Xiang Lan, Bo Li, Xiao-Fei Wang, Yong-Gang Wei, Lu-Nan Yan and Ji-Chun Zhao

Chengdu, China

Potential etiopathogenesis of seventh day syndrome following living donor liver transplantation: ischemia of the graft?

Xiang Lan, Bo Li, Xiao-Fei Wang, Yong-Gang Wei, Lu-Nan Yan and Ji-Chun Zhao

Chengdu, China

(Hepatobiliary Pancreat Dis Int 2010; 9: 22-26)

seventh-day syndrome;living donor;liver transplantation;ischemic hepatitis;etiopathogenesis;hepatocellular necrosis

Introduction

Sudden and fatal failure of liver graft at about 1 week after operation is called seventh-day syndrome(7DS) as described by Memon et al[1]after orthotopic liver transplantation as well as by Hwang et al[2]after living donor liver transplantation (LDLT). A few unexplained episodes of dramatic graft loss after rapid progression of graft dysfunction have been encountered in patients since the 1980s. These episodes were labeled septic hepatic gangrene, acute massive hepatic necrosis,massive hemorrhagic necrosis, and nonthrombotic infarction, but they must be excluded in a diagnosis of 7DS.[1-4]Since the etiopathogenesis of this syndrome is unclear, there is no effective treatment. In our center, 5 of 98 patients suffered from 7DS and had unique features.We compared the data of these patients with those of fully recovered patients and found some new characteristics of 7DS, which may reveal its etiopathogenesis.

MethodsPatients

We retrospectively studied 98 consecutive LDLT patients treated at the Division of Liver Transplantation of West China Hospital, Sichuan University between 2001 and 2007. Five recipients demonstrated clinical characteristics similar to 7DS. The demographics of these patients are shown in Table 1.

No primary non-function cases were found in our series. MELD score, operation time, cold ischemic timeof the allograft, diameter of the portal vein, age and preoperative waiting time were compared between the 5 patients and the other 93 recipients.

Table 1. Demographic data of 7DS patients

LDLT and postoperative treatment

Immunosuppressive therapy with tacrolimus (FK506)and mycophenolate mofetil was given to all patients,and the drug concentration in serum was monitored twice a week. Vascular patency was checked by daily Doppler ultrasonography during the stay in the liver transplantation intensive care unit. The levels of bilirubin, transaminase, creatinine and urea nitrogen in serum were monitored daily. Low-molecular-weight heparin was injected once or twice daily to prevent arterial thrombosis.

Statistical analysis

Statistical analysis was made with SAS version 9.0.The waiting time was analyzed using Wilcoxon's ranksum test, and mean of the other data was analyzed using the unpaired Student's t test or Student-Neuman-Keuls procedure. A P value less than 0.05 was considered statistically signi fi cant.

Results

In the 5 patients, a sudden peak of extremely high liver enzymes occurred at days 7 to 14 despite potent antirejection therapy. Doppler ultrasonography showed slow blood in fl ow of the portal vein and abnormal enzyme levels, the levels of serum creatinine and urea nitrogen increased, and the 24-hour urine volume decreased.Liver biopsy showed central lobular hemorrhage and hepatocellular necrosis and apoptosis. No evidence of vascular thrombosis, acute rejection, or small-for-size syndrome was found. We concluded that these patients indeed suffered from 7DS. Two of these patients had fever before the enzyme levels became abnormal (Fig. 1).

In our study, all the 5 patients received routine management after transplantation and their condition improved gradually. But 1 to 2 weeks (average 11 days)after operation, their serum enzyme levels sharply increased without any symptoms and their renal function deteriorated for example, 3 patients were subjected to hemodialysis. Finally, 4 patients died.

The data of the 5 patients were compared with the other 93 recipients (Table 2). Their age, waiting time to transplantation, MELD score, operation time,cold ischemic time, portal interceptive time, hepatic artery in fl ow and diameter of the portal vein were not signi fi cantly different. However, there was a difference in the fl ow rate of the portal vein when the enzyme levels increased (t=3.234, P＜0.001).

