The genomic landscape of Mongolian hepatocellular carcinoma.

Mongolia has the highest incidence of hepatocellular carcinoma (HCC) in the world, but its causative factors and underlying tumor biology remain unknown. Here, we describe molecular characteristics of HCC from 76 Mongolian patients by whole-exome and transcriptome sequencing. We present a comprehensive analysis of mutational signatures, driver genes, and molecular subtypes of Mongolian HCC compared to 373 HCC patients of different races and ethnicities and diverse etiologies. Mongolian HCC consists of prognostic molecular subtypes similar to those found in patients from other areas of Asia, Europe, and North America, as well as other unique subtypes, suggesting the presence of distinct etiologies linked to Mongolian patients. In addition to common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analysis, Mongolian HCC exhibits unique drivers (most notably GTF2IRD2B, PNRC2, and SPTA1), the latter of which is associated with hepatitis D viral infection. These results suggest the existence of new molecular mechanisms at play in Mongolian hepatocarcinogenesis.

Hepatitis B Virus and Hepatitis D Virus Recurrence in Patients Undergoing Liver Transplantation for Hepatitis B Virus and Hepatitis B Virus Plus Hepatitis D Virus.

BACKGROUND: In this study, we retrospectively analyzed the recurrence of hepatitis B virus (HBV) and hepatitis D virus (HDV) infection after liver transplantation for HBV and HBV+HDV co-infection. METHODS: Data from patients infected with HBV and HBV+HDV who underwent liver transplantation between March 2003 and June 2013 at the Liver Transplantation Institute of Inonu University were analyzed retrospectively. A total of 255 patients were included in the study. Group 1 (n = 127) comprised patients who underwent liver transplantation because of HBV, and group 2 (n = 128) comprised patients who underwent liver transplantation because of HBV+HDV. A positive HDV antibody serologic test result was taken to indicate liver disease caused by HBV+HDV. RESULTS: Thirteen of 255 were positive for the HBs Ag (5.1%). Nine (7.1%) and 4 (3.1%) patients were positive for the HBs Ag in groups 1 and 2, respectively (7.1%); the difference was not significant (P = .150). No HDV recurrence was detected in either group. The average time to HBs Ag seroconversion in 13 patients was 7.8 months after surgery (6.34 months in group 1 and 11.1 months in group 2). CONCLUSIONS: In our study, recurrence rate of HBV after liver transplantation is not statistically different than the recurrence rate of HBV+HDV co-infection. A low recurrence rate was achieved by the prophylaxis protocol in use at our center. There is no standard protocol for prevention of HBV and HDV recurrence; therefore, we need new studies.

Liver transplantation in a patient with hepatitis B, C and D coinfection associated with hepatocellular carcinoma: a management strategy for a rare condition. Case report / Transplante hepático em paciente com coinfecção pelos vírus B, C e D associada a carcinoma hepatocelular: uma estratégia de tratamento para uma condição rara. Relato de caso

CONTEXT: Orthotopic liver transplantation (OLT) is the treatment of choice for end-stage liver disease. Cirrhosis due to hepatitis C infection is the leading indication for liver transplantation worldwide. However, patients who are given transplants because of viral liver diseases often present clinical coinfections, including hepatitis B together with hepatitis D. Currently, different strategies exist for patient management before and after liver transplantation, and these are based on different protocols developed by the specialized transplantation centers. CASE REPORT: We present a rare case of a 58-year-old man with chronic hepatitis B, C and D coinfection. The patient developed cirrhosis and hepatocellular carcinoma. His treatment comprised antiviral therapy for the three viruses and OLT. The patient's outcome was satisfactory. CONCLUSION: OLT, in association with antiviral therapy using entecavir, which was administered before and after transplantation, was effective for sustained clearance of the hepatitis B and D viruses. A recurrence of hepatitis C infection after transplantation responded successfully to standard treatment comprising peginterferon alfa-2A and ribavirin.

