Eytan Mor

Treatment of Hepatocellular Carcinoma Associated with Cirrhosis in the Era of Liver Transplantation

Hepatocellular carcinoma is the most common primary malignant tumor of the liver and a major cause of death among patients with cirrhosis [1]. Underlying cirrhosis is found in most patients with hepatocellular carcinoma; viral hepatitis and alcohol are the most common causes of this cirrhosis [2]. The incidence of hepatocellular carcinoma varies worldwide and correlates with the frequency of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection [3]. The highest risk for hepatocellular carcinoma among cirrhotic patients, 30 cases per 100 000 persons per year, has been reported in some areas of the Far East and sub-Saharan Africa. In Europe and North America, the risk is only 2 cases per 100 000 persons per year [4]. In the United States in the 1980s, 6000 new cases were expected annually [5]. Awareness of the potential for cirrhosis-associated hepatocellular carcinoma has led to the establishment of screening programs, using ultrasonography and the measurement of -fetoprotein levels, in high-risk populations in eastern countries and in transplantation candidates in western countries [6, 7]. Such screening programs have been associated with early detection of small tumors, lower tumor stage at diagnosis, and less severe liver disease. These effects help explain the improved prognosis seen in recent years. With asymptomatic lesions identified in increasing numbers of patients and with the development of new medical and surgical techniques, approaches to the treatment of cirrhotic patients with hepatocellular carcinoma have changed. Low surgical mortality rates are reported in cirrhotic patients undergoing resection; however, because of tumor extent, tumor location, and hepatic dysfunction, only a minority of patients are candidates for resection. In addition, tumor recurrence due to multifocality and progression of underlying liver disease has limited the efficacy of resection [8]. As orthotopic liver transplantation became available, it seemed to be a more rational approach because it addressed the multifocal nature of the tumor as well as the underlying liver disease. In early experiences with unselected patient populations, however, liver transplantation for hepatocellular carcinoma was associated with high rates of death from recurrent disease [9-11]. Given our limited organ resources, these results called into question the justification of transplantation as a treatment for cancer. More recently, improved transplantation outcomes have been shown in selected patients with hepatocellular carcinoma. In addition to surgical methods, transcatheter arterial chemoembolization and percutaneous ethanol injection have emerged as techniques for local disease control in patients with inoperable hepatocellular carcinoma [12, 13]. Preliminary experience with transcatheter arterial chemoembolization before transplantation has shown promising results in patients with advanced-stage tumors [14, 15]. In this review, we discuss the treatment options for cirrhotic patients with hepatocellular carcinoma and suggest an updated approach to therapy based on the severity of liver disease and tumor stage. Methods We conducted a MEDLINE search of English-language articles published between 1981 and 1997. Original articles reporting the results of resection, liver transplantation, and invasive radiologic approaches (chemoembolization and ethanol injection) for the treatment of hepatocellular carcinoma in cirrhotic patients were selected. Priority was given to large series and to comparative studies of the various therapies. We also report the initial results of a multimethod approach combining liver transplantation with chemoembolization at the Mount Sinai Medical Center and of similar approaches at other large transplantation centers. The study design of each original report was assessed, and careful attention was paid to methods and aims. Relevant data on patient population, tumor stage distribution, treatment, survival, follow-up interval, and rate of recurrent disease were extracted and analyzed. The material was classified into treatment categories and discussed accordingly. Survival rates given in the text are cumulative survival rates as calculated by life-table estimates or the Kaplan-Meier method, unless they are noted to be actual survival rates (or the proportion of patients surviving at a specific time interval). Cirrhosis and Carcinogenesis Carcinogenesis associated with cirrhosis correlates with disease duration and the cause of primary liver disease [16, 17]. Ikeda and colleagues [16] noted that the cumulative rate of hepatocellular carcinoma at 15 years was 75.2% in patients with hepatitis C and only 27.2% in patients with hepatitis B [16]. Indeed, in Japan, where the incidences of chronic HBV infection and chronic HCV infection are the same, the reported incidence of hepatocellular carcinoma is higher in patients with chronic HCV infection than in