Juan Carlos Meneu

Clinical and histological efficacy of pegylated interferon and ribavirin therapy of recurrent hepatitis C after liver transplantation

Treatment of recurrent hepatitis C in liver transplant is controversial. The aim of our study was to evaluate the clinical and histological efficacy of pegylated interferon alpha 2b (PEG‐IFN) and ribavirin therapy of recurrent hepatitis C after liver transplantation (LT). We prospectively included 47 liver transplant patients with: 1) a positive test for hepatitis C virus (HCV)‐ribonucleic acid (RNA) in serum; 2) alanine aminotransferase (ALT) >45 UI/mL; and 3) a liver biopsy showing chronic hepatitis without rejection in the previous 2 months. Patients received PEG‐IFN (1.5 μg/kg/week) and ribavirin (800‐1,000 mg/day) for 12 months. Follow‐up was based on biochemical (ALT), virological (RNA‐HCV), and histological (liver biopsy) examinations. Follow‐up lasted a minimum of 6 months after the end of antiviral therapy. Sustained virological response (SVR) was achieved in 23% of the patients. A total of 33 (70%) patients had normalized ALT levels at the end of therapy. Inflammatory portal and lobular score declined significantly in patients with SVR (P < 0.05) but not in nonresponder patients. Fibrosis did not change significantly in either group. SVR was significantly associated with low γ‐glutamyltransferase GGT (P = 0.04) and HCV‐RNA levels (P = 0.03), a virological response at 12 weeks (P = 0.002) and patients compliance (P = 0.04). Ten (21%) patients were withdrawn prematurely due to adverse effects. In conclusion, Therapy with PEG‐IFN and ribavirin achieved SVR and a significant histological improvement in 23% of liver transplant recipients with chronic hepatitis C. Toxicity is an important drawback of this therapy. Liver Transpl 12:1805‐1812, 2006.

Incidence and risk factors for the development of lung tumors after liver transplantation

Tobacco and immunosuppression are risk factors for developing upper aerodigestive and lung tumors after transplantation. This study comprises 701 adult recipients who survived more than 2 months after transplant: 276 patients underwent orthotopic liver transplantation (OLT) for alcoholic cirrhosis (AC) and 425 for nonalcoholic disease. The aim is to analyze the incidence, clinical characteristics, risk factors, and outcome of patients who develop lung malignancies after OLT. Incidence of lung cancer was 2.1% (15 patients): 4.3% (12 patients) in the alcoholic group and 0.7% (three patients) in the nonalcoholic group (P < 0.001). Mean time from OLT to tumor diagnosis was 86 months. Thirteen patients were smokers; 12 patients were heavy drinkers; and 11 were drinkers and smokers. Squamous cell carcinoma was diagnosed in nine patients, large cell carcinoma in three, adenocarcinoma in two, and broncoalveolar in one. Tumor staging: 10 patients at stage IV; three at stage IIIB; and two at stage IIB. Tumor resection was performed in one patient, and three also received chemotherapy. Mean survival after tumor diagnosis was 5.4 months. There is a higher risk of lung cancer in smoker patients who have undergone OLT for AC, and have a very poor prognosis because tumors are diagnosed at advanced stages.

Incidence, risk factors, and outcome of chronic rejection during antiviral therapy for posttransplant recurrent hepatitis C

Antiviral therapy for recurrent hepatitis C in liver transplantation has been associated with the development of chronic rejection. The aim of this study was to assess the incidence, evolution, and risk factors associated with the development of chronic rejection during posttransplant hepatitis C virus antiviral therapy. Seventy‐nine patients with posttransplant recurrent hepatitis C who were treated with pegylated interferon and ribavirin were prospectively followed. Liver biopsy was performed before antiviral therapy was initiated and when liver tests worsened during therapy. Pretransplant and posttransplant factors were analyzed as potential risk factors for the development of chronic rejection. Seven of 79 patients (9%) developed chronic rejection during antiviral therapy. The mean time from the start of treatment to the development of chronic rejection was 5.8 months (3–12 months). An analysis of factors associated with the development of chronic rejection showed that the use of cyclosporine as immunosuppression therapy (6 of 19 patients who received cyclosporine developed chronic rejection in comparison with only 1 of 57 patients who received tacrolimus; P = 0.0013), achievement of sustained virological response (P = 0.043), and ribavirin discontinuation (P = 0.027) were associated with the development of chronic rejection. In conclusion, the development of chronic rejection during posttransplant pegylated interferon and ribavirin therapy is a severe complication. The use of cyclosporine, ribavirin discontinuation, and viral infection elimination seem to be associated with the development of this complication. Liver Transpl 15:948–955, 2009.

