Differences in Portal Hemodynamics Between Whole Liver Transplantation and Living Donor Liver Transplantation

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1 LIVER TRANSPLANTATION 16: , 2010 ORIGINAL ARTICLE Differences in Portal Hemodynamics Between Whole Liver Transplantation and Living Donor Liver Transplantation Shui-Ming Jiang, Qi-Shun Zhang, Guang-Wen Zhou, Shi-Feng Huang, Hai-Ming Lu, and Cheng-Hong Peng Department of General Surgery, Fourth Affiliated Hospital, Guangxi Medical University, Liuzhou, China The aim of this study was to investigate the differences in portal hemodynamics between whole liver transplantation and living donor liver transplantation (LDLT). Twenty patients who underwent LDLT (the L group) and 42 patients who underwent whole liver transplantation (the W group) were enrolled, and colored Doppler ultrasonography was performed preoperatively and on postoperative days (PODs) 1, 3, 5, 7, 30, and 90. The changes in the portal blood flow velocity (PBV) and portal blood flow volume (PBF) were monitored. The graft and spleen sizes were measured with angiographic computed tomography, and upper endoscopy was used to measure esophageal varices on PODs 14, 30, and 90. Although the portal venous pressure (PVP) decreased after graft implantation, it was higher in the L group with a smaller graft size ratio ( cm H 2 O forthelgroupand cm H 2 O for the W group, P < 0.05). PBF and PBV increased in both the W and L groups on POD 1 after transplantation; however, the PBF and PBV peaks were significantly higher in the W group. The postoperative PVP and graft volume were greatly related to PBF on POD 1. Grafts in the L group regenerated rapidly after the operation, and the volume increased from to ml as early as 1 month after transplantation. A rapid improvement in splenomegaly was observed in both groups. An improvement in esophageal varices was observed in the W group on POD 14 after transplantation, whereas no change was observed in the L group. The portal venous flow in patients with portal hypertension showed a high perfusion state after LDLT, but in contrast to whole liver transplantation, the PVP elevation after LDLT postponed the closing time of the collateral circulation and affected the recovery from splenomegaly. Liver Transpl 16: , VC 2010 AASLD. Received March 3, 2010; accepted July 9, It has been reported that the portal blood flow volume (PBF) and portal blood flow velocity (PBV) increase immediately and the splanchnic hyperkinetic hemodynamic circulation persists in patients with cirrhosis and portal hypertension after whole liver transplantation. 1-4 However, because of the reduction in the liver vasculature and the smaller portal vein anastomotic stoma in living donor liver transplantation (LDLT), it is still unclear whether there is a difference in the changes in the regulation of PBV and PBF between whole liver transplantation and LDLT. Partial liver allografts regenerate to adapt to the recipient environment, and the impact of graft regeneration on portal hemodynamics is rarely mentioned. In addition, the reduction in the liver vasculature could induce an elevation of the portal venous pressure (PVP). The impact of PVP elevation on esophageal varices after LDLT has rarely been reported. An understanding of this development is important because the correct interpretation of data during follow-up could lead to better prevention of repeated upper gastrointestinal hemorrhaging in the perioperative period. Abbreviations GV, graft volume; GW, graft weight; LDLT, living donor liver transplantation; MELD, Model for End-Stage Liver Disease; PBF, portal blood flow volume; PBV, portal blood flow velocity; POD, postoperative day; PSG, portal systemic gradient; PVP, portal venous pressure; SAL, splenic artery ligation; SFSS, small-for-size syndrome; SLV, standard liver volume. Address reprint requests to Shui-Ming Jiang, M.D., Department of General Surgery, Fourth Affiliated Hospital, Guangxi Medical University, 1 Liushi Road, Liuzhou, China Telephone: þ ; jiangshuiming202@yahoo.com.cn or Guang-Wen, M.D., Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Road, Shanghai, China Telephone: þ ; zhou_guangwen.com.cn DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2010 American Association for the Study of Liver Diseases.

