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Background: Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection., Methods: This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 micromol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 micrommol/L at 6 months., Results: The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (100 micromol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 micromol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time., Conclusions: Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.

Hepatopulmonary syndrome is characterized by the presence of portal hypertension with or without cirrhosis, an increased alveolar-arterial oxygen partial pressure difference greater than or equal to 15 mm Hg, and dilated pulmonary capillaries. Hepatopulmonary syndrome is found in up to 20% of patients with cirrhosis and should be considered in any patient who develops dyspnea or hypoxemia. Contrast echocardiography is enough to make the diagnosis of hepatopulmonary syndrome. The exact pathophysiology of hepatopulmonary syndrome remains unknown but nitric oxide is an important factor underlying hepatopulmonary syndrome. Hypoxemia progressively deteriorates and worsens the prognosis of cirrhotic patients. Hypoxemic patients must be controlled regularly to optimise the timing of liver transplantation. Indeed, a preoperative PaO(2) of less than or equal to 50 mm Hg alone or in combination with an isotopic shunt fraction greater than or equal to 20% are the strongest predictors of postoperative mortality. There are currently no effective medical therapies for hepatopulmonary syndrome but garlic powder and iloprost inhalation demonstrate clinical improvements in the pre- and in the post-transplant period.

Supraselective transarterial chemoembolization (STACE) more efficiently targets chemotherapy delivered via the feeding arterial branches of the tumor than does conventional transarterial chemoembolization (TACE). However, the hypothesis of its greater efficacy compared with the latter is subject to controversy. The aim of the present study was to compare STACE to conventional TACE in a controlled study of candidates for liver transplantation (LT) for hepatocellular carcinoma (HCC). Patients were matched for factors associated with HCC recurrence and survival. Sixty patients were included: 30 who were treated with STACE and 30 treated with conventional TACE. The 2 groups were similar in terms of matched criteria. In the overall population (uni- and multinodular HCC), there was no marked difference between the 2 groups in 5-year disease-free survival: 76.8% vs. 74.8%. In sensitivity analysis of patients considered to be the best candidates for TACE (uninodular HCC < or =5 cm), there was a trend toward significance between STACE and TACE in 5-year disease-free survival: 87% vs. 64% (P = 0.09). The only factor associated with complete tumor necrosis was STACE in the overall population (30.8% vs. 6.9%, P = 0.02), with a similar trend in the subgroup of patients with a single nodule (33.3% vs. 6.7%, P = 0.06), whereas the mean number of procedures was similar in the 2 groups (mean, 1.3 procedures; range 1-5 procedures; P = NS). STACE is more efficient at inducing complete tumor necrosis in the liver. This study observed trends toward improvement in the disease-free survival of patients with uninodular HCC < or =5 cm. Future studies focusing on such patients are warranted.

New-onset diabetes mellitus (NODM) remains a common complication of liver transplantation (LT). We studied incidence and risk factors in 211 French patients who had undergone a primary LT between 6 and 24 months previously. This is a cross-sectional and retrospective multicenter study. Data were collected on consecutive patients at a single routine post-LT consultation. Demographic details, immunosuppressive regimens, familial and personal histories, hepatitis status, and cardiovascular risk were analyzed to compare those who developed NODM (American Diabetes Association/World Health Organization criteria) with the others. The overall incidence of NODM was 22.7%: 24% in tacrolimus (Tac)-treated patients (n = 175; 82.9%) and 16.7% in cyclosporine-treated patients (n = 36; 17.1%). A total of 81% of the cases were diagnosed within 3 months of LT (M3). Among hepatitis C virus (HCV)-infected (HCV(+)) patients, NODM incidence was 41.7% whereas among those patients negative for this virus (HCV(-)), the incidence was only 18.9% (P = 0.008). In Tac-treated patients, the incidence of NODM in the HCV(+) patients was significantly higher than in the HCV(-) patients (46.7% and 19.3%, respectively, P = 0.0014). Only 1 of 6 (16.7%) of the HCV(+) patients developed NODM on cyclosporine. Other independent pretransplantation risk factors for NODM included impaired fasting glucose (IFG) and a maximum lifetime body-mass index (BMI) over 25 kg/m2. In conclusion, emergence of NODM after LT is related to risk factors that can be detected prior to the graft, like maximum lifetime BMI, IFG, and HCV status. Tac induced a significantly higher incidence of NODM in the HCV(+) compared to the HCV(-) patients. The treatment should therefore be tailored to the patient's risk especially in case of HCV infection., ((c) 2006 AASLD.)