Pretransplant lymphocyte count predicts the incidence of infection during the first two years after liver transplantation

Patients with end‐stage liver disease (ESLD) show a low absolute number of peripheral blood lymphocyte subpopulations (PBLSs). We investigated if the baseline PBLS could categorize orthotopic liver transplantation (OLT) recipients into groups at high or low risk for infection after transplantation. PBLSs were prospectively studied in 63 consecutive patients (42 males; mean age ± standard deviation: 53.5 ± 10.3 years) with ESLD prior to OLT. Thirty‐five patients (55.6%) developed a total of 79 infectious episodes during the first 2 years post‐OLT. The median total lymphocyte count and PBLS levels [CD3+ T cells, CD4+ T cells, memory (CD45RO+) CD4+ T cells, T cell receptor αβ+ and γδ+ subsets, and CD19+ B cells] at baseline were significantly lower in patients with an infection compared with those without one (P < 0.05). There was a significant correlation between the risk of development of a post‐OLT infection and a baseline total lymphocyte count < 1.00 × 103/μL (P = 0.001), a baseline CD3+ T cell count < 0.75 × 103/μL (P = 0.009), and a baseline CD4+ T cell count < 0.5 × 103/μL (P = 0.008). In the multivariate analysis, this association between the baseline total lymphocyte level and infection remained significant (odds ratio: 10.1; 95% confidence interval: 1.9‐39.5). In conclusion, the pre‐OLT total lymphocyte count identifies a subset of patients at high risk for infection. PBLS monitoring prior to OLT may offer an opportunity for surveillance, tapering of immunosuppression, and preemptive therapy. Liver Transpl 15:1209–1216, 2009.

Long-Term Follow-Up of Donor Chimerism and Tolerance After Human Liver Transplantation

We aimed to quantify peripheral donor chimerism (DC) and to analyze its association with graft and recipient outcome. Forty‐two liver transplant recipients and their respective donors were studied, providing a total of 148 posttransplantation serum samples. DC was assessed with real‐time quantitative polymerase chain reaction (qPCR) to detect polymorphic markers. DC did not decrease with time post‐transplantation and was higher in child recipients versus adults and in recipients of deceased donor liver transplants versus recipients of live donor liver transplants. Higher levels of DC were detected in Rh‐positive blood group donors, in O blood group recipients versus A blood group recipients, and in recipients with hepatitis C virus versus recipients with alcoholic cirrhosis. High DC was associated with patients with organ damage due to recurrent disease and rejection. Stable, high levels of DC, in the absence of other major clinical events, may thus be a marker of transplantation tolerance, and this knowledge may help to tailor immunosuppressive treatment. In conclusion, qPCR is a useful technique for DC follow‐up in liver transplantation, although the evolution of DC levels should be analyzed in accordance with the clinical outcome of the patient. Liver Transpl 15:581–591, 2009.

Liver transplantation and transjugular intrahepatic portosystemic shunt

OBJECTIVE Describe the results of liver transplantation after installing Transjugular Intrahepatic Portosystemic Shunt (TIPS) and compare them with those of a control group in a comparative, longitudinal, retrospective study. MATERIALS AND METHODS Between April 1986 and October 2002, we performed 875 liver transplantations. Between January 1996 and October 2002, 26 transplantations were performed on TIPS carriers. This group was compared with a control cohort of 50 randomly selected patients who underwent transplantation in this period (non-TIPS carriers). Both groups were homogeneous with no significant differences between age, sex United Network for Organ Sharing (UNOS) score, Child stage, or etiology. RESULTS Actuarial survival rates at 1 and 3 years: TIPS group 96.15% and 89.29% versus control cohort 87.8% and 81%, respectively. In 73.9%, the TIPS was clearly effective; in 88.9%, a postoperative Doppler revealed normal flow. There were no statistically significant differences compared with time on the waiting list for transplant, duration of the operation, ischemia times, intraoperative consumption of hemoderivates, vascular or nonvascular postoperative complications, duration of stay in the intensive care unit, hospital stay, or retransplantation rate. CONCLUSIONS In our experience, TIPS insertion does not affect either the intraoperative or postoperative evolution and is not associated with an increased time on the liver transplant waiting list.

Peripheral blood lymphocyte populations in end-stage liver diseases.

Goals/Background The aim of this study was to decipher whether end-stage liver failure modifies peripheral blood lymphocytes (PBL) in a homogeneous manner, independently of the base pathology, or, if on the contrary, PBL subsets show a different profile in each hepatic disease. Methods We studied PBL subsets in 71 patients with end-stage liver disease, before liver transplant, and 74 healthy controls by flow cytometry. The results were statistically compared between patients and controls, and cohorts of patients classified according to their base pathology. Results We observed lower absolute numbers in all lymphocyte populations in patients compared with controls. We found an increment of CD3+ activated cells (P<10−5) and CD45RO+CD4+ (P<10−5) in chronic hepatitis C virus versus controls; hepatitis B virus showed high TCRγδ+ and CD8+ T cells with respect to controls (P=0.008 and P=0.029, respectively); alcoholic cirrhotic patients showed low CD8+, mainly CD45RA+CD8+ (P=0.007) and high CD45RO+CD4+ (P<10−5) compared with the normal population; autoimmune diseases showed lower CD3+ and TCRαβ+ (P=0.002 and P=0.0001) than controls. Conclusions Regardless of the base pathology, patients with end-stage liver disease show a low absolute number of lymphocyte populations compared with controls. However, PBL profiles are different, characteristic, and specific of every disease causing chronic liver failure.