2 LIVER TRANSPLANTATION, Vol. 16, No. 11, 2010 JIANG ET AL TABLE 1. Recipient Characteristics by Group Before and During the Operation Characteristic L Group (n ¼ 20) W Group (n ¼ 42) P Value Gender (male/female) 16/4 34/8 >0.05 Age (years) >0.05 Average operation time (minutes) >0.05 Cold ischemia time (minutes) <0.01 Mean GV (cm 3 ) <0.01 Mean GV/SLV (%) <0.01 MELD score >0.05 Therefore, the aim of the present study was to investigate the differences in portal hemodynamics between whole liver transplantation and LDLT, and the impact of the portal hemodynamic changes on collateral circulation was examined simultaneously. PATIENTS AND METHODS Between February 2005 and March 2009, 62 patients (16 females and 46 males) underwent LDLT with a right lobe graft (the L group; n ¼ 20) or whole liver transplantation (the W group; n ¼ 42) for chronic liver disease with portal hypertension at Ruijin Hospital (Shanghai, China) after the approval of the ethics and indications committee was obtained. The recipients ranged in age from 18 to 63 years (mean ¼ years). The indications for transplantation included hepatitis B virus cirrhosis in 31 recipients, hepatitis B virus cirrhosis complicated by hepatocellular carcinoma in 16 recipients, hepatitis C virus cirrhosis in 2 recipients, primary biliary cirrhosis in 4 recipients, alcoholic cirrhosis in 3 recipients, and Wilson s disease in 6 recipients. According to the Child- Pugh classification, 37 patients were classified as Child C, 19 patients were classified as Child B, and 6 patients were classified as Child A. Table 1 shows the preoperative and intraoperative characteristics of the recipients in both groups. The recipient age, gender, and Model for End-Stage Liver Disease (MELD) score at the time of transplantation were similar between the groups. The mean graft volume (GV)/standard liver volume (SLV) ratio was found to be significantly different: 56.1% 6 7.5% in the L group and 109.8% % in the W group. The living right lobe donors [n ¼ 20 (5 females and 15 males), age ¼ years] served as the control group (ie, the D group). Postoperative Immunosuppressive Management The recipients of grafts were administered a triple-therapy regimen including methylprednisolone, tacrolimus, and mycophenolate mofetil to prevent rejection. PVP and Portal Systemic Gradient (PSG) Measurements A 16-gauge antithrombotic catheter was inserted via the inferior mesenteric vein before the native liver was dissected. The top of the catheter was positioned in the recipient portal vein. Low-dose heparin (10 U/ hour) was continuously infused through the catheter for the prevention of occlusion. PVP was measured before and after the implantation of the new graft during the operation. PSG was calculated as follows: PSG ¼ PVP Central venous pressure Color Doppler Ultrasonography Recipients and living right lobe donors were examined by color Doppler ultrasound with a GE Logiq Book color Doppler ultrasound diagnostic apparatus with a 3.5- MHz sector electronic probe preoperatively and after transplantation on postoperative days (PODs) 1, 3, 5, 7, 30, and 90. The monitoring indices included the following: (1) PBV, which was measured as the mean of the maximal velocity of the portal vein multiplied by a coefficient of 0.57, and (2) PBF, which was obtained by multiplication of the portal vein cross-sectional area by PBV under the assumption of a circular shape of the portal vein section, as previously reported. 5,6 All measurements were randomly performed by 1 of 2 operators. To minimize the interobserver variability, the 2 operators had previously trained together, and they always adhered to accepted guidelines. Doppler ultrasonography was performed after at least 15 minutes of bed rest preceded by 4 hours of fasting. Evaluation of the Liver and Spleen Volumes Angiographic computed tomography of the upper abdomen was performed with a GE LightSpeed 16-slice spiral computed tomography apparatus preoperatively and after transplantation on PODs 7, 30, and 90. Vascular reconstruction and measurement of the liver volume and spleen size were conducted with Advanced Workstation volumetric software (version 4.2). The remnant liver volume in the D group was measured with the same method. In principle, eligible donor criteria included an estimated GV > 40% of the SLV and a remnant liver volume > 30% of the total liver volume. The liver regeneration rate during the first 3 postoperative months was expressed with the following formula: Graft regeneration rate ¼ðGV on PODs 7; 30; and 90 GV on day 0Þ=GV on day 0 100%: GV on day 0 was measured with the water displacement method.