Unlabelled: The purpose of the study was to introduce mycophenolate mofetil (MMF) in liver transplant recipients with renal dysfunction to decrease calcineurin inhibitor (CNI) dosages without increasing rejection risk. In this prospective, multicenter, randomized study, chronic CNI-related renal dysfunction was defined by an increase in serum creatinine with values >140 micromol/L and <300 micromol/L. Patients were randomized in 2 groups., Study Group: combination of MMF (2 to 3 g/day) and reduced dose of CNI >or=50% of initial dose; control group: no MMF, but with the ability to reduce CNI doses, but not below 75% of initial dose. Fifty-six patients were included, 27 in the study group and 29 in the control group. In the study group, there was a significant decrease in serum creatinine values, from 171.7 +/- 24.2 micromol/L at day 0 to 143.4 +/- 19 micromol/L at month 12 and a significant increase in creatinine clearance, from 42.6 +/- 10.9 mL/min to 51.7 +/- 13.8 mL/min. No rejection episode was observed in the study group. In the control group, there was no improvement of renal function, assessed by the changes in serum creatinine values, from 175.4 +/- 23.4 micromol/L at day 0 to 181.6 +/- 63 micromol/L at month 12, and in creatinine clearance, from 42.8 +/- 12.8 mL/min to 44.8 +/- 19.7 mL/min. The differences between the 2 groups were significant: P = 0.001 for serum creatinine, and P = 0.04 for creatinine clearance. In conclusion, the introduction of MMF combined with the reduction of at least 50% of CNI dose allowed the renal function of liver transplant recipients to significantly improve at 1 year, without any rejection episode and without significant secondary effects.

Patients with chronic liver disease are at higher risk of hepatitis B (HB) virus infection before and after liver transplantation, and they commonly have a suboptimal immune response to HB vaccines. In this randomized trial, we compared the immunogenicity of primary vaccination with 2 doses of an experimental adjuvanted HB vaccine (adjuvant system 04 containing aluminium and monophosphoryl lipid A [HB-AS04]) to that of 3 double doses of a licensed HB vaccine in 93 liver transplant candidates. Depending on the waiting list for liver transplantation, a booster dose of HB-AS04 or double booster dose of the licensed HB vaccine was given before or after surgery, at 6 to 12 months after initiation of the vaccination course. The percentage of subjects with seroprotective anti-HB surface antibody concentrations 1 month after booster was twice as high in the HB-AS04 group (60.0%), vs. patients in the comparator group (32.0%) (P = 0.035). In subjects who did not undergo liver transplantation before administration of the booster, better immunogenicity results were obtained: 80% of subjects were seroprotected after HB-AS04 vaccination vs. 60% with the comparator (P = 0.2302). Despite a slightly higher reactogenicity, the safety profile of the HB-AS04 vaccine was clinically acceptable. In conclusion, an improved antibody response was observed in liver transplant candidates with 3 doses of HB-AS04, as compared to 4 double doses of a comparator. Liver transplant candidates could benefit from the use of this experimental adjuvanted HB vaccine to further increase their protection against HB infection.

Pegylated interferon and ribavirin combination therapy represent the standard-of-care treatment for chronic hepatitis C, that allows to cure more than half of the patients. However, the success of this bitherapy is in balance with numerous side effects, especially hematologic and psychiatric. This review is focused on complementary treatments (erythropoietin, G-CSF, vitamin E, glutathion, ursodeoxycholic acid and antidepressants) likely to bring a benefit in maintaining adequate interferon and ribavirin dosages and in improving quality of life. This analysis has been performed by using the Medline(R) data base and with data from laboratories which commercialized these molecules. Erythropoietin, G-CSF and antidepressants are the best tools to optimize the bitherapy in its dose and its duration while privileging the quality of life of HCV-infected patients.

