Objectives: Despite living-donor liver transplant being a life-saving therapy for patients with hepatitis B virus with or without hepatocellular carcinoma, outcomes for patients with these diseases are worse. Hepatitis B virus recurrence or relapse of hepatocellular carcinoma can result in subsequent graft loss or patient death. In this study, we discuss the postoperative outcomes of patients with hepatitis B virus infection after living-donor liver transplant.
Materials and Methods: We retrospectively analyzed 125 patients with hepatitis B virus-related end-stage liver disease, comparing results with 1228 control patients who had other pathologies, including hepatitis C virus, combined hepatitis B virus and hepatitis C virus, and neither virus.
Results: Survival rates of patients with hepatitis B virus did not differ from the control groups (P > .05). Patients with concurrent hepatitis B virus and hepatocellular carcinoma were significantly older (P < .0001), had critical status (P < .0001), had chronic underlying pathology (P = .001), lower graft-to-recipient body weight ratio (P = .047), needed more intraoperative plasma transfusion, and experienced more rejection episodes than those without hepatocellular carcinoma. Of interest, in 5 patients who had hepatitis B virus recurrence after living-donor liver transplant, Model for End-Stage Liver Disease score was significantly higher than those who did not have recurrence (P = .015). In addition, 2 patients had hepatocellular carcinoma recurrence in the form of peritoneal metastasis, with both patients having high preoperative alpha-fetoprotein levels.
Conclusions: Our study provides details on long-term outcomes of patients with hepatitis B virus infection who had undergone living-donor liver transplant. Based on our results, we suggest that prolonged antiviral prophylactic therapy in the form of hepatitis B immunoglobulin with either lamivudine or entecavir be considered for patients who associated with risk factors to prevent postoperative recurrence.
Key words : Hepatitis C virus, Hepatocellular carcinoma, Recurrence
In Asia, particularly in Japan, living-donor liver transplant (LDLT) is considered the treatment of choice for patients with end-stage liver disease resulting from hepatitis B virus (HBV) infection.1,2 Hepatocellular carcinoma (HCC) is a common sequel of chronic HBV, which can also be successfully treated with LDLT.3-5 Hepatocellular carcinoma recurrence after LDLT has long been recognized as a reason for high patient mortality.6-8 In addition, the risk of HBV reinfection after LDLT can be minimized by efficient combinations of therapeutic prophylactic agents.9-13 However, emergence of drug mutations, such as emergence of the HBV polymerase gene locus known as tyrosine-methionine-aspartate-aspartate (YMDD), can result in resistance to the commonly used HBV prophylactic agents, including the purine nucleoside analog reverse-transcriptase inhibitor lamivudine.14-16 Thus, both HCC recurrence and HBV relapse after LDLT are major complications that can affect patient mortality. However, information on the long-term outcomes of HBV-infected patients after LDLT regarding HCC recurrence and HBV recurrence is scarce. Moreover, information regarding how different pathologic characteristics of HBV affect patient and graft survival after LDLT remains limited. Therefore, in this study, we analyzed data from patients with hepatitis B-related diseases undergoing LDLT to determine the clinicopathologic and perioperative features of HBV-infected patients and the contribution of this disease to the long-term outcomes of these patients.
Materials and Methods
Between June 1990 and May 2010, 1463 LDLTs were performed in 1391 cases at Kyoto University Hospital (Kyoto, Japan). Our patient group included 1353 patients.