3 1238 JIANG ET AL. LIVER TRANSPLANTATION, November 2010 TABLE 2. PVP Changes in the Recipients Before and After the Operation Preoperative PVP (cm H 2 O) Postoperative PVP (cm H 2 O) P Value L group (GV/SLV ¼ 56.1%6 7.5%) <0.01 W group (GV/SLV ¼ 109.8%6 11.5%) <0.01 P value >0.05 <0.05 Collateral Circulation The development of esophageal varices was evaluated with upper endoscopy preoperatively and after transplantation on PODs 14, 30, and 90. Semiqualitative morphology methods were used to assess esophageal varices. A light varicose vein occupied just the outstanding mucosa of the esophagus, a medium varicose vein occupied less than one-third of the lumen of the esophagus, and a heavy varicose vein occupied more than one-third of the lumen of the esophagus. Statistical Analysis All results were expressed as means and standard deviations. Differences between 2 groups were assessed with 1-way analysis of variance, and the Student t test was used for paired samples. Only P values less than 0.05 were considered significant. Multiple regression analysis was performed to identify predictive factors independently associated with PBF on POD 1. The clinical parameters (gender, age, preoperative PBF, postoperative PVP, and GV on day 0) were used as independent factors. RESULTS Changes in PVP and PSG After the Operation There was no significant difference in PVP between the W group and the L group in the opened abdomen before the operation. PVP in the L group with a smaller graft size ratio decreased from to cm H 2 O after graft implantation; this was still significantly higher than that in the W group (Table 2). PSG was also significantly different after the operation: cm H 2 O in the L group and cm H 2 O in the W group (P < 0.05). Changes in the Portal Hemodynamics After the Operation The changes in the portal hemodynamics after the operation are shown in Figs. 1 and 2. PBF and PBV in both the W and L groups were lower than those in the D group before the operation (P < 0.01). They increased significantly and peaked after transplantation on POD 1; however, the PBF and PBV peaks in the W group were significantly higher (Figs. 3 and 4). PBF in both the W and L groups decreased gradually afterward. PBF in the W group decreased rapidly (by 34.8%6 14.8% from the peak as early as 1 month after the operation); however, the values of the L group gently decreased (by 25.4%6 12.2% within 3 months after LDLT). In the D group, PBF decreased on PODs 1 and 3, but it gradually increased from POD 3 to POD 7 to a steady level. In multivariate regression analysis, only postoperative PVP and GV on day 0 were found to be significant factors for PBF on POD 1 (Table 3). Changes in the Liver and Spleen Volumes After the Operation The liver volume in the W group showed no significant difference after the operation. Livers regenerated faster in the L group, with the liver volume increasing from to ml 30 days after LDLT (Fig. 5). The liver regeneration rate in the L group reached % % as early as 30 days after LDLT, whereas the liver volume in the D group increased gradually and reached approximately 94.15% % 90 days after LDLT. In both the W and L groups, a rapid improvement in splenomegaly Figure 1. Changes in PBF after liver transplantation. PBF in both the W and L groups significantly increased and peaked on POD 1 after transplantation. Until 90 days after transplantation, PBF in the W and L groups was significantly higher than that in the D group. Figure 2. Changes in PBV after liver transplantation. PBV in both the W and L groups increased. However, until 90 days after liver transplantation, PBV in the W and L groups was significantly higher than that in the D group.

4 LIVER TRANSPLANTATION, Vol. 16, No. 11, 2010 JIANG ET AL Figure 3. Changes in PBF on POD 1 after whole liver transplantation. was observed. The spleen volume in the W group decreased by 30.7%6 12.5% at 1 month, whereas the volume in the L group (n ¼ 19) decreased by 18.7%6 16.0%. One patient with a spleen volume of 390 ml in the L group had an increase in the spleen volume after LDLT. Conversely, the spleen volume in the D group increased in a compensatory manner 3 months after LDLT (from to ml, P < 0.01). Changes in Esophageal Varices Esophageal varices were found in 58 patients (n ¼ 39 for the W group and n ¼ 19 for the L group) before surgery. A significant improvement in esophageal varices was observed in the W group on POD 14. Three light esophageal varices completely disappeared, 1 heavy and 8 medium esophageal varices changed into light esophageal varices, and 5 heavy esophageal varices changed into medium esophageal varices; however, no change was observed in the L group (Figs. 6 and 7). Analysis of Two Cases of Small-for-Size Syndrome (SFSS) There were 2 cases of SFSS in the L group. One patient had a PVP of 36 cm H 2 O and a spleen volume of 2280 ml before graft implantation. GV was 605 ml (ie, 46.47% of the SLV). Although splenic artery ligation (SAL) was performed, PVP was still 32 cm H 2 