Compative study of bladder versus enteric drainage in pancreas transplantation.

INTRODUCTION There is some controversy concerning the choice of best technique for drainage of exocrine secretions in pancreas transplantation. We compared patients with bladder drainage (BD) versus those with enteric drainage (ED). PATIENTS AND METHODS From March 1995 to September 2008, 118 patients (68 men and 50 women) of overall mean age of 37.8 +/- 7.8 years underwent pancreas transplantation. There were 109 simultaneous pancreas-kidney, and 9 pancreas after kidney procedures. Recipients were divided in a BD (n = 66 patients) and an ED group (n = 52). RESULTS Donor characteristics were similar in both groups. Thirty-two patients (48.5%) of the BD group versus none in the ED group experienced urinary tract infections (UTI; P < .001), and 16 patients (24.2%) BD versus 15 (29.4%) ED developed intraabdominal infections (P = NS). The overall rate of relaparotomies was 33.9% (n = 40): 34.8% (n = 23) in the BD versus 32.7% (n = 17) in the ED group (P = NS). Thirty patients (25.4%) lost their pancreas grafts: 21 (31.8%) in the BD group versus 9 (17.3%) in the ED group (P = .055). The acute rejection rates were 12.7%; namely, 15.2% in the BD versus 9.8% in the ED (P = NS). Three-year patient and graft survivals were equivalent in both groups: 96.1% and 65.3% in the BD versus 89.0% and 74.0% in the ED group, respectively (P = NS). CONCLUSIONS ED is a good alternative to BD for drainage of pancreatic graft exocrine secretions because both techniques have the same patient and graft survival, but BD is associated with a significantly higher rate of UTI and urologic complications.

Changes in the incidence and severity of recurrent hepatitis C after liver transplantation over 1990–1999

BACKGROUND/AIM Changes in immunosuppression and other factors may have changed the severity of recurrent hepatitis C during recent years. This study sought to establish the changes in incidence and severity of recurrent hepatitis C, and its association with the changes in acute rejection and induction immunosuppressive therapy between 1990 and 1999. PATIENTS AND METHODS Among 213 liver transplants in HCV-infected recipients, 129 grafts were selected for this study: all grafts with severe recurrent hepatitis C (fibrosis 3-4 in Scheuers score or fibrosing cholestatic hepatitis), and those grafts without severe recurrence with at least 2 years of follow up. Grafts were divided in 5 groups depending on the year of transplantation to compare recurrent hepatitis C-related variables, AR incidence and induction immunosuppression. RESULTS Hepatitis-free survival decreased in recent years (p=0.015). The incidence of fibrosing cholestatic hepatitis was higher among 1996-1997 and the 1998-1999 periods (p=0.019). Survival free of severe hepatitis at 1 year follow up was 95% in 1990-1991 and 80% in 1998-1999; however, in the long-term the survival was similar between groups (p=0.933). HCV-related graft survival at 5 years was 93.5% in the 1990-95 period and 82.5% in 1996-99 (p=0.068). Neither AR nor any regimen of induction immunosuppression was associated with changes in the occurrence of recurrent hepatitis C related survival. CONCLUSIONS Severity of recurrent hepatitis C and HCV-related graft loss after liver transplantation were higher in the second half of the 1990s; however, there was no association with AR or induction immunosuppression.

Single Nucleotide Change in the Cannabinoid Receptor-1 (CNR1) Gene in Colorectal Cancer Outcome

The cannabinoid receptor-1 (CNR-1) and endogenous agonists of this receptor are present in the central and peripheral nervous systems including the gastrointestinal nervous system. The surgically rejected specimens of human colorectal cancers and paired normal tissues were studied to detect mutations in the CNR1 gene by sequencing method. The results were compared to clinicopathological parameters and correlated with overall survival time. Sixty-three colorectal cancer patients, who underwent surgical excision of colorectal carcinoma, were included in this study. The coding region of the CNR1 gene was studied: a nucleotide change (G→A) at position 1359 was identified by direct sequencing of PCR. Thirty-eight patients had the G/G genotype (wild type) in tumor areas and 25 patients had G/A heterozygous or A/A homozygous genotype. Univariate analysis revealed 2 independent variables associated with CNR1 gene mutation. The results show that the patients with Dukes stage C and D had a 2.9 times (p = 0.04) and patients that were lymph node positive had 2.8 times (p = 0.05) greater probability of nucleotide change in CNR1 gene. Genotype G/A plus A/A had a shorter overall survival time than G/G wild-type patients (p < 0.05). Indeed nontumor paired colorectal tissues showed nucleotide change. A large number of patients with mutation in the CNR1 gene were observed. These preliminary findings highlight the importance of further studies in the use of cannabinoid analogs as receptor ligands to analyze potential therapeutic effects.