Surgical procedure and immunosuppression therapy
The surgical techniques and preoperative treatment of transplant recipients at our center have been previously described in detail. In brief, tacrolimus and corticosteroids were used as the main immunosuppressants.17,18 Additional immunosuppressive agents, such as azathioprine, mizoribine, or mycophenolate mofetil, were administered to inhibit humoral rejection or to decrease the doses of corticosteroids and tacrolimus whenever indicated. In case of rejection, tacrolimus and steroid pulse therapy were administered.19,20
Anti-hepatitis B virus therapy
Either lamivudine at 150 mg/day (before March 2000) or 100 mg/day (after March 2000) or entecavir at 0.5 mg/day (after 2006) was given before transplant, most often when the patient was admitted and scheduled for transplant. After the transplant procedure, a combination of either entecavir or lamivudine with hepatitis B immunoglobulin was started. Hepatitis B immunoglobulin was administered intravenously at 200 IU/kg body mass during the anhepatic phase of LDLT and repeated every day for the first 5 days posttransplant. Tests for hepatitis B virus serologic markers were performed every week during the first 2 months after transplant and then at monthly intervals thereafter, and 1000 to 5000 IU of hepatitis B immunoglobulin (based on body mass and hepatitis B surface antibody levels) were periodically administrated to maintain the serum antihepatitis B titers at greater than 500 IU/L during the first 6 months and 200 IU/L thereafter throughout follow-up.21
Viral markers and hepatis B virus DNA follow-up
Preoperative diagnosis of HBV and hepatitis C virus (HCV) infection in recipients and donors was performed by analyzing the serum markers of HBV and HCV and HBV DNA. Seropositive donors were excluded. These markers were also measured before preoperative lamivudine administration. Posttransplant follow-up was in accordance with the Kyoto method.21 Recurrence of HBV infection was diagnosed by hepatitis B surface antigen or HBV DNA positivity. Enzyme-linked immunoassay assays (Dinabott Inc., Tokyo, Japan) were used to detect HBV markers (hepatitis B surface antigen and antibody, hepatitis B core antibody, and hepatitis B e antigen and antibody). Positivity for HBV DNA was quantitatively detected using a transcription-mediated amplification and hybridization protection assay with patient sera as previously described.21,22
Tyrosine-methionine-aspartate-aspartate mutation after lamivudine therapy was suspected if there was a rise in HBV DNA levels despite ongoing lamivudine therapy, if HBV reinfection occurred with hepatitis B surface antigen positivity after seroconversion, and/or if hepatitis B e antigen levels seroconverted to positive or had increased. We used the SMITEST HBV-YMDD motif ELMA (Genome Science Laboratories Co., Ltd., Fukushima, Japan) for YMDD mutational testing.21
Postoperative antimicrobial prophylaxis
Oral flomoxef, an oxacephem antibiotic, was started immediately after transplant and continued for 3 days thereafter to prevent bacterial infection. Patients received prophylactic treatment against pneumocystis, including sulfamethoxazole/trimethoprim, once daily. Oral miconazole was administered for 1 week after transplant as antifungal prophylaxis. Antiviral prophylactic agents, including ganciclovir, were administered for seronegative recipients who received allografts from cytomegalovirus-seropositive donors.23,24
Patient infections and measured variables
Bacterial, fungal, and viral infections were defined using the Kyoto University protocol and in accordance with the criteria proposed by the United States Centers for Disease Control and Prevention.23-26
In our study, preoperative, operative, and postoperative variables were evaluated. The preoperative variables included age at the time of LDLT, sex, clinical status, and preoperative diagnosis. Laboratory variables included complete blood cell count, liver function markers (aspartate transaminase, alanine transaminase, total bilirubin, and albumin levels), coagulation factors (international normalized ratio, antithrombin III, platelet count, and prothrombin time), renal function markers (serum urea nitrogen and creatinine levels), ABO mismatching, preoperative HBV treatment, Child-Turcotte-Pugh score, and Model for End-Stage Liver Disease score. Operative variables included transplant procedure time, cold ischemic time, warm ischemic time, blood or blood product transfusion (packed red blood cells, fresh frozen plasma, and platelets), fluid transfusion (5% albumin), blood loss, and graft-to-recipient body weight ratio. Postoperative variables included surgical complications (intra-abdominal hemorrhage, bile leak, and intestinal perforation), acute respiratory distress syndrome, portal vein thrombosis, hepatic artery thrombosis, renal dialysis, infection, rejection, and HBV, HCV, or HCC recurrence.
Graft dysfunction was defined as persistent abnormal liver function with serum aminotransferase levels 2 to 3 times above normal, with or without elevated bilirubin levels, and abnormal biopsy finding.
Statistical analyses were performed with SPSS Software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA). Data are presented as means ± standard deviations, median, range, or percentage where appropriate. The log-rank test was used to compare patient and graft survival between patients according to their diagnosis. We used t test for quantitative data or chi-square test for qualitative data comparisons between LDLT recipients where appropriate.
Patient characteristics are detailed in Table 1. Over a 20-year period (from June 1990 to May 2010), 1391 patients underwent 1463 LDLTs at Kyoto University Hospital. Seventy patients received a second transplant, and 2 patients required a third transplant. Our study included 1353 patients; the median follow-up was 99.68 months (range, 3.03-246.41 mo). Patients who did not survive longer than 3 months or had incomplete data were not included in this study. Among the patients, 125 patients (9.3%) had HBV infections, 173 patients (12.8%) had HCV infections, and 5 patients (0.37%) had both HBV and HCV; 1050 patients (77.6%) were referred for transplant for other pathologies (these constituted the 4 patient groups).