O, and PBF/GW exceeded 450 ml/minute/100 g. In another case, GV was 598 ml, and GV/SLV was 50.96%. PVP was 30 cm H 2 O, and PBF/GW was more than 350 ml/minute/100 g after LDLT. A 4.5-mm inferior right hepatic vein was ligated during the operation, and this led to congestion of the segment VI graft, which was approximately one-quarter of the Figure 4. graft. Thus, the actual efficient GV/SLV value decreased to 38.22%, so the remnant hepatic tissue received all of the portal venous flow and suffered from hyperperfusion injury. The 2 patients were diagnosed by liver biopsy with SFSS, which resulted from severe portal hyperperfusion injury. They were treated with somatostatin (6 mg/day) and prostaglandin E immediately. PBF/GW decreased to 297 and 182 ml/ minute/100 g, respectively, and all the clinical indices improved significantly 1 and 2 days later. They were discharged from the hospital after 1 month. DISCUSSION Changes in PBF on POD 1 after LDLT. Derangement of the splanchnic circulation is initiated by elevated portal resistance and liver failure in patients with cirrhosis, and it is often accompanied by splenomegaly and the development of portosystemic collateral pathways. 7 It is accepted that orthotopic whole liver transplantation restores normal portal resistance and pressure and liver function. 8 However, hyperkinetic hemodynamic splanchnic circulation persists in patients with cirrhosis after whole liver transplantation. 1-4 Analyzing patients who underwent transplantation for liver cirrhosis, we were able to verify that PBV and PBF markedly increased in the first days after whole liver transplantation. However, because of the reduction in the liver vasculature and the smaller portal vein anastomotic stoma in LDLT, it is still unclear whether there are differences in the regulation of PBV and PBF between whole liver transplantation and LDLT. The present study shows that patients with cirrhosis experience increases in portal blood flow after LDLT. However, the PBF and PBV peaks in the L group were significantly lower. These differences may be related to the following: 1. There was a significant difference in the graft size ratio between whole liver transplantation and LDLT. The reduction in the liver vasculature TABLE 3. Influences on PBF on POD 1: Multivariate Analysis L Group (n ¼ 20) W Group (n ¼ 42) t P Gender (male/female) 16/4 34/ Age (years) Preoperative PBF (ml/minute) Postoperative PVP (cm H 2 O) Mean GV on day 0 (cm 3 )

5 1240 JIANG ET AL. LIVER TRANSPLANTATION, November 2010 Figure 5. Changes in the liver volume after liver transplantation. The liver volume in the W group showed no significant difference postoperatively. The rate of liver regeneration was higher in the L group versus the D group on PODs 7 and 30. in the L group led to elevated portal resistance and pressure (Table 1). Compensatory enlargement of the spleen in the D group after surgery also proved that the reduction in the liver vasculature could induce elevated portal resistance. In multivariate regression analysis, postoperative PVP and GV were found to be significant factors for PBF after the operation (Table 3). 2. The lack of a middle hepatic vein impaired venous drainage of the liver. 3. In contrast to whole liver transplantation, PVP elevation in the L group inevitably delayed the closing time of portosystemic collateral pathways, so some splanchnic blood went straight through the portosystemic collateral pathways of relatively low vascular impedance. For this reason, there was no difference in esophageal varices on POD 14 after LDLT. This also reminds us to prevent rehemorrhaging during the perioperative period in patients with a history of gastroesophageal variceal hemorrhaging. 4. A significant increase in PBF was observed with normalization of the portal resistance after whole liver transplantation. However, because of the PVP elevation after LDLT, there was congestion of the spleen, and some splanchnic blood could not flow into the liver immediately. After whole liver transplantation, because of improvements in splenomegaly, complete recovery of cardiac output, and normalization of serum nitrogen Figure 6. Changes in the esophageal varices in the W group. There was a significant improvement in the esophageal varices on POD 14. Figure 7. Changes in the esophageal varices in the L group. There was no change in the esophageal varices in the L group on POD 14. monoxide, 4,9 the amount of splanchnic blood will decrease rapidly, and this will lead to a rapid reduction in PBF. In our study, PBF in the W group decreased by 34.8%6 14.8% from the peak as early as 1 month after the operation. However, a partial liver allograft regenerates to adapt to the recipient environment. What is the impact of an enlarged liver volume on the portal hemodynamics? Analyzing the data of living right lobe donors without abnormal splanchnic circulation, we were able to verify that liver regeneration was followed by a gradual increase in PBF. As time goes on, graft regeneration, followed by an increase in the liver vasculature and normalization of PVP, theoretically needs more portal blood inflow. However, because the reduction in splanchnic blood played a leading role, a gentle reduction in PBF after LDLT was observed, with PBF decreasing by 25.4% % from the peak 3 months after LDLT. Although the portal venous flow in patients with cirrhosis showed a high perfusion state in both the L and W groups, a small-for-size graft was influenced by portal venous flow more significantly in comparison with a whole liver allograft. Overly increasing the portal venous flow and pressure would produce hyperperfusion injury and SFSS even with GV/SLV > 40%. 