CONTEXTO: O transplante ortotópico de fígado (TOF) é o tratamento de escolha em pacientes com doença hepática terminal. A cirrose por hepatite C é a principal indicação de transplante hepático no mundo. No entanto, pacientes transplantados por hepatopatias virais frequentemente apresentam coinfecções, como hepatite B associada a hepatite D. Atualmente, existem diferentes estratégias de manejo em pacientes pré e pós-transplantados conforme diferentes protocolos de conduta de serviços especializados em transplante. RELATO DE CASO: Apresentamos o raro caso de um homem de 58 anos diagnosticado com as hepatites crônicas B, C e D. O paciente evoluiu com cirrose e carcinoma hepatocelular. O tratamento consistiu de terapia antiviral para os três vírus e de transplante ortotópico de fígado. O desfecho do paciente foi satisfatório. CONCLUSÃO: O transplante ortotópico de fígado, associado à terapia antiviral com entecavir antes e após o procedimento, foi eficaz na depuração sustentada dos vírus B e D. A recidiva do vírus C após o transplante respondeu com sucesso ao tratamento padrão com alfapeginterferon 2A e ribavirina.

Liver transplantation in a patient with hepatitis B, C and D coinfection associated with hepatocellular carcinoma: a management strategy for a rare condition. Case report.

CONTEXT: Orthotopic liver transplantation (OLT) is the treatment of choice for end-stage liver disease. Cirrhosis due to hepatitis C infection is the leading indication for liver transplantation worldwide. However, patients who are given transplants because of viral liver diseases often present clinical coinfections, including hepatitis B together with hepatitis D. Currently, different strategies exist for patient management before and after liver transplantation, and these are based on different protocols developed by the specialized transplantation centers. CASE REPORT: We present a rare case of a 58-year-old man with chronic hepatitis B, C and D coinfection. The patient developed cirrhosis and hepatocellular carcinoma. His treatment comprised antiviral therapy for the three viruses and OLT. The patient's outcome was satisfactory. CONCLUSION: OLT, in association with antiviral therapy using entecavir, which was administered before and after transplantation, was effective for sustained clearance of the hepatitis B and D viruses. A recurrence of hepatitis C infection after transplantation responded successfully to standard treatment comprising peginterferon alfa-2A and ribavirin.

Liver transplantation in delta virus infection.

Liver transplantation is the only therapy for patients with end-stage liver disease, hepatocellular carcinoma, or fulminant hepatitis due to hepatitis D virus (HDV) and hepatitis B virus (HBV) coinfection or superinfection. Patients chronically coinfected with HDV are less at risk of HBV recurrence and have a better survival rate than patients infected with HBV alone. Patients coinfected with HDV generally do not require pretransplant antiviral therapy. Rates of recurrent HBV-HDV infection are lower than 5% using low-dose intramuscular (IM) HBIg and antiviral prophylaxis in combination. Few studies have evaluated the possibility of using shorter-term HBIg (12-24 months) then switching to antiviral therapy. Although HBV replication can be controlled by potent HBV-polymerase inhibitors, reappearance of HBsAg and/or the persistence of HBV DNA in serum, liver, or peripheral blood mononuclear cells might have deleterious consequences in the setting of HBV-HDV coinfection as they may provide the biologic substrate to the reactivation of HDV. No effective antiviral drug is available for the treatment of graft infection with HDV.

Course of a HBsAg positive liver transplantation in a hepatitis B and D virus coinfected recipient.

The increasing demand for transplantation has led to consideration of liver grafts from donors exposed to hepatitis B virus (HBV). Six transplantations of liver grafts from hepatitis B surface antigen (HBsAg) positive donors have been reported; two recipients suffered from HBV/HDV (hepatitis Delta virus) coinfection and were followed up for 10-12 months. Here, we report a 56 months follow-up of a HBV/HDV-coinfected recipient of a HBsAg positive liver graft. Posttransplant combination prophylaxis consisted of hepatitis immunoglobulin, lamivudine and adefovir dipivoxil. HBsAg remained positive during stable posttransplant follow-up and subclinical HDV reinfection with low replication rate was detected at 1 month. Pegylated interferon therapy was introduced after documentation of histological evidence of mild chronic hepatitis, but without virological response after 48 weeks. Finally, antiviral treatment was switched to tenofovir disoproxil fumarate. More than 50 months posttransplant the recipient revealed clinical symptoms of decompensated liver cirrhosis and has been relisted for liver transplantation. In conclusion HBsAg positive liver grafts in HBsAg positive recipients with HDV coinfection may result in virological recurrence and rapid development of liver cirrhosis.