Analyses of patients with hepatitis B virus infection compared with other
Characteristics of all study patients are listed in Table 1. The mean age at time of transplant significantly varied among patients groups (P < .0001), with patients who had neither HBV nor HCV infection being significantly younger. There were also more female patients with HBV and HCV infections compared with the other patient groups (P < .0001). Indications for LDLT in the 4 patient groups were significantly different (P < .0001). In patients with HBV infection only, chronic liver cirrhosis/hepatitis accounted for 83.2% (104 patients), fulminant hepatic failure accounted for 11.2% (14 patients), and acute and chronic hepatitis accounted for 5.6% (7 patients) of transplants. In patients with HCV infection only, chronic liver cirrhosis/hepatitis accounted for 99.4% (172 patients) and fulminant hepatic failure accounted for 0.6% (1 patient) of transplants. In patients with both HBV and HCV infection, chronic liver cirrhosis/hepatitis accounted for 100% (5 patients) of transplants, with no fulminant hepatic failure cases reported. In patients with neither HBV nor HCV infection, chronic liver cirrhosis/hepatitis accounted for 95% (52 patients) and fulminant hepatic failure accounted for 7.4% (78 patients) of transplants, with the remaining 920 patients (87.6%) receiving transplants for different reasons.
Pretransplant biopsies consistent with a diagnosis of HCC revealed that 61 patients with HBV infection (48.8%) had HCC, whereas 104 patients with HCV infection (60.1%) had HCC. In those with both HBV and HCV infection, 4 patients had HCC and lastly; 23 patients (2.2%) with neither HBV nor HCV had HCC.
Patient and graft survival
In our cohort, 335 patients died; of these patients, 33 patients had HBV infection, 52 patients had HCV infection, 4 patients had both HBV and HCV, and 246 had neither HBV nor HCV. Patient survival was significantly different among the 4 groups (P < .0001; Figure 1A).
Graft survival was also significantly different (P < .0001) among the groups. In our cohort, 377 patients lost their grafts; of these, 34 patients had HBV infection, 53 patients had HCV infection, 4 patients had both HBV and HCV, and 286 had neither HBV nor HCV (Figure 1B).
Perioperative characteristics of patients with hepatitis B virus infection
According to pathology results, the patients with HBV infection could be divided into 2 groups: HBV patients with HCC and HBV patients without HCC. Preoperative characteristics of patients with HBV infection are listed in Table 2; patients without HCC were significantly younger than those with HCC (P < .0001). The preoperative status of patients with concomitant HCC was significantly different from those without HCC (P < .0001). Similarly, diverse underlying hepatic pathology was found between the 2 groups, as chronic hepatitis and liver cirrhosis were predominant pathologies in patients with HCC, whereas fulminant hepatic failure was a predominant pathology in patients without HCC (P = .001). In addition, graft-to-recipient body weight ratio was significantly higher in patients without HCC than in those with HCC (P = .047). However, the proportion of female patients, ABO mismatch, Child-Turcotte-Pugh scores, and Model for End-Stage Liver Disease scores did not differ between the 2 groups.
Interoperative characteristics of patients with hepatitis B virus infection
There was significantly more need for plasma transfusion in patients with HCC than in those without HCC (P = .046). However, no differences were shown regarding surgical procedure time, cold ischemia time, warm ischemia time, blood loss, packed red blood cells, fresh frozen plasma, or platelet transfusion between the 2 groups.
Postoperative characteristics of patients with hepatitis B virus infection
Patients with HCC had a significantly lower number of rejection episodes than those without HCC (P = .002). In our cohort, there were posttransplant infections in 57 patients with HCC and in 45 patients without HCC; however, results were not significantly different.
During a median follow-up of 4.8 years posttransplant, 5 patients (4%) had HBV recurrence (at 5.2 ± 2.2 y; range, 3-5 y), which was significantly related to high Model for End-Stage Liver Disease score (P = .015); 2 of these patients had HCC at LDLT. One patient among the 5 patients with HBV recurrence died as a result of recurrence.
In patients with HCC, 2 patients had HCC recurrence after LDLT. The first patient was a 53-year-old male who had been diagnosed with liver cirrhosis due to HBV infection. In 2001, he was diagnosed with 1 nodule of HCC in S5 (about 36 mm in diameter), which was treated with radiofrequency ablation. One year later, HCC recurred at S8. After 1 year, a metastatic lesion in the lung was noticed. Subsequently, the patient’s status deteriorated and he was admitted to the intensive care unit with grade 3 hepatic coma and bilateral atelectasis with arterial oxygen level of 68 mm Hg, with improved condition with BiPAP mask (Philips Respironics Murrysville, PA, USA). He underwent LDLT during the same month, with a class C Child-Turcotte-Pugh score (11 points) and a Model for End-Stage Liver Disease score of 13 points; tumor marker levels before transplant showed an increase in the α-fetoprotein of 2234 ng/dL. The patient was also treated in accordance with our general clinical and immunosuppressive protocol.
