Relationship Between Graft Liver Function and the Change of Graft Liver and Spleen Volumes After Technical Variant Liver Transplantation

Relationship Between Graft Liver Function and the Change of Graft Liver and Spleen Volumes After Technical Variant Liver Transplantation Y. Hirataa,*, Y. Sanadaa, T. Urahashia, Y. Iharaa, N. Yamadaa, N. Okadaa, M. Tashiroa, T. Katanoa, S. Otomob, K. Ushijimac, and K. Mizutaa a c

Department of Transplant Surgery, Jichi Medical University; bDepartment of Pharmacy, Jichi Medical University Hospital; and Department of Clinical Pharmacology, Jichi Medical University, Shimotsuke City, Tochigi, Japan

ABSTRACT Background. Although there have been a few reports describing the changes of graft liver and spleen volumes after liver transplantation (LT), little is known about the relationship between graft liver function and the changes of these volumes after technical variant liver transplantation (TVLT). We therefore performed a retrospective study to investigate the relationship between graft liver function and these volumes after TVLT. Methods. We retrospectively investigated the cases of 140 TVLT procedures that were performed in our department between July 1987 and October 2012 and in which follow-up was conducted at our department. We calculated the graft liver volume to standard liver volume (GV/SLV) ratio, the spleen volume to standard spleen volume (SV/SSV) ratio, and the spleen volume to graft liver volume (S/L) ratio by CT volumetry. We clarified the relationship between graft liver function (according to the pathological findings) and the graft liver and spleen volumes at 2, 5, and 10 years after TVLT. Results. In the normal liver function group, the GV/SLV, SV/SSV, and S/L ratios decreased until 6 months after TVLT and then converged at 10 years after TVLT to 0.95, 1.27, and 0.27, respectively. In the graft liver failure group, the GV/SLV, SV/SSV, and S/L ratios at 10 years after TVLT were 0.67, 5.01, and 1.55, respectively. A significant correlation was observed between the GV/SLV ratio and the presence of mild liver fibrosis at 2 and 5 years after TVLT (P ¼ .03 and P ¼ .04, respectively). Conclusions. Post-transplant CT-volumetry is a noninvasive and effective means of evaluating graft liver status.

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HERE have been reports describing the changes of spleen volume after liver transplantation (LT) [1e3], which becomes smaller after LT [2e4]. However, few reports have described the relationship between graft liver function and the graft liver and spleen volumes after LT. The technical variant liver (TVLT), including reducedsize, split, and living donor liver transplantation (LDLT), can use a partial graft liver to replace the role of a whole organ, thereby releasing the burden of appropriate-sized whole liver grafts [5]. We previously reported that the persistence of post-living donor liver transplant portosystemic shunts and progressive splenomegaly results in graft liver failure [6]. Thus, the evaluation of the changes

in the graft liver and spleen volumes after TVLT may enable the early diagnosis and treatment of graft liver dysfunction. We herein report the findings of our retrospective study on the relationship between graft liver function and the graft liver and spleen volumes after TVLT.

*Address correspondence to Yuta Hirata, Department of Transplant Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke City, Tochigi 329-0498, Japan. E-mail: yutaktyy1234@ jichi.ac.jp

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0041-1345/16 http://dx.doi.org/10.1016/j.transproceed.2015.12.089

Transplantation Proceedings, 48, 1105e1109 (2016)

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HIRATA, SANADA, URAHASHI ET AL Table 1. Demographic Data of Recipient and Graft Characteristics

Recipient and Graft Characteristics

Sex Median age at TVLT (years) Period at TVLT Original disease (n ¼ 140)

Male, n ¼ 65; female, n ¼ 75 1.6 (0.1e19.1) July 1987 and October 2012 Biliary atresia (n ¼ 108), ornithine transcarbamylase deficiency (n ¼ 7), Alagille syndrome (n ¼ 6), congenital extra-hepatic portosystemic shunt (n ¼4), fulminant hepatic failure (n ¼ 3), liver graft failure (n ¼ 3), neonatal hemochromatosis (n ¼ 2), liver cirrhosis (n ¼ 2), others (n ¼ 7)

METHODS We conducted a study of 140 cases (biliary atresia, n ¼ 108; ornithine transcarbamylase deficiency, n ¼ 7; Alagille syndrome, n ¼ 6; others, n ¼ 19) in which a TVLT was performed and in which follow-up was carried out at our department between July 1987 and

Fig 1. Changes in post-transplant graft liver and spleen volumetry in the normal liver function group (n ¼ 137).