Fig. 1. Changes in biochemical data after LDLT. When the liver enzyme levels began to rise, the fl ow rate of the portal vein decreased(green lines). In the patients who died (patients 2-5), serum TB level rose suddenly just before death but at the same time the liver enzyme levels decreased to normal. This phenomenon, which indicates a large area of hepatocyte necrosis, did not appear in patient 1 (the only survivor).

Fig. 2. ALT and TB in 7DS, acute rejection and artery thrombosis. The levels of serum enzymes increased sharply in 7DS and the elevated degree of serum TB was greater in acute rejection.

Table 2. Information about the two groups

Fig. 3. Liver biopsy showing hepatocellular ischemic necrosis and no evidence of acute rejection of hepatocytes.

To further analyze these features, the biochemical data of these patients were compared with those who suffered from acute rejection (n=10) and arterial thrombosis (n=5) (Fig. 2). In patients with acute rejection, the serum levels of total bilirubin and enzymes increased but the elevation of bilirubin was greater than in 7DS patients. All the 5 patients underwent liver biopsy, but there was no evidence of acute rejection (Fig.3).

Discussion

7DS, a serious complication in liver transplantation,has been given different names such as massive hemorrhagic necrosis of the liver and acute hepatocyte apoptosis.[5,6]So far, there is no effective treatment for this complication, and re-transplantation might be the only choice of treatment.[1]In our study, none of the patients received re-transplantation because of lack of donors. Only one patient survived, but his treatment was not different from that of the other 4 patients. The serum bilirubin level of the survivor decreased after the reduction of serum enzymes (Fig. 1), but the 4 deaths presented the phenomenon of ‘bilirubin-enzyme disassociation’ which is similar to fulminant hepatitis,suggesting a large area of hepatocyte necrosis. The prognosis is poor once this phenomenon appears. The cause of hepatocellular necrosis might be related to the reduction of portal vein in fl ow.

The in fl ow of the portal vein was monitored daily after operation by ultrasound in our series. When serum enzymes were abnormal, the in fl ow of the portal vein decreased or even reversed. Meanwhile, the levels of serum creatinine and urea nitrogen increased gradually and the 24-hour urine volume decreased.These characteristics which suggested that the liver and kidney were undergoing hypoperfusion or ischemia.Although the fl ow rate in the hepatic artery was normal after operation, the reduction of portal vein in fl ow alone led to hepatocellular ischemic necrosis, and this might be the etiopathogenesis of 7DS. There is no suf fi cient evidence to associate portal vein in fl ow with 7DS. And the cause of hypoperfusion is still unclear.Moriel et al[7]reported a case of ischemic hepatitis caused by cardioversion, which was characterized by a marked rise in transaminases within 24-48 hours of circulatory failure. Liver function tests revealed the high levels of aspartate aminotransferase and alanine aminotransferase, but total bilirubin within normal limits. Liver biopsy showed hepatocyte necrosis.

In this study, we compared the 5 patients with those who suffered from arterial thrombosis (Fig. 2), and found that the serum enzyme levels increased markedly in the latter.[8-10]We know that there are two bloodsupply systems for the liver. In healthy adults, there is no problem if only one of the systems is obstructed. But obstruction can lead to graft failure in transplantation patients.[8,11]Many complications can in fl uence portal in fl ow, such as thrombosis of the portal vein, diameter of the portal vein, and stenosis of the anastomotic stoma.[11]But there was no evidence that the 5 patients suffered from these complications. In our study, the diameter of the portal vein and anastomotic stoma was different from that in other recipients. So the reduction of portal vein in fl ow was not related to stenosis of the portal vein. Tao et al[12]reported a single center study of recipients with portal vein thrombosis and concluded that those recipients tended to suffer from posttransplantation complications like renal failure and lower portal vein fl ow rate. But our patients were nonthrombotic before operation.