Peritoneal dissemination was diagnosed in this patient 1 year after LDLT. He started to receive chemotherapy and radiotherapy. He died 5 years after transplant.
The second patient with HCC recurrence after LDLT was a 51-year-old man with liver cirrhosis due to HBV infection since 1986 who was treated with interferon with no improvement. Starting in 2002, he was treated with lamivudine; 1 year after that, HBV DNA levels started to increase, and the patient was diagnosed as YMDD, which necessitated use of advair treatment in 2004. The patient developed esophageal and gastric varices and was found to have HCC in 2003 and admitted to the intensive care unit for LDLT in 2004, with a class C Child-Turcotte-Pugh score (13 points), Model for End-Stage Liver Disease score of 19, and α-fetoprotein level of 3209 ng/dL. After surgery, α-fetoprotein levels started to rise; at 1 year, histopathologic examination revealed lymph node enlargement of hepatic origin. An intra-abdominal resection was performed in 2006, the patient received chemotherapy, and 2 months later the patient developed intestinal penetration. However, the patient’s condition deteriorated during the next 5 months, and the patient died 2.8 years after LDLT.
Worldwide, HBV infection is still considered one of the leading factors for liver cirrhosis and consequently HCC. In Japan, LDLT is currently considered an efficient, life-saving therapy for HBV, with or without HCC. However, LDLT is more troublesome for patients who undergo this procedure for coexisting HBV infection and HCC, as HBV recurrence or relapse of HCC may result in subsequent graft or patient loss. In this study, we described our center’s 20-year experience, analyzing 125 patients with HBV infection, showing that the overall survival did not differ between those who are HBV free or even those who are infected with HCV. Consequently, we observed important findings regarding factors that influence postoperative HBV reinfection and HCC recurrence, mainly the use of effective preoperative anti-HBV prophylactic treatment and the proper selection of HCC patients.
We found that patients with HBV infection who underwent LDLT were of similar age to patients with HCV infection or combined HBV and HCV infection. However, these patients were significantly older than patients who underwent LDLT but had neither HBV nor HCV infection (P < .001). These observations were in accordance with the previous reports of LDLT at Kyoto Institution, in which cholestatic diseases were the main indication of LDLT in young patients, followed by congenital metabolic disease, and fulminant hepatic failure.2 Although sex did not differ among patients infected with HBV, HCV, or both, we found a significantly higher number of male patients who had LDLT but had neither HBV nor HCV infection (P < .001). Patients with HBV infection had a lower incidence rate of HCC versus than those who had HCV infection alone or HCV and HBV. However, patient with HBV infection had a significantly higher incidence of HCC than those who had no HBV and no HCV infection. Similar to our previous findings from Japan,27 a study in the United States28 revealed a higher incidence of HCC among patients with HCV infections than those with HBV infections. Moreover, Mazzaferro and associates29 reported that, among the 48 HCC patients enrolled in their study, 11 (22.9%) had HBV and HCC compared with 32 (66.7%) who had HCV and HCC. Notably, among the 125 patients with HBV infection in our study, 21 (16.8%) had acute hepatic failure either due to fulminant hepatic failure or acute and chronic failure, a finding that was significantly different from the remaining groups (P < .0001). These data were previously supported by reports from our center and others.30,31
Posttransplant survival rates in patients with HBV have become comparable to rates shown in patients with HCV or those without HBV and HCV. Therefore, transplant outcomes (patient survival or graft survival rate) in our cohort did not differ among patients with HBV, HCV, or neither HBV nor HCV. Miyagawa and associates also could not find significant differences in patient disease-free survival rates after hepatectomy for HCC among 175 patients with either HBV, HCV, or neither HBV nor HCV.28 This can be largely attributed to the greatly reduced recurrence rate of hepatitis after liver transplant in patients with HBV infection after the introduction of prophylactic therapy in the form of either lamivudine and hepatitis B immunoglobulin or entecavir and hepatitis B immunoglobulin.9,21,32-35 We found significantly low patient and graft survival in patients with both HBV and HCV in our study; this finding is similar to the results of Waki and associates,36 who analyzed data from the United Network for Organ Sharing for liver graft survival in patients with different types of viral hepatitis and found that recipients with HBV had the highest graft survival compared with patients with HCV infection or patients with combined HBV and HCV. In our study, we only had 5 patients with combined HBV and HCV; all of these patients had fulminant hepatic failure and 4 had concomitant HCC, which resulted in worse prognosis.31