Liver involvement in hereditary hemorrhagic telangiectasia may lead to high-output cardiac failure. Few data have been reported on orthotopic liver transplantation (OLT) for these patients. In this paper, we describe two patients treated by OLT as a salvage procedure for cardiac failure, and we review literature on this subject. Our two patients resumed normal cardiac function after OLT. This procedure appears to be a promising therapy with good long-term results despite dissection difficulties encountered due to the collateral arterial network reorganization.

Some clinical studies in liver transplantation have recently reported safety advantages and similar acute rejection rates with early steroid withdrawal. The aim of this study was to evaluate the efficacy and safety of an immunosuppressive regimen with steroid withdrawal at day 14. A multicenter, 1-year, comparative, double blind, placebo-controlled study was performed. Patients undergoing a first cadaveric liver transplantation were recruited and all received basiliximab + cyclosporine + intravenous methylprednisolone. Patients without severe postoperative complications were randomized at day 7 to receive a maintenance regimen with Neoral (cyclosporine) + prednisolone (group 1) or without steroids (Neoral + placebo; group 2), after a 7-day blinded oral steroid tapering period. A total of 174 patients were randomized at day 7 (group 1: n = 90; group 2: n = 84). The incidence of biopsy-confirmed and treated acute rejection at 6 months was 38.1% in group 2 vs. 24.4% in group 1 (P = .03) with a trend for a higher incidence of Grade II / III acute rejection (28.6% vs. 18.9%; P = .12). Changes from baseline were similar with regard to metabolic parameters (glycemia, total cholesterol, and triglycerides). A trend toward a better glucose tolerance was observed, as fewer patients received an antidiabetic treatment in the placebo group (2 vs. 10). In conclusion, this first double-blind, placebo-controlled study of steroid withdrawal at day 14 showed a higher incidence of acute rejection, only balanced by a trend of a lower need of antidiabetic treatment.

Objectives: The objective of this prospective study was to determine whether sociological and/or alcohol-related behavioral factors could be predictive of relapse after orthotopic liver transplantation for alcoholic liver disease., Methods: Fifty-five liver-transplanted patients out of a series of 120 alcoholic cirrhotic patients were enrolled in a randomized prospective study. This study was initially designed to compare the 2 year survival in intent-to-transplant patients versus in-intent-to-use conventional treatment patients. For all patients, an identical questionnaire was completed at inclusion, and every 3 months for 5 years to collect data on alcohol-related behavior factors., Results: Fifty-one patients fulfilled the criteria for the study. The mean follow-up was 35.7 months (range: 1-86). Rate of alcohol relapse was 11% at one year and 30% at 2 years. Alcohol intake above 140 g a week was declared by 11% and 22% of patients at one and 2 years, respectively. The only variable leading to a significantly lower rate of relapse was abstinence for 6 months or more before liver transplantation (23% vs 79%, P=0.0003). This variable was also significant for patients whose alcohol intake was greater than 140 g per week (P=0.003) (adjusted relative risk=5.5; 95%CI=1.3-24.5; P=0.02). Multivariate analysis (Cox model) showed that abstinence for 6 months or more before liver transplantation was the unique predictive variable., Conclusion: In this prospective study of 51 patients transplanted for alcoholic liver disease, abstinence before liver transplantation was the only predictive factor of alcohol relapse after liver transplantation.

Hepatitis C virus (HCV) infection invariably recurs after liver transplantation (LT), and sequels of chronic hepatitis of the graft are a significant cause of morbidity and mortality. In an uncontrolled trial, 31 patients with histologically confirmed hepatitis C after LT received, sequentially, ribavirin (10 mg/kg body weight q.d.) for 12 weeks, followed by ribavirin at the same dose q.d. plus interferon-alpha (IFN-alpha) [3 million units three times a week (3 MU TIW)] for another 48 weeks. Based on an intent-to-treat analysis, the percentages of patients with undetectable HCV RNA in their serum were 0%, 38.7% and 45.2% after 12, 36 and 60 weeks of therapy, respectively. A sustained virological response, as defined by undetectable serum HCV RNA 24 weeks after the end of treatment, was observed in 9/31 patients (29%). Sustained responders had a significant improvement of their liver inflammatory activity score (P=0.025), but not of their liver fibrosis score. The chances of sustained virological response correlated with the length of treatment, but not with the HCV genotype or baseline HCV RNA level. In conclusion, patients with recurrent hepatitis C after LT might benefit from ribavirin/IFN-alpha therapy, provided that the treatment is tolerated for a sufficient duration of time.

