Impact of simultaneous splenectomy and orthotopic liver transplantation in patients with end-stage liver diseases and splenic hyperfunction

Chongqing,China

Introduction

End-stage liver diseases are often complicated by severe hypersplenism.[1-3]At present,it remains unclear whether performing a splenectomy simultaneously during liver transplantation in patients with end-stage liver diseases is beneficial.Studies[4,5]have shown that splenectomy together with living donor liver transplantation can prevent the occurrence of small-for-size syndrome,and is also beneficial for the postoperative treatment of hepatitis C.[6]Others[7,8]reported that splenectomy may increase the surgical risk.Clinically it was found that the surgical risk of simultaneous splenectomy during liver transplantation is related to preoperative conditions such as coagulation function,portal vein thrombosis,and perisplenitis.At present there are no reports on the advantages and disadvantages of simultaneous splenectomy and liver transplantation according to the preoperative status of patients with liver diseases.The present study was undertaken to investigate the outcomes of simultaneous splenectomy and liver transplantation in high- and low-risk patients based on prolonged preoperative prothrombin time (PT),portal vein thrombosis,and severe perisplenitis.

Methods

Patients

From January 2005 to January 2011,42 patients (36 males,6 females; aged 41.5±8.9 years) with end-stage liver diseases complicated by severe hypersplenism underwent orthotopic liver transplantation at our department.Patient demographics are shown in Table 1.Simultaneous splenectomy was performed in 19 of the 42 patients,whereas the spleen was retained in the remaining 23.Patients were classified as either high- or low-risk for the operation based on their preoperative findings.Fifteen patients were defined as high-risk because they had at least one of the following conditions:preoperative PT＞5 seconds,portal vein thrombosis,and severe perisplenitis.Patients without at least one of these findings were classified as low-risk.The patients were then grouped based on their risk for the operation and whether a splenectomy was performed previously.High-risk patients who underwent a splenectomy were included in group A (n=7),high-risk patients who retained their spleen were included in group B(n=8),low-risk patients who underwent concomitant splenectomy were included in group C (n=12),and low-risk patients who underwent liver transplant only without splenectomy were included in group D (n=15).For all patients,operative time,intraoperative bloodloss,postoperative bleeding,pulmonary infection,perioperative mortality,and postoperative platelet recovery were analyzed.

Table 1.Baseline patient clinicodemographics

Outcome measures

Platelet counts and PT data were obtained from the medical records of patients who underwent orthotopic liver transplantation.The diagnostic criteria for hypersplenism included splenomegaly,significant decrease of both or either leukocytes and platelets,and exclusion of primary hypersplenism.[9,10]Severe thrombocytopenia was defined by a platelet count＜50×109/L before transplantation.[11]Platelet recovery was assessed for 6 months following transplantation.Portal vein thrombosis was diagnosed by abdominal contrast-enhanced CT,and severe perisplenitis was diagnosed intraoperatively by the presence of close adhesion between the spleen and diaphragm,stomach,and omentum,difficulty in dissecting the spleen from its surrounding tissue,and the possibility of massive hemorrhage in an attempt to dissect the spleen.Operative time and intraoperative blood loss were obtained from the surgical records.

The criteria indicating a reoperation for postoperative bleeding were as follows:1) blood from peritoneal drainage ＞100 mL/h continuously for the first 5 hours after surgery; and 2) blood pressure ＜90/60 mmHg and incoagulable blood obtained during abdominal aspiration.

Pulmonary infection was diagnosed if body temperature ＞37.5 ℃,white blood cell count ＞10×109/L,neutrophils ＞90%,and radiographic or CT findings in the lungs consistent with infection.

Either cyclosporine or tacrolimus in combination with either mycophenolate mofetil or sirolimus was prescribed for immunosuppression after transplantation.In addition,corticosteroids were prescribed 3 months after surgery,then tapered and discontinued.

Statistical analysis

Data were presented as mean±SD,and categorical data were presented as constituent ratio.Quantitative data were analyzed by analysis of variance and SPSS 16.0(SPSS Inc.,Chicago,IL.,USA).P＜0.05 was considered statistically significant.