Patients with HBV were divided based on the pathologic feature of presence or absence of HCC and analyzed. We found that most patients with HBV and HCC were significantly older than those with HBV but without HCC, as the majority of those with both diseases had liver cirrhosis in comparison to those with HBV but without HCC who had either fulminant hepatic failure or acute and chronic hepatic failure. Together, this contributes to the understanding that chronic illnesses, such as liver cirrhosis and malignancy, are usually found in older patients. Moreover, more than one-half of the patients with both diseases were critically ill before transplant, whereas only one-fourth of patients with HBV but without HCC had acute hepatic failure and needed admission to an intensive care unit. Graft-to-recipient body weight ratio was significantly higher in patients without HCC than in those with HCC, although both were > 0.85%, the suggested minimal amount for graft-to-recipient body weight ratio in adults to avoid small-for-size syndrome and related complications.37 Acute rejection episodes were more frequent in patients with HBV but without HCC, perhaps attributable to differences in underlying pathology as most these patients had fulminant hepatic failure and urgent procedures done for them, although most of these rejection attacks were treated successfully, showing graft survival.
Although our prophylactic protocol in the form of lamivudine plus hepatitis B immunoglobulin therapy before December 2006 and entecavir plus hepatitis B immunoglobulin or lamivudine plus hepatitis B immunoglobulin after December 2006 and regular follow-up for virologic markers elicited a favorable outcome in preventing HBV relapse after LDLT, careful assessment of patients with concurrent HBV before LDLT is mandated, as here we observed that a higher Model for End-Stage Liver Disease score was associated with recurrence after liver transplant.
Careful assessment of patients with concurrent HCC before LDLT is crucial, as here we observed that the 2 patients with metastatic recurrence after liver transplant had a worse preoperative course in the form of high Model for End-Stage Liver Disease score, high Child-Turcotte-Pugh score, and metastatic lesions as previously reported.4 Consequently, it is likely that differences in preoperative status of patients should be considered in decisions about LDLT in HCC patients.
This is the first report to provide detailed long-term outcomes of patients with HBV infection who underwent LDLT, although a study limitation is that we could not include patients who had incomplete medical records. We suggest that the identified risk factors in this study should be considered in the perioperative care of patients with HBV, which can help to identify effective prevention and treatment strategies.
Volume : 14
Issue : 2
Pages : 207 - 214
DOI : 10.6002/ect.2015.0206
From the 1Department of Microbiology and Immunology, Faculty of
Medicine, Assiut University, Assiut, Egypt; the 2Department of
Hematology and Immunology, Faculty of Medicine, Umm Al-Qura University, Mecca,
Saudi Arabia; the 3Department of Anesthesia, Faculty of Medicine,
Assiut University, Assiut, Egypt; the 4Department of Anesthesiology,
King Abdullah Medical City, Mecca, Saudi Arabia; the 5Department of
clinical pathology faculty of medicine Assiut University, Assiut, Egypt; and the
6Department of Hepatobiliary Pancreatic Surgery and Transplantation,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
Acknowledgements: The authors declare that they have no conflicts of interest and received no funding for this study. Hanaa Nafady-Hego, Hamed Elgendy, Asmaa Nafady, and Shinji Uemoto carried out the research. Hanaa Nafady-Hego, Hamed Elgendy, Asmaa Nafady, and Shinji Uemoto wrote the paper. Hanaa Nafady-Hego, Hamed Elgendy, and Shinji Uemoto participated in research design. Hanaa Nafady-Hego conducted the data analysis. Shinji Uemoto directed the transplant program.
Corresponding author: Hanaa Nafady-Hego, Hepatobiliary Pancreatic Surgery and Transplantation, Graduate school of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, 606-8507-Kyoto, Japan
Phone: +81 75 751 4328
Fax: 81 75 751 4328
E-mail: email@example.com - firstname.lastname@example.org
Table 1. Characteristics of Patients with Hepatitis B, Hepatitis C, and Both, or Neither Hepatitis B and C Infections
Table 2. Perioperative Characteristics of Patients with Hepatitis B Virus Infection
Figure 1. Patient and Graft Survival in Study Patients After Living-Donor Liver Transplant