Liver transplantation in bearers of hepatitis B associated or not with delta hepatitis in the age of the new antiviral drugs: is hyperimmune globulin still necessary?

Hepatitis B (HBV) is a public health problem worldwide; one-third of the population has already been in contact with HBV, and 350 million people are chronic carriers of virus. The appearance of hyperimmune gamma globulin and antiviral drugs has allowed that group to undergone hepatic transplantation, achieving satisfactory results to prevent a relapse. But the use of hyperimmune gamma globulin has an extremely high cost, and combined therapies with new antiviral drugs seem to be a therapeutic alternative. We analyzed 21 patients with hepatitis B associated or not with Delta hepatitis over a mean follow-up period of 19.5 months, concluding that use of only nucleotide analogues has sufficient to achieve satisfactory results.

Liver transplantation using donors older than 80 years: a single-center experience.

AIM: The shortage of organs for orthotopic liver transplantation (OLT) has forced transplantation centers to expand the donor pool by using donors traditionally labeled as "extended criteria donors." One such example is OLT using a donor with advanced age. MATERIALS AND METHODS: We retrospectively evaluated 10 patients who received a liver graft from cadaveric donors older than 80 years. We analyzed pretransplantation donor and recipient characteristics, as well as the evolution of the recipients. RESULTS: All 10 donors were older than 80 years (median age, 83.5; range, 80-93). No steatosis (>30%) was accepted in the older donor group. Medium follow-up was 19.5 months. The most frequent cause for OLT was hepatitis C virus (HCV) cirrhosis (8/10 patients). We had 1 case of primary nonfunction, 1 patient died immediately after surgery because of extrahepatic complications (cardiac arrest), and 2 other patients had a severe HCV recurrence and died after 1 and 2 years from OLT, respectively. Five patients had HCV recurrence and biliary complications were present in 60% of the patients. No cases of acute or chronic rejection were described. Overall survival rates after 1 and 3 years were 80% and 40%, respectively. CONCLUSIONS: Old donor age is not an absolute contraindication to OLT. Liver grafts from donors older than 80 years can be used knowing that there is a high risk of postoperative complications. Furthermore, the increased risk of developing severe HCV recurrence, related to older donor age, suggests that such livers should be used in HCV-negative recipients.

The recipient with portal thrombosis and/or previous surgery.

INTRODUCTION: Portal vein thrombosis (PVT) has been considered to be an absolute contraindication to liver transplantation (OLT) and previous upper abdominal surgery was considered to render it a high-risk procedure. Currently, these are only conditions considered risk factors increasing recipient morbidity and mortality. The objective of this study was to compare OLT perioperative morbidity, mortality, blood product consumption, and length of hospital stay among patients with or without PVT or with or without previous surgery. MATERIALS AND METHODS: Among 366 OLTs performed between July 1999 and November 2007, 33 liver transplant recipients displayed previous PVT while 34 had undergone previous surgery. The two groups of marginal recipients were compared with a cohort of 33 patients without PVT or previous surgery. RESULTS: The groups were homogeneous in terms of epidemiological variables, surgical techniques, and donor-related variables. In the PVT group, all analyzed parameters were the same as the control group; surgical time, anhepatic phase duration, early surgical complication, intensive care unit and hospital length of stay, and overall mortality. The only significant difference was the incidence of portal rethrombosis (P < .035). Among the previous surgery group, we did not observe significant differences. CONCLUSIONS: PVT and previous surgery should no longer be considered contraindications for OLT.

Longer survival of liver transplant recipients with hepatitis virus coinfections.

Hepatitis virus coinfections [HBV plus HCV coinfection (HBV/HCV) or HBV plus HDV coinfection (HBV/HDV)] may progress more rapidly to cirrhosis than hepatitis B or C monoinfections in immunocompetent patients. Only limited information is available on the outcome of coinfected patients after liver transplantation. We studied survival rates of 204 patients with viral hepatitis transplanted at our center between 1972 and 1997. HBV/HDV and HBV/HCV coinfections were present in 23 and nine individuals, respectively, while 97 patients had monoinfection by HCV and 75 had HBV monoinfection. Survival of coinfected patients was significantly longer than that of monoinfected patients (14.4 +/- 0.9 vs. 8.5 +/- 0.6 yr; p = 0.0003). The same was true for graft survival (p = 0.0002). In Cox's regression, viral coinfection (p = 0.0001), absence of hepatocellular carcinoma (HCC) (p = 0.00001) and no retransplantation (p = 0.02) were independently associated with patient survival. After exclusion of patients with HCC (n = 62), survival of coinfected patients was still significantly longer than that of monoinfected individuals (p = 0.002). The improved outcome was similar for both HBV/HDV and HBV/HCV coinfections. In contrast to immunocompetent patients, individuals with multiple hepatitis virus infections had an improved outcome after liver transplantation. Thus, viral coinfections may be associated with ameliorated courses of diseases under certain conditions.