Results

Operative time and intraoperative blood loss

The operative time was longer in group A than in groups B-D (P＜0.01),but there was no difference in operative time between groups B-D (P＞0.05).Intraoperativeblood loss was greater in group A than in groups B-D(P＜0.01),and intraoperative blood loss was greater in group B than in groups C and D (P＜0.01).However,no difference was seen between groups C and D (P＞0.05;Table 2).

Table 2.Operative time and intraoperative blood loss in different groups

Table 3.Postoperative bleeding,pulmonary infection,perioperative mortality,and postoperative platelet recovery in different groups

Reoperation after postoperative bleeding,pulmonary infection,and perioperative mortality

In group A,postoperative bleeding (requiring additional surgery) was seen in 3 patients,pulmonary infection in 5,and perioperative mortality in 2.The number of patients in the other groups who were diagnosed with postoperative bleeding,pulmonary infection,and perioperative mortality was lower than in group A (Table 3).

In high-risk patients (groups A and B),the rate of reoperation for postoperative bleeding,pulmonary infection,and perioperative mortality was higher in group A than in group B.In low-risk patients (groups C and D),the rate of reoperation for postoperative bleeding,pulmonary infection,and perioperative mortality in group C was similar to that in group D (Table 3).

Platelet recovery

In patients who underwent splenectomy,their platelet counts normalized within 6 months after surgery.Persistent thrombocytopenia was observed 6 months after surgery in 3 of 23 patients with the preserved spleen.One of the three patients was at highrisk and the remaining two were at low-risk (Table 3).

Discussion

Chronic liver disease is often complicated by hypersplenism,which causes serious thrombocytopenia.[1-3]Hypersplenism can be treated by splenic embolization.[12,13]Currently,splenectomy is the more popular choice of treatment for hypersplenism and thrombocytopenia,[6,14,15]but it remains controversial over whether splenectomy can be performed simultaneously during liver transplantation in patients with end-stage liver diseases associated with severe hypersplenism.Previous studies[7,8]suggested that splenectomy would increase the risk of surgery.In contrast Cescon et al[16]considered splenectomy as an acceptable option for patients with thrombocytopenia or when it is necessary to change the portal flow.Many studies[17-19]proposed indications for simultaneous splenectomy and liver transplantation,which include severe thrombocytopenia,small-for-size syndrome,ABO incompatibility,and postoperative treatment of hepatitis C.Further,it was noted that the risk of simultaneous splenectomy during liver transplantation is associated with preoperative coagulation,portal vein thrombosis,and perisplenitis.

This study revealed that high-risk patients undergoing simultaneous splenectomy and transplantation had a longer operative time and more intraoperative blood loss than the other groups.In group A,reoperation was due to postoperative bleeding (3 patients),pulmonary infection (5),and perioperative mortality (2).The number of patients in the other three groups,was much lower than that in group A.This indicated that the operative risk is higher in high-risk patients undergoing simultaneous splenectomy during liver transplantation than in high-risk patients with the preserved spleen.There are a number of explanations for this finding.First,PT is often significantly prolonged in patients with terminal liver diseases.If the prolonged PT is combined with portal hypertension,increased bleeding from the wound surface may occur after splenectomy,and this is attributable to poor hemostasis and prolonged operative time.Portal vein thrombosis aggravates portal hypertension,increases collateral circulation in the operationfield,and adds difficulty in hemostasis during splenectomy.In addition,perisplenitis causes adhesions between the spleen and adjacent tissues,resulting in the formation of blood vessels and collateral circulation.On the background of portal hypertension,difficulty in hemostasis and unexpected massive bleeding can occur during splenectomy.Each of these conditions increases the operative risk.Although simultaneous splenectomy and liver transplantation are used in the treatment of hepatitis C,prevention of ABO incompatibility,and small-for-size syndrome,[17-19]the results of the present study suggest that splenectomy should be avoided during liver transplantation in high-risk patients.But splenic embolization or splenectomy is advisable in high-risk patients when they recover from the transplantation.Chao et al[20]reported that splenic embolization after liver transplantation is indicated for patients with hypersplenism,gastroesophageal variceal hemorrhage,and splenic artery steal syndrome.Kato et al[21]reported successful laparoscopic splenectomy after living-donor liver transplantation for thrombocytopenia caused by antiviral therapy.