October 2012. We analyzed the data obtained from 140 patients and a total of 1423 sessions of CT volumetry. The data of the patients are shown in Table 1. The median age at TVLT was 1.6 years (range, 0.1e19.1 years). The recipients were classified into 2 groups according to the presence or absence of graft liver failure: the normal liver function group (n ¼ 137), which included patients who did not have post-transplant complications (reeliver transplantation (re-LT), vascular complications, steroid-resistant rejection) and whose liver function test (LFT) results were normal; and the graft liver failure group (n ¼ 3), which included patients who underwent

Fig 2. The changes in post-transplant graft liver and spleen volumetry in the graft liver failure group (n ¼ 3).

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Table 2. GV/SLV, SV/SSV, and S/L Ratios at 10 Years After TVLT in the Normal Liver Function Group and the Graft Liver Failure Group 10 Years After TVLT

GV/SLV ratio SV/SSV ratio S/L ratio

Normal Liver Function Group

Graft Liver Failure Group

P Value

0.95 1.27 0.27

0.67 5.01 1.55

.06 .13 .06

a re-LT or who died because of graft liver failure. The graft liver fibrosis in protocol biopsy was graded on the basis of the Metavir scoring systems. In our institution, we examined the graft liver and spleen volumes at 1 to 2 months, 6 months, and 1 year after LT with the use of CT volumetry. From 1 year to 5 years after LT, the volumes were examined annually; thereafter they were examined every 2 years. We performed CT volumetry according to the criteria of the as low as reasonably achievable concept. The following measurements were applied to the volumetry calculations: SLV was calculated as: SLV (mL) ¼ 706.2  body surface area (m2) þ 2.46 [7] and SSV was calculated as SSV (cm3) ¼ 0.7 þ (4.6  body weight [kg]) [8]. We calculated the GV/SLV, SV/SSV, and S/L ratios using the CT volumetry values from before and after LT. We clarified the relationship between the graft liver function by performing a graft liver biopsy examination and by the CT volumetry values of the graft liver and spleen at 2, 5, and 10 years after TVLT.

Statistical Analysis The significance of the differences between the 2 groups was evaluated by Welch’s test and the Mann-Whitney U test. The statistical

results are expressed as median values. All of the statistical analyses were performed using the EZR software program (Saitama Medical Center, Jichi Medical University, Japan). Values of P < .05 were considered to indicate statistical significance.

RESULTS

In the normal liver function group, the GV/SLV, SV/SSV, and S/L ratios decreased until 6 months after TVLT. The GV/SLV, SV/SSV, and S/L ratios converged at 10 years after TVLT to reach 0.95, 1.27, and 0.27, respectively (Fig 1). In the graft liver failure group, the GV/SLV ratio decreased until re-LT or death, whereas the SV/SSV and S/L ratios increased until re-LT or death (Fig 2). In the graft liver failure group, the GV/SLV, SV/SSV, and S/L ratios at 10 years after LT were 0.67, 5.01, and 1.55, respectively (P ¼ .06, P ¼ .13, P ¼ .06) (Table 2). The GV/SLV, SV/SSV, and S/L ratios showed a tendency to deviate from the normal group until re-LT or death. Patient 1 had immunological liver dysfunction and underwent a re-LT due to reduced portal vein flow with portal vein thrombosis (PVT). The histopathological diagnosis was nonalcoholic steatohepatitis (NASH) and mild fibrosis caused by de novo autoimmune hepatitis (AIH). The patient’s Metavir score was F2. The GV/SLV, SV/ SSV, and S/L ratios in the same patient at re-LT were 0.68, 7.47, and 2.23, respectively (Fig 3A). Patient 2, who had immunological liver dysfunction, also required a re-LT because of reduced portal vein flow with PVT. The