Background: Posttransplant lymphoproliferative disorder (PTLD) is a well-known complication of organ transplantation that leads to death in more than 50% of cases. The aim of this work was to identify specific risk factors for lymphoproliferative disorders after liver transplantation in adults., Methods: A total of 480 consecutive patients who underwent transplantation between 1986 and 1997 were studied (323 men, 157 women; mean age: 49.8+/-10.4 years). Demographics, the indication for transplantation, the immunosuppressive regimens, the incidence of rejection episodes, and Epstein-Barr virus infection were analyzed. Univariate and multivariate analysis were used to identify factors predictive of PTLD., Results: Sixteen cases of PTLD (3.3%) occurred at a median of 5.5 (range, 1-39) months after liver transplantation. All 16 cases occurred in patients with evidence of exposure to Epstein-Barr virus before transplantation. In multivariate analysis, the use of antilymphocyte antibodies (P=0.007, relative risk [RR]=4.2, 95% confidence interval [CI]=1.5-11.7), age older than 50 years (P=0.037, RR=3.5, 95% CI=0.95-13.0), liver transplantation for hepatitis C virus cirrhosis (P=0.015, RR=8.7, 95% CI=1-78.3), and liver transplantation for alcoholic cirrhosis (P=0.015, RR=9.6, 95% CI=1.2-77.2) were independently associated with the onset of PTLD., Conclusion: Liver transplantation for hepatitis C virus-related and alcoholic cirrhosis and age older than 50 years are three additional risk factors for lymphoproliferative disorder independent of the use of antilymphocyte antibodies. The use of antilymphocyte antibodies after liver transplantation should be avoided in these categories of patients, especially those older than 50 years.

Between 1986 and 1991, 21 patients received liver grafts in our center for incurable alveolar echinococcosis (AE). The aim of this study was to analyze the long-term results in 15 of these 21 patients who survived more than 1 year after undergoing a liver transplantation (LT). The follow-up, mainly aimed at the diagnosis of recurrence, consisted of repeated radiological and specific immunological investigations. The role of pre- and post-LT benzimidazole (BZM) therapy was also evaluated. Among the 15 patients, 8 patients had a palliative LT related to previously known pulmonary AE metastases and/or inextirpable abdominal parasitic foci. In the 7 remaining patients, LT was considered curative. In June 1998, the mean follow-up duration was 96 months (range: 28-138 months). Five late deaths occurred, 2 of them were directly related to residual AE. A reinfection of the graft was observed in 4 patients. Preoperative BZM therapy seemed useful in preventing or delaying the parasitic recurrence. Post-LT BZM was able to stabilize and even to reduce residual AE. The anti-Em2 enzyme-linked immunosorbent assay (ELISA), which is the standard test used in patient follow-up after partial liver resection for AE, did not appear useful in detecting recurrence here; however, an ELISA, using a crude heterologous antigen (Echinococcus granulosus) allowed early diagnosis of residual AE. In conclusion, primary disease recurrence is not rare after LT for AE. Immunosuppressive therapy may favor larval growth in extrahepatic sites; therefore, an extensive extrahepatic radiological check-up has to be performed before LT. BZM therapy seems to stabilize residual foci. Anti-Eg immunoglobulin G (IgG) follow-up is the most useful test for early diagnosis of parasite recurrence.