Orthotopic liver transplantation in a malignant hyperthermia susceptible patient.

We present a patient with hepatitis C and D and hepatocellular carcinoma who underwent preoperative evaluation for orthotopic liver transplantation. In his past medical history, he reported a life-threatening event during tonsillectomy in 1975. Intubation was impossible due to extreme jaw muscle tension, followed by excessive elevation in body temperature, tachycardia, and coma for a few days. We evaluated him for malignant hyperthermia, according to the European Malignant Hyperthermia Group Protocol, and found him highly positive in both the halothane and caffeine test, respectively. Three months later, we performed an orthotopic liver transplantation. During retransplantation 4 years later, due to ischemic-type biliary lesions, he suffered massive intraoperative bleeding. Blood products, as well as coagulation factors and aprotinin, were well tolerated. Anesthesia was performed in a trigger-free total intravenous technique without dantrolene prophylaxis, but dantrolene was readily available in sufficient quantities in the operating room. The patient did not encounter a malignant hyperthermia crisis in either perioperative period.

Successful minimally invasive management of late portal vein thrombosis after splenectomy due to splenic artery steal syndrome following liver transplantation: a case report.

Portal vein thrombosis (PVT) after liver transplantation (OLT), which occurs in 1% to 2.7% of cases, can compromise patient and graft survival. Percutaneous transhepatic portal vein angioplasty offers an option to treat PVT, diminishing surgically related morbidity and the need for retransplantation. We describe a case of late PVT after OLT, which was successfully treated by a minimally invasive percutaneous transhepatic approach using both mechanical fragmentation and pharmacologic lysis of the thrombus followed by anticoagulation. The patient has had a good clinical course with normal graft function and patent portal blood flow at 6-month follow-up. This case report confirms the possibility of successful recanalization of the portal vein in a patient with late PVT after liver transplantation. Sustained anticoagulation/antiaggregation therapy for at least 6 months after the procedure is advisable.

Liver transplantation and HBsAg-positive postnecrotic cirrhosis: adequate immunoprophylaxis and delta virus co-infection as the significant determinants of long-term prognosis.

BACKGROUND/AIMS: The place of liver transplantation in hepatitis B viral (HBV)-related diseases remains controversial because of the high rate of reinfection. The aim of this study was to define the determinants of long-term prognosis after transplantation. METHODS: Fifty-eight patients were transplanted during the period February 1984-September 1996. Six patients died during the early (< 3 months) posttransplant period from causes unrelated to HBV infection. All 52 long-term (> 3 months) survivors were evaluated in relation to the mode of presentation, viral replication at time of transplantation, absence of hepatocellular cancer at time of transplantation and use of adequate immunoprophylaxis (IP). Adequate immunoprophylaxis, defined as maintenance of anti-HBs levels over 100 mUI/ml, was introduced in December 1989. Intention-to-treat IP analysis compared patients transplanted before and after this date. The median follow-up was 74 months (range 4 to 131). Forty-seven patients (90%) had a minimal follow-up of 3 years. RESULTS: Five-year actuarial survival rates of 58 patients and of 52 long-term survivors were 72 +/- 6% and 80 +/- 6%, respectively. Univariate analysis showed that delta co-infection (n = 25) significantly improved survival (p < 0.001) [96 +/- 4% vs 63 +/- 10% in HBV patients (n = 27) at 5 years] as did absence of hepatocellular cancer (n = 36) (p = 0.020) [89 +/- 5% vs 61 +/- 12% in 16 non-cancer patients]. IP, however, significantly influenced 5-year survival in the HBV-patient group (n = 17) (p = 0.001) [85 +/- 10% vs 30 +/- 14% in 10 patients without IP). Multivariate analysis selected delta co-infection (p = 0.002) and IP (p = 0.01) as the significant determinants of prognosis independently influencing survival. Uni- and multivariate analyses showed that survival without reinfection was significantly influenced by IP (p = 0.002) [73 +/- 8% (n = 31) versus 33 +/- 12% in 15 non-treated patients). CONCLUSIONS: Delta virus co-infection and immunoprophylaxis are the most important prognostic factors after transplantation for postnecrotic HBsAg-positive cirrhosis. Transplantation can be proposed as a therapeutic tool only if life-long adequate adjuvant therapy can be achieved. Under this condition good results can even be obtained if there is viral replication at the time of transplantation.