Fig 3. (A) Changes in post-transplant graft liver and spleen volumetry in patient 1. (B) Changes in post-transplant graft liver and spleen volumetry in patient 2. (C) Changes in post-transplant graft liver and spleen volumetry in patient 3.

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Fig 4. (A) Distribution of the Metavir score according to the graft liver and spleen volumes at 2 years after TVLT. (B) Distribution of the Metavir score according to the graft liver and spleen volumes at 5 years after TVLT. (C) Distribution of the Metavir score according to the graft liver and spleen volumes at 10 years after TVLT.

histopathological diagnosis was cirrhosis of the graft liver caused by de novo AIH. The patient’s Metavir score was F4. The GV/SLV, SV/SSV, and S/L ratios in the same patient at re-LT were 0.51, 1.97, and 0.87, respectively (Fig 3B). Patient 3, who had immunological liver dysfunction, died as the result of reduced portal vein flow with severe uncontrollable PVT while waiting for a transplant from a brain-dead donor. The histopathological diagnosis was mild fibrosis caused by de novo AIH. The patient’s Metavir score was F1. The GV/SLV, SV/ SSV, and S/L ratios in the same patient at death were 0.51, 1.97, and 0.87, respectively (Fig 3C). The 3 box plot graphs in Fig 4 show the distribution of the Metavir scores according to the graft liver and spleen volumes at 2 years after TVLT. There was a significant difference in the GV/SLV ratios at 2 years after LT in the patients with Metavir scores of F0 and F1 (P ¼ .03) (Fig 4A) and in the GV/SLV ratio at 5 years after TVLT in the patients with Metavir scores of F0 and F2 (P ¼ .04) (Fig 4B). No significant differences were found at 10 years after TVLT (Fig 4C). A significant correlation was observed between the GV/SLV ratio and the presence of mild liver fibrosis at 2 and 5 years after TVLT. No significant correlations were observed between the graft liver

and spleen volumes and liver fibrosis at 10 years after TVLT. DISCUSSION

It is difficult to objectively evaluate the circulatory dynamics of intra-abdominal organ blood flow, which is important for the transplanted liver. Evaluations by blood tests or Doppler ultrasonography alone are not sufficient. The evaluation of the graft liver and spleen volumes by CT can reflect the portal vein dynamics and is useful for the early diagnosis of potential post-transplant complications that may lead to graft liver failure. A previous study reported that patients with an increased SV/SSV ratio after LDLT tend to show disease progression [3]. However, few reports have described the relationship between the graft liver and spleen volumes and the occurrence of graft liver failure over the course of long-term follow-up period after TVLT. In the long-term follow-up after TVLT, 3 patients in the present study transitioned into graft liver failure. Two of the patients required a re-LT due to reduced portal vein flow with PVT. In a recent meta-analysis report, the incidence of PVT was significantly higher in TVLT than in whole liver transplantation [5]. The GV/SLV, SV/SSV, and S/L ratios of the

