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Background: We report on a pilot study investigating the feasibility of early immunosuppression withdrawal after liver transplantation (LT) using antithymocyte globulin (ATG) induction and rapamycin., Methods: LT recipients received 3.75 mg/kg per day ATG from days 0 to 5 followed by rapamycin-based immunosuppression. In the absence of acute rejection (AR), rapamycin was withdrawn after month 4. Immunomonitoring included analysis of peripheral T-cell phenotypes and clonality, cytokine production in mixed lymphocyte reaction, and characterization of intragraft infiltrating cells., Results: Ten patients were enrolled between October 2009 and July 2010. In the first three patients, complete withdrawal of immunosuppression after month 4 led to AR. No further withdrawals of immunosuppressive were attempted. Two AR occurred in the remaining seven patients. ATG induced profound T-cell depletion followed by CD8(+) T-cell reexpansion exhibiting memory/effector-like phenotype associated with progressive oligoclonal T-cell expansion (Vβ/HPRT ratio) and gradually enhanced anti-cytomegalovirus and anti-Epstein-Barr virus T-cell frequencies. Patients developing AR were characterized by decreased TCAIM expression. AR were associated with increased donor-specific production of interferon (IFN)-γ and interleukin (IL)-17, increased intragraft expression of IFN-γ mRNA, and significant CD8(+) T-cell infiltrates colocalizing with IL-17(+) cells., Conclusion: High-dose ATG followed by short-term rapamycin treatment failed to promote early operational tolerance to LT. AR correlates with expansion of memory-type CD8(+) T cells and increased levels of IFN-γ and IL-17 in mixed lymphocyte reaction and in the graft. This suggests that resistance and preferential expansion of effector memory T-cell in lymphopenic environment could represent the major barrier for establishment of tolerance to LT in approaches using T-cell-depleting induction.

Several surgical techniques have been developed to allow liver transplantation in cases of complete portal vein thrombosis in the recipient. Despite this, these transplantations remain associated with a significant complication rate. We report herein a case of liver transplantation in a patient with complete portal vein thrombosis, underlying the potential pitfalls and the risk of intestinal sutures in case of hepaticojejunostomy. We discuss the technical options and their relative indications in such cases., (Copyright © 2011 Elsevier Inc. All rights reserved.)

We designed a pilot trial in cadaveric liver transplantation to determine whether induction with antithymocyte globulins (ATG) and sirolimus would allow immunosuppression withdrawal. Patients received ATG 3.75 mg/kg per day from day 1 to 5 after transplantation followed by sirolimus for 4 to 6 months. We monitored interleukin (IL)-7 serum levels, interferon (IFN)-gamma, and IL-2 mRNA accumulation in mixed leukocyte reaction and intragraft IFN-gamma mRNA expression. In the first three patients, immunosuppression discontinuation was followed by reversible acute rejection occurring on days 280, 246, and 163 posttransplantation, corresponding to days 140, 40, and 39 after drug withdrawal, respectively. At the time of rejection, blood CD8+ T-cells counts had returned to or above pretransplant levels in two of three patients, whereas CD4+ T-cell count remained low. IL-7 serum levels rose in all three patients in the first months after transplantation and IFN-gamma mRNA accumulated in mixed leukocyte reaction between recipient T cells and donor spleen cells at the time of rejection. High levels of IFN-gamma mRNA were consistently detected in liver biopsy performed at the time of rejection. In conclusion, lymphopenia-induced IL-7 production after induction with ATG and sirolimus might lead to emergence of IFN-gamma-secreting CD8+ T-cells responsible for acute rejection after immunosuppression withdrawal.

Minimization or withdrawal of immunosuppressive treatments after organ transplantation represents a major objective for improving quality of life and long-term survival of grafted patients. Such a goal may be reached under some clinical conditions, particularly in liver transplantation, making these patients good candidates for tolerance trials. In this context in liver transplantation, the central questions are (1) how to promote the natural propensity of the liver graft to be accepted, (2) which type of immunosuppressive drug should be used for induction and maintenance, and (3) which biomarkers could be used to discriminate tolerant patients from those requiring long-term immunosuppression. Induction therapies using aggressive T-cell-depleting agents may favor graft acceptance. However, persistent and/or rapidly reemerging cell lines, such as memory-type cells or CD8(+) T cells, could represent a significant barrier for induction of tolerance. The type of maintenance drugs also remains questionable. Calcineurin inhibitors may be eventually deleterious in the context of tolerance protocols, through inhibitory effects on regulatory T cells, that are not observed with rapamycin. In conclusion, significant efforts must be made to achieve reliable strategies for immunosuppression minimization or withdrawal after organ transplantation into the clinics.

Acute liver failure is a challenging clinical condition, associated with high morbidity and mortality. In well-selected patients, LT (LT) is the only therapeutic which has been demonstrated to improve patient survival. Clichy and King's College criteria are the two mains scoring systems used to select the patients for liver transplantation. Both models achieve high specificity but remain associated with limited negative predictive value. Several other predictive factors have been evaluated, but none of them have been strongly validated so far. Globally, whole LT appears as the procedure of choice for patients within Clichy and/or King's College criteria. Due to the severity of the disease and its multisystemic consequences, the results of LT for fulminant liver failure remain inferior to those obtained in elective indications. Accord-ing to local conditions, namely expected waiting time before urgent transplantation and surgical expertise, living donor transplantation and auxiliary transplantations appear as valuable alternatives. These techniques have the respective potential advantages to limit the waiting period before transplantation and to avoid the need for lifelong immunosuppression when native liver recovers, but overall results remain inferior to those obtained with whole LT.

Background: Due to the organ shortage, marginal donors are increasingly used in liver transplantation (OLT). These grafts may be safely used in less critical recipients but, the real influence of extended donor criteria (EDC) remains uncertain when graft-recipient matching is not applied. Our study analyzed the impact of EDC on initial graft function within the Eurotransplant patient-driven allocation system., Patients and Methods: We reviewed 70 OLT performed between 2004 and 2006. The impact of the following EDC were analyzed: age > 60; intensive care unit (ICU) stay > 4 days; peak serum Na(+) > 160 mEq/L; body mass index (BMI) > 30; cardiac arrest with cardiopulmonary resuscitation, and high doses of vasopressors. Early graft function, as defined according to peak transaminase level and spontaneous prothrombin time within the first 5 posttransplant days, was compared between the donors with none or one criterion (group A = 39) and those with >1 criterion (group B = 31)., Results: The most frequent EDC were high vasopressor use, ICU stay > 4 days and BMI > 30, were present in respectively 44%, 27%, and 16% of the donors. No EDC were present in 13 donors, one in 26, three in eight, and four in three. Demographics and origin and severity of the liver disease were similar in both groups. We failed to observe significant differences in initial graft function., Conclusion: The presence of EDC did not significantly affect early graft function in a population where donor and recipient were not matched. While this observation must be confirmed in a multicenter analysis, it tends to support the use of marginal liver grafts, even in patient-driven allocation systems.

Long-term results of organ transplantation are still limited by serious side effects of immunosuppressive drugs. A major issue, therefore, is to elaborate novel therapeutic protocols allowing withdrawal or minimization of immunosuppressive therapy after transplantation. We report on 3 patients prospectively enrolled in an original protocol designed to promote graft acceptance in living donor liver transplantation, using posttransplant conditioning with high doses of antithymocyte globulin followed by injection of donor-derived stem cells. In 2 patients, early immunosuppression withdrawal was possible, without subsequent graft deterioration. In these 2 cases, in vitro studies showed indices of immunological tolerance as assessed by specific hyporesponsiveness to donor alloantigens in mixed lymphocytes culture. In the third patient, acute rejection rapidly occurred after discontinuation of immunosuppression, and minimal immunosuppression has to be maintained during long-term follow-up. In this case, a clearly distinct immunoreactive profile was observed as compared to tolerant patients, as no specific modulation of the antidonor response was observed in vitro. Of note, no macrochimerism could be detected in any of the 3 patients during the follow-up. In conclusion, these clinical observations demonstrated that, despite the absence of macrochimerism, donor stem cells infusion combined with recipient conditioning may allow early immunosuppression withdrawal or minimization after liver transplantation.

The MELD score has now been implemented in the United States for liver allocation, but it has not been validated in Europe. Its association with posttransplant outcome is unclear. Optimal cutoff values of MELD and Child-Pugh scores to predict death on the liver waiting list were defined in a series of 137 cirrhotic patients listed for liver transplantation. Six-month actuarial survival while on the waiting list was 90% with a Child-Pugh <11 and MELD <17, whereas it decreased progressively to 40% at 6 months after listing for those having a Child-Pugh and MELD score >10 and >16. Analysis of a series of 112 patients (85 chronic liver disease and 27 hepatocellular carcinoma) revealed no change in MELD value at the time of transplantation compared to the score at the time of listing (mean +/- SD: 15.5 +/- 7.7 vs 15 +/- 5.8) with a mean waiting time of 118 days. Using either the optimal cutoff for MELD score (<17 or >16) or seven different strata (3 to 7, 8 to 10, 11 to 13, 14 to 16, 17 to 19, 20 to 22, 23 to 39), whether measured at listing or just before liver transplantation, there was no significant difference (chi(2) 4.97, P = .58) in survival: 82.7% and 63% at 6 and 60 months, overall. Our data confirm that the MELD score with only three parameters is as good as the Child-Pugh score to predict mortality on the Eurotransplant waiting list. The optimal cutoff to assess higher priority for the bad category is >16. There was no negative impact on short- or long-term prognosis of the bad categories of MELD.

Better tools for predicting the risk of death while awaiting transplantation are urgently needed because organ shortage is increasing the numbers on transplantation waiting lists. The aminopyrine breath test (ABT), model for end-stage liver disease (MELD), and Child-Pugh (C-P) score were compared as predictors of this risk in 137 cirrhotic candidates for liver transplantation. Eighty-three were transplanted within 3 months of registration, 35 others survived, 13 died before transplantation, and 6 were removed from the list. By univariate analysis, the continuous variables significantly associated with death while awaiting transplantation were: history of infected ascites, C-P score, ABT, and international normalized ratio or prothrombin time. Receiver operating characteristic curves for quantitative variables showed that the area under the curve was greatest for ABT (0.858 +/- 0.067). By Youden curve analysis, the best cut-off points for identifying cirrhotic patients at high risk of death while on the waiting list were: > 10, > 16, and < 0.7% for the C-P score, MELD score, and ABT, respectively. These results show that ABT is as good as the MELD and C-P scores, or better, as a predictor of death among cirrhotic patients awaiting liver transplantation.

The limited number of donor organs has placed a burden on the medical community to improve patient selection and timing of liver transplantation (LT). We aim to evaluate short- and long-term survival of 124 consecutive patients with a diagnosis of nonbiliary cirrhosis. Seventeen clinical, biochemical, functional, and hemodynamic parameters were computed. Patient survival was evaluated in the short term (3 months) by logistic regression, and the predictive power of the model was evaluated using receiver operating characteristic curves and the log likelihood ratio. For the long-term (up to 5 years) prognosis, the Cox proportional model was used. During follow-up, 54 patients died and 20 patients underwent LT. In the short-term study, the Model for End-Stage Liver Disease score (including bilirubin level, international normalized ratio [INR], and creatinine level) was as predictive as our score, which contained only two independent indicators (bilirubin and creatinine levels). In the long-term study, three independent variables (albumin level, INR, and creatinine level) emerged from the Cox model, and patients were classified into three survival-risk groups according to a prognostic index (PI): -1.039 x albumin (grams per deciliter) + 1.909 x log(e) INR + 1.207 x log(e) serum creatinine (milligrams per deciliter). Survival probabilities at 1 and 5 years were 89% and 80%, 63% and 52%, and 23% and 10% with a low, medium, and high PI, respectively. The validation study using the split-sample technique and data from independent patients confirmed that a high PI (>-2.5) identifies patients with a poor prognosis within 5 years. We thus have shown and validated that risk for death at the short and long term of patients with nonbiliary cirrhosis can be predicted with great accuracy using models containing a few simple and easily obtained objective variables, and these survival models are useful tools in clinical decision making, especially in deciding to list patients for LT and prioritization on the liver waiting list.

Background: We report a case of domino liver transplantation using the liver harvested from a patient who underwent a combined liver and kidney transplantation for primary hyperoxaluria (PH)., Method: A cadaveric liver transplantation was performed in a 19-year-old man with PH. In a second step, the PH liver harvested from the first patient was transplanted in a 69-year-old man with hepatitis C-related cirrhosis, not a candidate for a classic liver graft owing to multifocal hepatocellular carcinoma., Results: At 8 months after transplantation, the domino recipient has normal hepatic function and no signs of tumoral recurrence, but he progressively developed hyperoxalemia, hyperoxaluria, and renal insufficiency., Conclusion: Regarding the favorable postoperative clinical evolution, domino liver transplantations using livers from PH patients may represent a new opportunity for marginal candidates for liver transplantation. However, the progressive renal insufficiency expected in such domino recipients should limit this procedure to selected cases.

Hepatitis C-related cirrhosis is the major indication for liver transplantation (LT). This disease recurs histologically in nearly all the HCV-infected patients during the first postoperative year. Chronic hepatitis C evolves to cirrhosis in 20% of the cases within 5 years after LT. However, the 5-year survival for a HCV-infected recipient is still comparable to that of a patient grafted for another indication; it will become worse later. High viremia after LT is associated with a more severe liver recurrent disease. The influence of viral genotype remains controversial. The impact of the type of immunosuppression on HCV recurrence is unclear. Steroids, that increase viremia, might have a deleterious effect on the outcome of chronic HCV-disease after LT. Antiviral combined therapy (Interferon + Ribavirin) soon after transplantation, before disease recurrence, is probably the best treatment at the present time; this remains still unproven. Retransplantation for HCV recurrent cirrhosis allows a 60% survival at 1 year.

Accurate prediction of short-term survival rate after liver transplantation is one way of selecting recipients and should improve organ allocation. We observed, during the first ten years of our program a striking decline in postoperative mortality with time, a well known observation in Europe as well as in the United States. In 65 adults with parenchymal cirrhosis having received a liver transplant between 1984 and 1994, we examined the possible influence of various preoperative risk factors on one-month mortality rate which was 13.8% in this series. Univariate analysis led to the identification of five significant risk factors: date of transplantation, low serum sodium, previous history of jaundice, ascites and encephalopathy. In the final multivariate analysis however, the date of transplantation emerged as the sole predictive factor of early mortality rate. Therefore, factors such as pretransplantation state of the patient and poor hepatic reserve are counterbalanced by the improvement of surgical skill and other technical aspects, as well as by better perioperative management which have all contributed to the improved results of liver transplantation with time.

Hepatorenal syndrome is a rapidly lethal complication of cirrhosis. The present case provides further evidence of the efficacy of terlipressin in this context even with concomitant treatment with propranolol. A 56 year old male with HBV related cirrhosis developed renal failure characteristic of hepatorenal syndrome. He was also taking propranolol for primary prophylaxis of variceal bleeding. Terlipressin 6 mg/day was administered during haemodialysis and after 1 week plasma creatinine dropped from 6.2 to 2.8 mg%. Daily urinary volume, plasma sodium and natriuresis dramatically increased during the treatment. Discontinuation of the treatment led to a rapid relapse of renal failure (plasma creatinine from 1.8 to 2.2 mg%) and the drug was readministered until a successful liver transplantation could be performed 1 month after the beginning of the treatment. The patient has now a near normal renal function 3 months after transplantation.

Alveolar echinococcosis of the liver is an uncommon and fatal disease resulting from hepatic infection by Echinococcus multilocularis. Liver transplantation has been proposed for unresectable cases with chronic complications, but up to now, no long-term follow-up has been reported. We report the case of a 29-year-old female who is disease-free more than six years after liver transplantation for a recurrent alveolar echinococcosis of the liver, confirming the place for liver transplantation in this disorder.

Background: We report our current experience using endoscopic retrograde cholangiography in the management of post-transplantation biliary tract complications., Methods: Twenty-three patients among 109 adult liver transplant recipients underwent retrograde cholangiography because of cholestasis (18 patients) or bile leaks (5 patients)., Results: Eleven of 18 patients developed anastomotic strictures, all successfully dilated by plastic stents; one patient required Roux-en-Y revision due to recurrent cholangitis while stented. Three had biliary calculi extracted following sphincterotomy. Two developed intrahepatic ductal strictures secondary to severe rejection. One patient had hepatic artery thrombosis with a hilar stricture. One cholangiogram was normal. Three patients developed bile peritonitis following T-tube removal, all treated by sphincterotomy and nasobiliary drainage. Choledochal perforation resulting from an impacted T-tube limb was detected in two patients, both treated with sphincterotomy and nasobiliary drainage., Conclusions: Strictures within 3 months of surgery required 3 months of stenting; those occurring later required longer periods of time to respond. Bile leaks responded uniformly and rapidly to drainage. Endoscopic retrograde cholangiography is a useful diagnostic and therapeutic intervention for post-transplantation biliary tract complications.

Listeria is an uncommon cause of hepatitis in adults. We report the case of a liver transplant recipient who presented with a clinical picture of acute hepatitis, 8 months after grafting. Blood cultures yielded Listeria monocytogenes. The patient made a full clinical recovery after adequate antimicrobial therapy (ampicillin and gentamicin intravenously for 4 weeks). Hepatitis was attributed to the Listeria infection. We believe this is the first reported case of Listeria hepatitis in an organ transplant recipient.

A liver transplant recipient developed infection of a perihepatic haematoma due to Trichoderma viride. Before the infection was diagnosed, the patient received intense immuno-suppressive and prolonged antibacterial and anti-fungal therapies. Although the death of the patient was not directly related to the fungal infection, abundant quantities of this pathogen were recovered in the haematoma at post-mortem examination, despite previous surgical removal and treatment with amphotericin B and fluconazole.

The aim of our study was to develop simple and highly effective scores to estimate prognosis at 1 year for patients with parenchymal cirrhosis and to define the optimum time for liver transplantation with the same degree of accuracy as the prognosis estimation for primary biliary cirrhosis. The prognostic value of 19 variables was studied retrospectively in 91 patients with parenchymal cirrhosis using multivariate analysis and logistic regression. The best prognostic index was obtained with two independent variables: ascites and aminopyrine breath test. Although the receiver operating characteristic (ROC) curve for these two variables was better than the ROC curve for Pugh score, the percentage of correct prediction was excellent for both indices: 92% and 87%, respectively. The critical cut-off value of the Pugh score was 8.8. The prognostic value of a Pugh score < or = 8 or > 8 was confirmed in a prospective study of 145 cirrhotic patients with 78% correct prediction. During this period, 21 patients with parenchymal cirrhosis received transplants with a preoperative Pugh score of 9.5 +/- 2.0 (mean +/- SEM) and 60% 1- and 2-year survival. In conclusion in parenchymal cirrhosis, a Pugh score > 8 indicates a poor prognosis at 1 year. This is a simple, easy and highly effective tool to define the optimal time for liver transplantation in this category of patients.

Somatostatin can be helpful after liver transplantation in some well-defined indications. In uncontrolled digestive haemorrhage, a short course of somatostatin therapy can be of great help in controlling the acute bleeding and to avoid emergency laparotomy. Somatostatin could also be helpful in bilio-pancreato-intestinal fistula, but in this case its advantage over elective surgical treatment remains to be confirmed.

In our early experience, orthotopic liver transplantation was found to be successful in fulminant and subacute hepatic failure due to viral hepatitis in adults, with 66% 1-year survival rate. In the future, more accurate prognostic criteria would probably improve overall survival rate in acute hepatic failure, by allowing better and earlier selection of patients requiring liver transplantation.

The aim of our study was to design simple and practical quantitative scores or indices suitable for deciding a pre-liver transplantation work-up in patients with parenchymal cirrhosis. A Pugh score (combining five variables) superior to 8 or a p value inferior to 0.7 of a logistic regression equation containing only two variables (score of ascites and result of 14C aminopyrine breath test) were found to be highly effective for making this decision.