patients with chronic HBV infection (10.4% compared with 3.9%) [18]. Although the association between viral infection and tumor development is a worldwide phenomenon, the risk for tumor development varies according to geographic location. The reported annual incidence of new cases of hepatocellular carcinoma among patients with HCV-related cirrhosis is 3% in western countries and 6% in Japan [19]; this suggests that nonviral etiologic factors are also involved in the pathogenesis of this tumor. Certain metabolic disorders that lead to cirrhosis, including hemochromatosis, hereditary thyrosinemia, 1-antitrypsin deficiency, and type I glycogen storage disease, are also associated with an increased risk for hepatocellular carcinoma [20]. Aflatoxin B1 contamination has been identified as a major risk factor that probably acts synergistically with HBV infection [20]. Other chemical carcinogens, inorganic arsenic, androgenic steroids, and oral contraceptive steroids may also increase the risk for hepatocellular carcinoma. Some differences exist in the activity and modes of cancer promotion of HBV and HCV infection. In patients with HBV infection and hepatocellular carcinoma, HBV integrates into host genomic DNA in most cases, both in tumor cells and in nontransformed hepatocytes [21]. This suggests that viral integration at one or a few sites in host DNA may result in the deregulated expression of oncogenes or tumor-suppressor genes [22]. Integration of HBV also promotes genomic instability [23], which is a common feature of carcinogenesis. The mechanism by which HCV infection promotes the development of hepatocellular carcinoma is unclear. Hepatitis C virus was found to infect and replicate in hepatocellular carcinoma cells in vivo [24]; integration of HCV viral sequences into the host genome was not seen. Other possible mechanisms of hepatocarcinogenesis after infection with HCV include the direct induction of tumorigenesis through a viral gene product, the activation of cellular proto-oncogenes, or the inactivation of cellular tumor suppressors. Recent studies [25, 26] have suggested that the third nonstructural gene of HCV (NS3) is involved in cell transformation. The NS3 protein, a serine protease with a helicase activity, can induce cell death and oncogenic transformation [26]. Another difference between HBV and HCV is that hepatocellular carcinoma is always found in the setting of chronic liver disease in patients with hepatitis C but may develop in asymptomatic carriers of hepatitis B surface antigen (HBsAg) [27]. Of note, patients infected with both HCV and HBV have an increased relative risk for hepatocellular carcinoma; this suggests that the two viruses have a synergistic effect in hepatocarcinogenesis [28]. In a prospective study of 400 cirrhotic patients [29], the annual incidence of hepatocellular carcinoma was 6.6% in patients with HBsAg alone, 7.0% in patients with anti-HCV alone, and 13.3% in patients with both HBV and HCV infection. Histologic sections of resected specimens have shown a pathway from the regenerative nodules typically found in cirrhotic livers to adenomatous hyperplasia and hepatocellular carcinoma [30, 31]. A report of multiple foci of hepatocellular carcinoma in a macroregenerative nodule further suggests that these are precancerous lesions [32]. Although the mechanism by which cirrhosis potentiates malignant transformation is not well established, it is important to recognize this relation when designing treatment approaches for cirrhotic patients with hepatocellular carcinoma. Resection for Hepatocellular Carcinoma Resection remains the mainstay of treatment for hepatocellular carcinoma. Resectability of a tumor in cirrhotic patients, however, is limited by the diminished functional reserve of the cirrhotic liver and the attendant risk for intraoperative bleeding and postoperative liver failure [33]. The reported resectability rate is about 10% in western countries but 28% in eastern countries, which have earlier detection as a result of screening programs and more widespread expertise in techniques for limited resection [34]. Attempts have been made to quantify hepatic reserve and thus to estimate the extent of resection that may safely be performed. Kawasaki and coworkers [35] used volume of ascites, bilirubin level, and indocyanine green clearance in a formula to estimate liver reserve. In this series, perioperative mortality among 112 patients undergoing liver resection was only 1.8%. Tumor size is an important determinant of resectability: In one series [36], the resectability rate was only 41% in patients with large tumors (>5 cm in diameter) compared with 89% in patients with small tumors. Measurement of the hepatic-vein wedge pressure gradient was recently reported to be valuable in patients with Child A cirrhosis who were undergoing resection [37]. The presence of significant portal hypertension (hepatic-vein wedge pressure gradient >10 mm Hg) was the best predictor of postoperative hepatic decompensation associated w