Interestingly,there was no significant difference in operative time and intraoperative blood loss between groups C and D.In addition,the number of patients who underwent reoperation for postoperative bleeding,developed a pulmonary infection or died in the perioperative period was similar in the two groups (0,3,and 0 in group C and 1,3,and 0 in group D).Possibly because the portal vein was unobstructed,portal pressure in the spleen was relatively low after transplantation.Moreover,there were no adhesions or neovascularization around the spleen in patients without perisplenitis,and their relatively good coagulation function made simultaneous splenectomy together with liver transplantation a reasonable option.Thus,the risk of simultaneous splenectomy with liver transplantation in low-risk patients is not higher than that in patients with the preserved spleen.

Platelet count can take up to 6 months to normalize after surgery in both high- and low-risk patients who undergo splenectomy and liver transplantation concurrently.In this study,marked thrombocytopenia was still observed in 3 of the 23 patients,in whom splenectomy was not performed.This indicates that even though hypersplenism can be relieved in most patients who do not undergo splenectomy,a few patients continue to suffer from hypersplenism after liver transplantation.This is an important consideration because the use of immunosuppressants after organ transplantation induces thrombocytopenia in some patients.[22,23]Anti-hepatitis C virus drugs,such as interferon,are also known to cause thrombocytopenia.[24,25]For these patients,repeated operation can be avoided if simultaneous splenectomy is performed during liver transplantation.For low-risk patients,if PT is less than 5 seconds and there is no portal vein thrombosis or perisplenitis,simultaneous splenectomy and liver transplantation appears to be a reasonable option.

In conclusion,for patients with preoperative PT of more than 5 seconds,thrombosis of the portal vein,or serious in flammation of the spleen,splenectomy should be avoided in orthotopic liver transplantation.Simultaneous splenectomy together with orthotopic liver transplantation is warranted in low-risk patients for the recovery of postoperative platelet count.

Contributors:LDW proposed the study and wrote the first draft.LDW and DCY performed research.FB collected and analyzed the data.All authors contributed to the design and interpretation of the study and to further drafts.LDW is the guarantor.

Funding:None.

Ethical approval:Not needed.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

1 Bashour FN,Teran JC,Mullen KD.Prevalence of peripheral blood cytopenias (hypersplenism) in patients with nonalcoholic chronic liver disease.Am J Gastroenterol 2000;95:2936-2939.

2 Afdhal N,McHutchison J,Brown R,Jacobson I,Manns M,Poordad F,et al.Thrombocytopenia associated with chronic liver disease.J Hepatol 2008;48:1000-1007.

3 Gonzalez-Casas R,Jones EA,Moreno-Otero R.Spectrum of anemia associated with chronic liver disease.World J Gastroenterol 2009;15:4653-4658.

4 Yoshizumi T,Taketomi A,Soejima Y,Ikegami T,Uchiyama H,Kayashima H,et al.The beneficial role of simultaneous splenectomy in living donor liver transplantation in patients with small-for-size graft.Transpl Int 2008;21:833-842.

5 Ikegami T,Soejima Y,Taketomi A,Sanefuji K,Kayashima H,Harada N,et al.Living donor liver transplantation with extra-small graft; in flow modulation using splenectomy and temporary portocaval shunt.Hepatogastroenterology 2008;55:670-672.

6 Sibulesky L,Nguyen JH,Paz-Fumagalli R,Taner CB,Dickson RC.Treatment modalities for hypersplenism in liver transplant recipients with recurrent hepatitis C.World J Gastroenterol 2009;15:5010-5013.

7 Wang WL,Gao L,Liang TB,Yao MY,Lu AW,Zheng SS.Effects of splenectomy on patients undergoing liver transplantation.Zhonghua Yi Xue Za Zhi 2006;86:1240-1243.

8 Neumann UP,Langrehr JM,Kaisers U,Lang M,Schmitz V,Neuhaus P.Simultaneous splenectomy increases risk for opportunistic pneumonia in patients after liver transplantation.Transpl Int 2002;15:226-232.