Fulminant hepatitis B virus: recurrence after liver transplantation in two patients also infected with hepatitis delta virus.

Liver transplantation for hepatitis B virus (HBV)-related liver disease is complicated by HBV recurrence and, consequently, poor patient and graft survival. Patients transplanted for hepatitis delta virus (HDV)-related cirrhosis are reported to have a diminished incidence of HBV recurrence and improved graft survival. However, only a few reported HDV-infected patients had active HBV replicative disease before liver transplantation. In our experience, we transplanted two HDV-infected patients, both of whom had active HBV replication before liver transplantation. In one patient, hepatitis B surface antigen (HBsAg) recurred four months after transplantation. Two months later, Hepatitis Be antigen (HBeAg) and HBV-DNA became positive, and the patient died of fulminant recurrent hepatitis B and hepatitis delta. In the other patient, HBV persisted after transplantation, and 2 months later the patient required retransplantation for fulminant recurrent hepatitis B and hepatitis delta. With the second graft, the patient remained free of HBV infection for 1 year. Thereafter, the patient experienced HBV recurrence with active replication and died of fulminant hepatitis B and delta recurrence. In the first case and in the second graft of the second case, hepatitis B immunoglobulin (HBIG) immunoprophylaxis was administered in an attempt to prevent recurrence of HBV. The literature suggests that an HDV infection inhibits the replication of HBV and therefore plays a role in preventing the recurrence of HBV and improving survival. Our experience with two patients suggests that HDV infection, in the presence of active HBV replication, may not play a protective role.

Liver transplantation in virus-induced chronic liver disease.

The current status of liver transplantation (OLTx) for chronic viral hepatitis is reviewed. The major issues addressed include the rate of recurrence of disease, its severity and natural history, and the potential for therapy. These issues vary markedly for each type of viral hepatitis. The development of new antiviral agents for clinical use may change the current restriction on liver transplantation for hepatitis B virus (HBV)-related liver disease such that it begins to challenge hepatitis C virus (HCV) as the principal indication for OLTx world-wide.

[Viral hepatitis and liver transplantation]. / Hépatites virales et transplantation hépatique.

Chronic liver diseases due to hepatitis viruses are the main indication for liver transplantation. Recurrence of viral infection on the liver graft is responsible for the occurrence of chronic hepatitis, liver cirrhosis, or liver failure. The risk of viral recurrence may influence the indications for liver transplantation. The risk of viral B recurrence is higher in patients transplanted for viral B liver cirrhosis than for viral B-delta liver cirrhosis, and for fulminant hepatitis B. This risk is higher in patients with active viral B replication at time of transplantation. Long-term administration of anti-HBs immunoglobulins reduces significantly the HBV recurrence rate and the related mortality, especially in patients without active HBV replication at transplantation. Middle-term results for patients transplanted for viral C related liver cirrhosis are good, but the recurrence rate of HCV infection is high. Protocols of prevention of HCV recurrence after transplantation are mandatory.

Role of liver transplantation in viral hepatitis.

Liver transplantation remains difficult in end-stage liver disease caused by chronic viral hepatitis because of recurrent viral infection in the liver graft. After transplantation for chronic hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis delta virus (HDV) disease, recurrence is nearly universal. Patients with actively replicating HBV infection before transplantation appear to be the most likely to experience clinically significant recurrent hepatitis, whereas recurrence in liver transplant patients with HCV and HDV infection before transplantation seems to be less serious in the transplanted liver. At present, hepatitis B Ig immunoprophylaxis can be given to reduce the rate of HBV recurrence in liver graft. However, further studies are needed on ways to prevent and treat viral recurrence in liver transplant patients with viral hepatitis.