Another complication, called post-reperfusion syndrome, can lead to postoperative liver and renal dysfunction after revascularization of the graft during liver transplantation,[13]fi rst described by Aggarwal et al[14]in 1987. It is a syndrome of severe cardiovascular dysfunction, bradyarrhythmia, decreased mean arterial pressure and systemic vascular resistance, along with an increased mean pulmonary artery pressure, pulmonary capillary wedge pressure, and central venous pressure.But retrospective analysis of our series showed that none of them presented features similar to those described by Aggarwal et al[14]during operation; therefore we excluded the possibility that the 5 patients suffered from postreperfusion syndrome.

Serial core biopsies and explanted livers of patients with 7DS showed a signi fi cantly higher number of apoptotic hepatocytes than in other transplanted patients,suggesting that 7DS is a distinct entity associated with early graft dysfunction and characterized by marked hepatocyte apoptosis. Fas receptor activation or other pathways of programmed cell death have been implicated in the occurrence of 7DS.[15,16]

One interesting feature is that 3 of 5 pairs of donorrecipients were group O in our study. Earlier fi ndings have shown that 5 of 10 7DS patients had O-type blood as reported by Memon et al,[1]and all 3 cases had O-type blood reported by Hwang et al.[2]It seems that group O patients have a tendency to suffer 7DS, but there is insuf fi cient evidence to associate blood group with 7DS.

Only 2 of the 5 patients in our study had fever,which differs from the reports of Memon et al[1]and Hwang et al.[2]They found all cases had fever before morbidity and suggested fever of unknown etiology after transplantation as a sign of 7DS.

In summary, although we still lack knowledge of the causes of 7DS, our study showed that hypoperfusion or ischemia of the liver graft after operation might be the leading factor. Whether this is a common event in 7DS remains unclear, so large-scale analysis of clinical data and experimental studies are needed to understand and treat this syndrome.

Funding: None.

Ethical approval: Not needed.

Contributors: LB proposed the study. LX wrote the fi rst draft and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. LB is the guarantor.

Competing interest: No bene fi ts 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 Memon MA, Karademir S, Shen J, Koukoulis G, Fabrega F,Williams JW, et al. Seventh Day Syndrome--acute hepatocyte apoptosis associated with a unique syndrome of graft loss following liver transplantation. Liver 2001;21:13-17.

2 Hwang S, Lee SG, Ahn CS, Kim KH, Moon DB, Ha TY.Reappraisal of seventh-day syndrome following living donor liver transplantation. Transplant Proc 2006;38:2961-2963.

3 Pastacaldi S, Teixeira R, Montalto P, Rolles K, Burroughs AK. Hepatic artery thrombosis after orthotopic liver transplantation: a review of nonsurgical causes. Liver Transpl 2001;7:75-81.

4 Demirhan B, Bilezik?i B, Haberal AN, Sevmis S, Arat Z,Haberal M. Hepatic parenchymal changes and histologic eosinophilia as predictors of subsequent acute liver allograft rejection. Liver Transpl 2008;14:214-219.

5 Ludwig J. Histopathology of the liver following transplantation. In Maddrey WC (ed): Transplantation of the Liver.New York: Elsevier; 1988:191.

6 Hübscher SG, Adams DH, Buckels JA, McMaster P, Neuberger J, Elias E. Massive haemorrhagic necrosis of the liver after liver transplantation. J Clin Pathol 1989;42:360-370.

7 Moriel M, Morali G, Rosenmann E, Shaheen J, Tzivoni D.Cardioversion-induced fulminant ischaemic hepatitis. Eur J Gastroenterol Hepatol 2001;13:1481-1483.

8 Stange BJ, Glanemann M, Nuessler NC, Settmacher U,Steinmüller T, Neuhaus P. Hepatic artery thrombosis after adult liver transplantation. Liver Transpl 2003;9:612-620.