Coumarin is a drug which is extensively used to treat lymphedema. We report two cases of acute hepatitis probably due to coumarin. Two women, 40 year and 45 year-old, were treated with 90 mg/d of coumarin for 5 months. Clinical features included jaundice, pruritus, and diarrhea. A marked increase in serum aminotransferases was observed (ALT: 30 and 100 times the upper limit of normal, respectively). Coumarin withdrawal was rapidly followed by a favorable outcome in both cases. Rechallenge in one case induced a relapse of symptoms and liver test abnormalities. Coumarin can induce acute cytolytic hepatitis.

Liver transplantation is currently the standard treatment for terminal stage liver disease. Overall actuarial survival rate at 5 years is 65 to 70%. However, because of the increasing number of transplantations being performed throughout the world, the number of potential recipients exceeds the number of donor organs available. The long waiting lists thus imply rigorous candidate selection. At the same time, the indications for transplantation have evolved. In light of survival rates, certain indications, such as hepatitis B with viral replication before transplantation or hepatocellular carcinoma less than 3 cm in diameter, may be debatable. There are also new indications with excellent short-term results, such as alcoholic cirrhosis or hepatitis C cirrhosis. The long waiting lists have led to the development of intermediary management schemes: intrahepatic porto-systemic shunts to decrease portal pressure and facilitate subsequent dissection; neoadjuvant chemotherapy for hepatocellular carcinoma; or lamivudin to inhibit B virus replication. The limiting factor remains the lack of sufficient donor organs. It will not be possible to pursue wider indications unless the number of donors can be increased. This objective raises a vital challenge to the medical community.

Objectives: Chronic active hepatitis C is an important public health issue because of its prevalence, evolution, and overall cost. Treatment by recombinant alpha-interferon is both expensive and exacting and its effectiveness is limited. We report the results of a cost-effectiveness analysis of alpha-interferon treatment in patients with chronic active hepatitis C., Methods: Direct medical costs of caring for patients with chronic active hepatitis C and its complications, based on treatment or no treatment, were assessed with retrospective data collected from the files of 137 hospital patients. Seventy-seven patients were treated with alpha-interferon between 1988 and 1994. The overall costs of caring for chronic active hepatitis C patients, without treatment or with alpha-interferon treatment (3 millions units three times a week) for 6 months (strategy A), 12 months (strategy B), or 12 months but discontinuing treatment when there was no response (strategy C), was reported and compared to the respective effectiveness of each., Results: With an actualization rate of 5%, the real overall cost of caring for a chronic active hepatitis C patient was 143290 FF. Considering the contraindication rate (15%), the treatment acceptance (85%), the response rate to treatment (50%), and the prolonged response rate (25 to 30%), treating patients with strategy A induced a real overall cost of caring to 140731 FF to avoid 0.11 cases of cirrhosis, to 150277 FF to avoid 0.13 cases of cirrhosis with strategy B, and to 136947 FF to avoid 0.13 cases of cirrhosis with strategy C., Conclusion: Alpha-interferon treatment in patients with chronic active hepatitis C provides a long-term saving compared to cases which receive no treatment. Strategy C was the most cost-effective, inducing the reduction of both the number of cases of cirrhosis and the cost of care.

To assess the efficacy of liver transplantation in patients with alcoholic cirrhosis, we compared 2-year survival of 169 liver transplantation patients in 12 French centres with survival of two control groups treated conservatively. The matched group was 169 patients of similar age, cirrhosis severity, and bleeding history; the simulated group was 169 patients whose theoretical survival was determined in a cohort of 797 patients with alcoholic cirrhosis. The probability of survival to 2 years in transplanted patients was 73 (95% confidence interval 67-79%) versus 67% (59-75) in the matched and 67% (63-71) in simulated controls. When prognostic factors were taken into account, transplantation was associated with survival (r = 0.527; p = 0.069). Patients with severe liver disease (high-risk group) benefited most for 2-year survival: 64% (42-86) vs 41% (23-59) in the matched and 23% (19-27) in the simulated control groups (p < 0.01). There was no difference for patients at low and at medium risk. Liver transplantation increases the 2-year survival of patients with severe alcoholic cirrhosis. In patients with less severe disease, further studies should be done by non-randomised controlled studies with longer follow-up or by randomised trials.