Prolonged preservation in University of Wisconsin solution associated with hepatic artery thrombosis after orthotopic liver transplantation.

Hepatic artery thrombosis (HAT) after liver transplantation (LTx) usually mandates retransplantation. Prolonged preservation with Eurocollins solution has been associated with HAT. We reviewed our experience with 359 LTx patients to identify risk factors for HAT. All grafts were preserved in University of Wisconsin solution. HAT developed in 12 patients (3%) within 50 days. Seven patients were asymptomatic; four presented with biliary sepsis and 1 with poor graft function. Two patients had suffered acute rejection; another 2 had severe preservation injury. Technical problems accounted for 4 cases; in the remaining 8, no etiology was found. Diagnosis was at a mean 14.7 days after LTx. One patient maintains normal graft function 3 years after LTx without intervention. Eight underwent re-LTx, 3 of whom died. Routine surveillance via duplex enabled early diagnosis and revascularization in 3 patients; in all 3, no biliary complications occurred between 6 and 20 months. Overall graft and patient survival after HAT were 33.3% and 75%, respectively. Cold ischemic time (CIT) averaged 813 min in patients with HAT and 669 min in those without HAT (P<.05). HAT occurred in 7/165 patients with CIT > 12 hr, and in 3/ 234 patients with CIT < 12 hr (P=0.0699). By avoiding CIT > 12 hr, we have recently avoided HAT in 78 consecutive patients. We conclude that CIT > 12 hr may increase the risk of HAT. When HAT is diagnosed before biliary sepsis develops, flow can often be restored and retransplantation averted.

Successful use of an enhanced immunosuppressive protocol with plasmapheresis for abo-incompatible mismatched grafts in liver transplant recipients

Graft and patient survival rates after transplantation of ABO-incompatible liver allografts have been poor. We used plasmapheresis and a potent immunosuppressive regimen to control hemagglutinin levels and prevent early rejection. Ten patients who had a United Network for Organ Sharing status of 4 received ABO-incompatible allografts. Quadruple immunosuppression consisted of OKT3, Cytoxan, cyclosporine, and steroid taper; prostaglandin E-1 was administrated intravenously the first week. All patients underwent perioperative plasmapheresis to maintain hemagglutinin levels < 1:16. Patient survival was 80%; graft survival was 60% at 140-505 days. The rejection rate was 90%. Three recipients (A1-->O) lost their grafts to severe rejection at 5, 12, and 30 days after transplantation. All 3 had pretransplantation hemagglutinin levels > or = 1:100. Elevated hemagglutinin levels preceded the diagnosis of severe acute cellular rejection; plasmapheresis failed to lower anti-A titers in these 3 patients. We conclude that in an urgent setting, lowering of preformed hemagglutinins via plasmapheresis in combination with quadruple induction immunosuppression allows liver transplantation across ABO barriers. In patients with high baseline levels of preformed hemagglutinins, the risk of subsequent graft loss may be increased and transplantation with an ABO-incompatible graft may serve as a lifesaving intermediate step.

Obviation of prereperfusion rinsing and decrease in preservation/reperfusion injury in liver transplantation by portal blood flushing.

Liver allografts are traditionally rinsed with cold lactated Ringers (LR) prereperfusion to clear K+-rich preservation solution from the hepatic vasculature. LR has been shown, however, to be injurious to the graft. By restoring portal blood flow without rinsing and discarding the initial blood traversing the liver (PB flush), we sought to eliminate rinsing without inducing hyperkalemia. Between August 1988 and December 1992, 481 OLTx were performed in 412 pts. Four rinsing methods were used sequentially: group 1 (157 pts)—low-flow-rate cold LR rinse (500 ml, 100 ml/ min via standard i.v. tubing at 100 cm H2O [LFLR]) during lower caval anastomosis; Group 2 (120 pts)—LFLR as in group 1, at reperfusion, 500 ml PB flush via IVC catheter; group 3 (66 pts)—high-flow-rate LR rinse (500 ml, 1 L/min using large-bore tubing with 100 cm H2O rinsing pressure [HFLR]), PB flush as in group 2; Group 4 (62 pts)—no LR rinse; PB flush as in groups 2 and 3. Poor early graft function (PEGF) was defined as peak ALT or AST >2500 U or PT >16 sec (on POD 2); PEGF causing re-OLTx or death within 14 days was called primary nonfunction (PNF). Group 1 and Group 3 had high PEGF rates. Group 4 had significantly less PEGF than Group 1, with a trend toward a significant difference from Group 3. In Group 1, 3 pts. had intra-operative hyperkalemic cardiac arrest; this did not occur when PB flush was performed. PB flush without prior rinsing optimizes graft function without risk of hyperkalemia. LR rinse, alone or followed by PB flush, is unnecessary and may be deleterious.