9 Perkins JD. Thrombolysis for early hepatic artery thrombosis:de fi nitive therapy or diagnostic aid? Liver Transpl 2007;13:927-928.

10 Silva MA, Jambulingam PS, Gunson BK, Mayer D, Buckels JA, Mirza DF, et al. Hepatic artery thrombosis following orthotopic liver transplantation: a 10-year experience from a single centre in the United Kingdom. Liver Transpl 2006;12:146-151.

11 Woo DH, Laberge JM, Gordon RL, Wilson MW, Kerlan RK Jr. Management of portal venous complications after liver transplantation. Tech Vasc Interv Radiol 2007;10:233-239.

12 Tao YF, Teng F, Wang ZX, Guo WY, Shi XM, Wang GH, et al. Liver transplant recipients with portal vein thrombosis: a single center retrospective study. Hepatobiliary Pancreat Dis Int 2009;8:34-39.

13 Ramsay M. The reperfusion syndrome: have we made any progress? Liver Transpl 2008;14:412-414.

14 Aggarwal S, Kang Y, Freeman JA, Fortunato FL, Pinsky MR.Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation. Transplant Proc 1987;19:54-55.

15 Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, et al. Lethal effect of the anti-Fas antibody in mice. Nature 1993;364:806-809.

16 Nagata S. Apoptosis by death factor. Cell 1997;88:355-365.

BACKGROUND: Seventh-day syndrome (7DS) is an early serious complication following liver transplantation with a high mortality because of its unknown etiopathogenesis. This study aimed to analyze the potential etiopathogenesis of 7DS.METHODS: A retrospective analysis of 98 consecutive living donor liver transplants performed from 2001 to 2007 at our center revealed that 5 patients had suffered from 7DS; their age, MELD score, portal vein in fl ow and other parameters were compared with those of the other recipients.

RESULTS: The 5 patients showed common features: (a)initial uneventful recovery, and a dramatic rise of serum liver enzyme levels 1 to 2 weeks later; (b) decreased in fl ow in the portal vein accompanied by augmentation of serum creatinine and urea nitrogen level; and (c) serial liver biopsy fi ndings of apoptosis and ischemic necrosis of hepatocytes. Four of the 5 patients died. Age, waiting time to transplantation, MELD score, operation time, cold ischemic time, portal interceptive time and diameter of the portal vein were not signi fi cantly different between the 2 groups,but a difference was found in the fl ow rate of the portal vein(t=3.234, P＜0.001).

CONCLUSIONS: The 5 patients suffered from a decreased portal vein in fl ow, ischemic liver necrosis, and renal failure.Hence, hypoperfusion of the liver graft was considered to be the etiopathogenesis of 7DS, for which, however suf fi cient evidence is lacking. More studies of 7DS are needed.

Author Af fi liations: Division of Liver Transplantation (Lan X, Li B, Wang XF, Wei YG and Yan LN) and Division of Vascular Surgery (Zhao JC), West China Hospital, Sichuan University, Chengdu 610041, China

Bo Li, MD, Division of Liver Transplantation,West China Hospital, Sichuan University, Chengdu 610041, China (Tel:86-28-81812470; Email: doclibo@163.com)

? 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.

right liver grafts (segmentsⅤ-Ⅷ) and the branch of the middle hepatic vein was reconstructed in 58 of them. Only one pediatric patient

a living-related left lobar graft and another 2 received living-related left and right lobar graft from different donors. A side-to-end anastomosis was made between the hepatic vein and the recipient inferior vena cava. Arterial anastomosis was usually made between the donor right hepatic artery and the common hepatic artery of the recipient with prolene 8/0. End-to-end portal vein anastomosis was made between the donor right branch and the stem of the recipient using a running suture with prolene 4/0 or 5/0.

Received February 9, 2009

Accepted after revision June 19, 2009