CHANGE OF GRAFT LIVER AND SPLEEN VOLUMES

3 patients tended to deviate from the normal group until reLT or death. The findings of this study suggest that patients who demonstrate a decrease in their GV/SLV ratio and increases in their SV/SSV and S/L ratios will probably transition to potential graft liver failure. In addition, we have reported that the persistence of posteliving donor liver transplant portosystemic shunting and progressive splenomegaly results in graft liver failure [6]. Thus, by evaluating the changes of graft liver and spleen volumes after TVLT, it may be possible to perform an early diagnosis of graft liver dysfunction and to provide early treatment. Partial splenic embolization (PSE) [9,10] and balloon-occluded retrograde transvenous obliteration (BRTO) [11,12] have been reported to improve hypersplenism, but there have been few reports describing the therapeutic indications of PSE and BRTO after LT. At present, there is no consensus regarding the treatment of hypersplenism after LT, and it is necessary to perform more studies. We usually use blood tests and radiological and pathological assessments in the long-term surveillance of the graft liver status after LDLT [13]. However, there is no consensus as to which surveillance methods should become the universal standard. In the early-term follow-up after TVLT, we showed a significant correlation between the GV/SLV ratio and the Metavir score. However, we also showed that there was no significant correlation between the graft liver and spleen volumes and the Metavir score in the long-term follow-up after TVLT. In the graft liver failure group, there was a tendency to deviate from the normal group at 10 years after TVLT. In the present study, the CT volumetric evaluation of the graft liver and spleen was a useful surveillance method in the long-term follow-up after TVLT. We strongly recommend using the GV/SLV, SV/SSV, and S/L ratios as liver function tests in addition to liver biopsy assessments. From the present study, we can conclude that the GV/SLV, SV/SSV, and S/L ratio may become new prognostic indicators in long-term surveillance after TVLT. CONCLUSIONS

In the long-term follow-up after TVLT, it is useful to compare the graft liver and spleen CT volumetry results

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with previous CT volumetry results. By evaluating the changes of graft liver and spleen volumes in the posttransplant course, it may be possible to effectively predict the graft liver status using a noninvasive method of assessment. REFERENCES [1] Chikamori F, Nishida S, Selvaggi G, et al. Effect of liver transplantation on spleen size, collateral veins, and platelet counts. World J Surg 2010;34:320e6. [2] Yanaga K, Tzakis AG, Shimada M, et al. Reversal of hypersplenism following orthotopic liver transplantation. Ann Surg 1989;210:180e3. [3] Egami S, Sugawara Y, Mizuta K, et al. Effect of pediatric living-donor liver transplantation on splenomegaly. Transplantation 2002;74:1639e42. [4] Kaneko J, Sugawara Y, Akamatsu N, et al. Spleen volume and platelet number changes after living donor liver transplantation in adults. Hepatogastroenterology 2004;51:262e3. [5] Ye H, Zhao Q, Wang D, et al. Outcomes of technical variant liver transplantation versus whole liver transplantation for pediatric patients: a meta-analysis. PLoS One 2015;10:e0138202. [6] Sanada Y, Mizuta K, Urahashi T, et al. Impact of posttransplant portosystemic shunts on liver transplantation. World J Surg 2012;36:2449e54. [7] Urata K, Kawasaki S, Matsunami H, et al. Calculation of child and adult standard liver volume for liver transplantation. Hepatology 1995;21:1317e21. [8] Schlesinger AE, Edgar KA, Boxer LA. Volume of the spleen in children as measured on CT scans: normal standards as a function of body weight. AJR Am J Roentgenol 1993;160:1107e9. [9] Yoshida H, Mamada Y, Taniai N, Tajiri T. Partial splenic embolization. Hepatol Res 2008;38:225e33. [10] Sockrider CS, Boykin KN, Green J, et al. Partial splenic embolization for hypersplenism before and after liver transplantation. Clin Transplant 2002;16:59e61. [11] Shigeta T, Kasahara M, Sakamoto S, et al. Balloon-occluded retrograde transvenous obliteration for a portosystemic shunt after pediatric living-donor liver transplantation. J Pediatr Surg 2011;46: e19e22. [12] Nagao Y, Akahoshi T, Uehara H, et al. Balloon-occluded retrograde transvenous obliteration is feasible for prolonged portosystemic shunts after living donor liver transplantation. Surg Today 2014;44:633e9. [13] Sanada Y, Matsumoto K, Urahashi T, et al. Protocol liver biopsy is the only examination that can detect mid-term graft fibrosis after pediatric liver transplantation. World J Gastroenterol 2014;20:6638e50.