemia time was slightly lower in the larger grafts group, which does not explain why the AST, ALT were relatively higher in the larger grafts. Yet this might be explained by the vulnerability of the large grafts for more profound ischemia reperfusion injury as demonstrated by Moreira et al.17 Despite that these differences were not significant, it highlights that there could be more cellular damage associated with larger grafts,18 which could be involved in the mechanistic process of volume reduction. The slightly higher bilirubin levels in the group with larger GRWR, along with the difference in the hepatic transaminases might be attributed to the higher preoperative MELD score in this group,19 or to the tendency that those patients receive nonstandard grafts.20 The higher creatinine levels could be a result of increased intra-abdominal pressure due to larger grafts.21 The majority of our recipients had hyper dynamic portal circulation due to cirrhosis.22 Perhaps this contributed to the latent decrease in size during the course of the follow up. Henderson reported that patients with portal hyper dynamic circulation do not have their circulation normalized early after transplantation.22 In spite of the effort done to reduce bias, our study is limited by the small number of included patients, which could introduce type II error to our conclusions. Therefore, further studies would be recommended to further explore this interesting issue.
Conclusion Large grafts do not significantly decrease in size. Nonetheless, grafts weighing >3% of the GRWR show a different trend towards decrease in size over time. Authors’ contribution Mohamed Bekheit wrote the manuscript draft and performed the volume measurements and data analysis. Muthukumarassamy Rajakannu participated in data collection. Petru Bucur participated in study design, and
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revision of the draft. Rene Adam, Antonio SaCunha, Denis Castaing and
11. Van Thiel DH, Gavaler JS, Kam I, Francavilla A, Polimeno L, Schade RR
Daniel Cherqui critically revised the manuscript. Eric Vibert designed the
et al. (1987) Rapid growth of an intact human liver transplanted into a
study, participated in the manuscript writing and critically revised the
recipient larger than the donor. Gastroenterology 93:1414–1419. 12. Troisi R, Cammu G, Militerno G, De Baerdemaeker L, Decruyenaere J,
manuscript.
Hoste E et al. (2003) Modulation of portal graft inflow: a necessity in Conflict of interest None declared.
adult living-donor liver transplantation? Ann Surg 237:429–436. 13. Klune JR, Tsung A. (2010) Molecular biology of liver ischemia/reperfusion injury: established mechanisms and recent advancements. Surg
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