10 Troisi and de Hemptinne 11 reported that the recovery of liver function would be slower and not better with PBF/GW > 250 ml/minute/100 g after LDLT. Ito et al. 12 reported that PVP elevation in the early phase was strongly associated with poor patient survival. Yagi et al. 13 also reported that the occurrence of cholestasis, a prolonged prothrombin time, and ascites obviously increased after the operation when PVP was excessively elevated (27 cm H 2 O). The method of protecting grafts from portal hyperperfusion injury has very important clinical significance. SAL could alleviate portal hypertension and may be applied for the prevention or treatment of hyperperfusion injury in small-for-size grafts. Ito et al. reported that SAL could immediately reduce PVP from 16 to 11 mm Hg. In addition, in our study, PBF/GW immediately decreased when somatostatin and prostaglandin E were used by the patients for the treatment of SFSS. Therefore, we suggest that the use of somatostatin in combination with prostaglandin E might be beneficial for patients with excessively high PVPs, even if SAL is undertaken. Somatostatin not only reduces PVP but also down-regulates intrahepatic endothelin 1, which

6 LIVER TRANSPLANTATION, Vol. 16, No. 11, 2010 JIANG ET AL reduces the formation of microthrombi in the liver, improves intrahepatic microcirculation, and relieves hyperperfusion injury of the liver. 14 In conclusion, the portal venous flow in patients with cirrhosis and portal hypertension shows a high perfusion state after LDLT, and PVP elevation postpones the closing time of the collateral circulation and affects the recovery from splenomegaly. REFERENCES 1. Hadengue A, Lebrec D, Moreau R, Sogni P, Durand F, Gaudin C, et al. Persistence of systemic and splanchnic hyperkinetic circulation in liver transplantation patients. HEPATOLOGY 1993;17: Alvarez D, Gerona S, Waisburg Z, Ciardullo M, de Santibañes E, Mastai R. Splanchnic hyperemia after liver transplantation in patients with end-stage liver disease. Liver Transpl Surg 1998;4: Bolognesi M, Sacerdoti D, Bombonato G, Merkel C, Sartori G, Merenda R, et al. Change in portal flow after liver transplantation: effect on hepatic arterial resistance indices and role of spleen size. HEPATOLOGY 2002;35: Piscaglia F, Zironi G, Gaiani S, Mazziotti A, Cavallari A, Gramantieri L, et al. Systemic and splanchnic hemodynamic changes after liver transplantation for cirrhosis: a long-term prospective study. HEPATOLOGY 1999;30: Bolognesi M, Sacerdoti D, Merkel C, Gerunda G, Maffei- Faccioli A, Angeli P, et al. Splenic Doppler impedance indices: influence of different portal hemodynamic conditions. HEPATOLOGY 1996;23: Sabbà C, Merkel C, Zoli M, Ferraioli G, Gaiani S, Sacerdoti D, et al. Interobserver and interequipment variability of echo-doppler examination of the portal vein: effect of a cooperative training program. HEPATOLOGY 1995;21: Zironi G, Gaiani S, Fenyves D, Rigamonti A, Bolondi L, Barbara L. Value of measurement of mean portal flow velocity by Doppler flowmetry in the diagnosis of portal hypertension. J Hepatol 1992;16: Navasa M, Feu F, Garcìa-Pagàn J, Jeménez W, Llach J, Rimola A, et al. Hemodynamic and humoral changes after liver transplantation in patients with cirrhosis. HEPA- TOLOGY 1993;17: Cao H, Wu Z, Zhang X, Zhang H, Chen Z, Kuang Y. The role of vasoactive substances in hyperhemodynamics after orthotopic liver transplantation in cirrhotic rats. Chin Med J (Engl) 2003;116: Heaton N. Small-for-size liver syndrome after auxiliary and split liver transplantation: donor selection. Liver Transpl 2003;9: Troisi R, de Hemptinne B. Clinical relevance of adapting portal vein flow in living donor liver transplantation in adult patients. Liver Transpl 2003;9:S36-S Ito T, Kiuchi T, Yamamoto H, Oike F, Ogura Y, Fujimoto Y, et al. Changes in portal venous pressure in the early phase after living donor liver transplantation: pathogenesis and clinical implications. Transplantation 2003;75: Yagi S, Iida T, Taniguchi K, Hori T, Hamada T, Fujii K, et al. Impact of portal venous pressure on regeneration and graft damage after living-donor liver transplantation. Liver Transpl 2005;11: Xu X, Man K, Zheng SS, Liang TB, Lee TK, Ng KT, et al. Attenuation of acute phase shear stress by somatostatin. improves small-for-size liver graft survival. Liver Transpl 2006;12: