Expansion of memory-type CD8+ T cells correlates with the failure of early immunosuppression withdrawal after cadaver liver transplantation using high-dose ATG induction and rapamycin.

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 In the absence of acute rejection (AR), rapamycin was withdrawn after month 4.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 (Vß/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.

Acute liver transplant rejection upon immunosuppression withdrawal in a tolerance induction trial: potential role of IFN-gamma-secreting CD8+ T cells.

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.

Endoscopic drainage of pyogenic liver abscesses with suspected biliary origin.

OBJECTIVES: Pyogenic liver abscesses remain an important and life-threatening clinical problem but their causes and management have changed over the last two decades. The aim of this study was to assess the feasibility and the impact of an endoscopic approach in the management of liver abscesses with suspected biliary origin. METHODS: We reviewed the records of 16 patients suffering from pyogenic liver abscess, who underwent endoscopic retrograde cholangiopancreatography (ERCP) in the setting of biliary diseases between January 1995 and December 2004. Nine patients had an underlying neoplastic disease; 13 had a history of biliary endoscopic maneuvers. When the collections were communicating with the biliary tree, an endoscopic drainage of the abscess was performed either by sphincterotomy, dilation, insertion of a nasobiliary catheter, or stenting. In noncommunicating liver abscesses associated with bile duct abnormalities, biliary decompression was obtained by insertion or replacement of biliary stents. RESULTS: Fourteen patients had liver abscesses communicating with the biliary system and underwent an endoscopic drainage of the cavity. Ten of these patients had an exclusive endoscopic drainage of the abscess, while four cases required additional percutaneous drainage. The two noncommunicating abscesses were associated with previous insertion of biliary stents; these were cured percutaneously after endoscopic stent replacement. Among the 16 patients, 13 had a rapid resolution of symptoms (81%). CONCLUSION: This initial clinical experience suggests that ERCP can demonstrate communications between the biliary tract and liver abscesses, and that an internal drainage of the cavity is feasible and safe.

Ageing and the liver.

Age does not spare the liver. We reviewed here the essential actual knowledge about age related modifications of this organ. Liver volume and blood flow decrease with age. Aging is also associated with a decline in the intrinsic metabolic activity of the hepatic parenchyma, and in the gene expression of proteins involved in intermediary metabolism, mitochondrial respiration and drug metabolism. Aged hepatocytes accumulate oxidative DNA damage, responsible for the increase in mutations, particularly in the mitochondrial genome. Histologically, aged hepatocytes are characterized by accumulation of ageing pigments into the cytoplasm and by pseudocapillarization of the sinusoid. Age is also of importance at the time of HCV infection: fibrosis progression is faster when the virus is acquired after 40 years. In liver transplantation, an old transplanted liver is now an identified cause of primary non-function of the graft and an independent cause of mortality after transplantation. The age of the donor is also a predictive factor of the severity of recurrent liver HCV-related disease on the graft.

Early immunosuppression withdrawal after living donor liver transplantation and donor stem cell infusion.

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.

Relationship between the degree of portal hypertension and the onset of spontaneous bacterial peritonitis in patients with cirrhosis.

BACKGROUND/AIM: Spontaneous bacterial peritonitis (SBP) is a severe complication of cirrhosis but its exact pathogenesis has not yet been elucidated and the role of portal hypertension in the development of SBP has been suggested. The aim of this study was to test the hypothesis that an association exists between the degree of portal hypertension and the occurrence of SBP. METHODS: 292 patients with cirrhosis who underwent a measurement of the hepatic venous pressure gradient (HVPG) were retrospectively studied. Following their ascites profile, patients were classified in three groups: patients with ascites who suffered from SBP, patients with sterile ascites, and patients who had no ascites. RESULTS: Among the 137 patients with ascites, 24 patients suffered from SBP (17.5%). The mean HVPG was significantly different: 20.7 +/- 6.2 mm Hg in the SBP group, 17.5 +/- 5.1 mm Hg in the sterile ascites group and 14.7 +/- 5.6 mm Hg in the group without ascites (p < 0.05). Patients with the most severe portal hypertension (HVPG > or =30 mm Hg) had the highest risk to suffer from SBP (50%). Using the multivariate analysis, only the serum albumin level (p = 0.004) and the HVPG (p = 0.02) were independently correlated with the occurrence of ascites infection. CONCLUSIONS: This study suggests that in patients with SBP the degree of portal hypertension is greater than in the non infected patients. Ascites infection is independently associated with a low serum albumin level and a high HVPG.

MR cholangiography with manganese dipyridoxyl diphosphate in the evaluation of biliary-enteric anastomoses: preliminary experience.

OBJECTIVE: The purpose of our study was to assess the usefulness of manganese dipyridoxyl diphosphate (Mn-DPDP)-enhanced T1-weighted MR cholangiography for evaluating patients with biliary-enteric anastomoses. CONCLUSION: Mn-DPDP-enhanced T1-weighted MR cholangiography may provide useful functional information and may aid in the assessment of the patency of biliary-enteric anastomoses.

Reduction of relapse rates by 18-month treatment in chronic hepatitis C. A Benelux randomized trial in 300 patients.

BACKGROUND/AIMS: Treatment of chronic hepatitis C with interferon can be ineffective due to relapse. We aimed to reduce the 40% relapse rate of 6 months interferon-ribavirin combination therapy by prolonging treatment to 18 months. METHODS: Three hundred patients with treatment-naive hepatitis C, were randomized to 18 months combination therapy with interferon (3MU tiw) and ribavirin (1000-1200 mg/day), 18 months interferon combined with placebo, or 6 months combination therapy with interferon and ribavirin, in a double blinded manner. All 295 patients who received at least one dose of treatment were included in the intention to treat analysis. RESULTS: At the end of treatment, HCV RNA was undetectable in 55 and 49% of those on 6 and 18 months combination therapy, respectively, versus 26% of those on monotherapy (P<0.001). The relapse rate was 38% for 6 months combination therapy, 38% for 18 months monotherapy, and only 13% for 18 months combination treatment (P=0.002). The sustained response rates were 34% for 6 months combination therapy, 16% for 18 months monotherapy and 43% for 18 months combination therapy (P<0.05). CONCLUSIONS: Reduction of relapse rates to 15% or less is feasible by prolongation of interferon-ribavirin treatment to 18 months.

Aminopyrine breath test compared to the MELD and Child-Pugh scores for predicting mortality among cirrhotic patients awaiting liver transplantation.

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.

New considerations for an overall approach to treat hepatocellular carcinoma in cirrhotic patients.

BACKGROUND: Increasing numbers of cases and organ shortage justify reconsidering the global therapeutic approach for hepatocelluar carcinoma in cirrhotic patients. METHODS: Recent literature was reviewed, focused on new therapeutic technologies such as radiofrequency. RESULTS: For small tumors, liver transplantation offers theoretically the best chance for cure. However, organ shortage may eliminate this advantage, because of tumor progression while waiting for a graft. For small tumors, arising on compensated cirrhosis, resection or radiofrequency ablation may provide efficient local tumor control without precluding subsequent transplantation in case of tumor recurrence and/or cirrhosis decompensation. CONCLUSIONS: For small tumors and compensated cirrhosis, resection or radiofrequency could represent acceptable first line treatments. In addition to permit safe and immediate tumor control, this strategy would allow a preferential redistribution of grafts to patients with decompensated cirrhosis in whom transplantation is the only possibility.

Predictive models of short- and long-term survival in patients with nonbiliary cirrhosis.

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.