9 Wang Q,Sun K,Li XH,Peng BG,Liang LJ.Surgical treatment for hepatocellular carcinoma and secondary hypersplenism.Hepatobiliary Pancreat Dis Int 2006;5:396-400.

10 Chen XP,Wu ZD,Huang ZY,Qiu FZ.Use of hepatectomy and splenectomy to treat hepatocellular carcinoma with cirrhotic hypersplenism.Br J Surg 2005;92:334-339.

11 Chang JH,Choi JY,Woo HY,Kwon JH,You CR,Bae SH,et al.Severe thrombocytopenia before liver transplantation is associated with delayed recovery of thrombocytopenia regardless of donor type.World J Gastroenterol 2008;14:5723-5729.

12 Palsson B,Verbaan H.Partial splenic embolization as pretreatment for antiviral therapy in hepatitis C virus infection.Eur J Gastroenterol Hepatol 2005;17:1153-1155.

13 He XH,Li WT,Peng WJ,Li GD,Wang SP,Xu LC.Total embolization of the main splenic artery as a supplemental treatment modality for hypersplenism.World J Gastroenterol 2011;17:2953-2957.

14 Ushitora Y,Tashiro H,Takahashi S,Amano H,Oshita A,Kobayashi T,et al.Splenectomy in chronic hepatic disorders:portal vein thrombosis and improvement of liver function.Dig Surg 2011;28:9-14.

15 Akahoshi T,Tomikawa M,Korenaga D,Ikejiri K,Saku M,Takenaka K.Laparoscopic splenectomy with peginterferon and ribavirin therapy for patients with hepatitis C virus cirrhosis and hypersplenism.Surg Endosc 2010;24:680-685.

16 Cescon M,Sugawara Y,Takayama T,Seyama Y,Sano K,Imamura H,et al.Role of splenectomy in living-donor liver transplantation for adults.Hepatogastroenterology 2002;49:721-723.

17 Jeng LB,Lee CC,Chiang HC,Chen TH,Hsu CH,Cheng HT,et al.Indication for splenectomy in the era of living-donor liver transplantation.Transplant Proc 2008;40:2531-2533.

18 Shimoda M,Marubashi S,Dono K,Miyamoto A,Takeda Y,Umeshita K,et al.ABO-incompatible adult liver transplantation when the anti-ABO antibody titer is high.Hepatogastroenterology 2009;56:1174-1177.

19 Usui M,Isaji S,Mizuno S,Sakurai H,Uemoto S.Experiences and problems pre-operative anti-CD20 monoclonal antibody infusion therapy with splenectomy and plasma exchange forABO-incompatible living-donor liver transplantation.Clin Transplant 2007;21:24-31.

20 Chao CP,Nguyen JH,Paz-Fumagalli R,Dougherty MK,Stockland AH.Splenic embolization in liver transplant recipients:early outcomes.Transplant Proc 2007;39:3194-3198.

21 Kato H,Usui M,Azumi Y,Ohsawa I,Kishiwada M,Sakurai H,et al.Successful laparoscopic splenectomy after livingdonor liver transplantation for thrombocytopenia caused by antiviral therapy.World J Gastroenterol 2008;14:4245-4248.

22 Moreno JM,Rubio E,Gómez A,Lopez-Monclus J,Herreros A,Revilla J,et al.Effectiveness and safety of mycophenolate mofetil as monotherapy in liver transplantation.Transplant Proc 2003;35:1874-1876.

23 Al-Uzri A,Yorgin PD,Kling PJ.Anemia in children after transplantation:etiology and the effect of immunosuppressive therapy on erythropoiesis.Pediatr Transplant 2003;7:253-264.

24 Morihara D,Kobayashi M,Ikeda K,Kawamura Y,Saneto H,Yatuji H,et al.Effectiveness of combination therapy of splenectomy and long-term interferon in patients with hepatitis C virus-related cirrhosis and thrombocytopenia.Hepatol Res 2009;39:439-447.

25 Yamane A,Nakamura T,Suzuki H,Ito M,Ohnishi Y,Ikeda Y,et al.Interferon-alpha 2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes.Blood 2008;112:542-550.