Stéphanie Faure

Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the primary indication

BACKGROUND & AIMS Beyond 5 years, poorer survival, related to alcohol relapse, is observed in patients with liver transplant for alcohol-related liver disease (ALD). However, alcohol consumption has been significantly understudied in non-ALD transplant recipients. We aimed at analyzing the impact of alcohol consumption on long-term survival irrespective of the indication for transplantation. METHODS This observational study included consecutive adult recipients of a primary liver graft between 1991 and 2007 in our hospital, who survived >6 months. Patients without ALD as primary indication, but with a history of excessive alcohol consumption before transplantation, were classified as secondary indication ALD. We studied the impact on survival of excessive consumption of alcohol after transplantation and several other variables. RESULTS The 441 patients had mean follow-up of 81.7 months. Among the 281 patients with excessive alcohol consumption before transplantation, 206 had ALD as primary indication. After transplantation, alcohol consumption was reported by 32.3% of the study population, 43.7% in primary indication ALD, and 24.3% in non-ALD patients. Survival was 82% at 5 years and 49% at 10 years for patients with excessive alcohol relapse, compared with 86% and 75%, respectively, for patients without persistent excessive alcohol relapse. By multivariable analysis, the independent risk factors of death were: excessive alcohol relapse, age >51 years, post-transplantation diabetes mellitus, cyclosporine-based immunosuppression, and non-hepatic cancer. CONCLUSIONS Excessive alcohol consumption has a negative impact on long-term survival after liver transplant, irrespective of the primary indication. Death is mainly due to recurrence of liver disease and non-hepatic cancer.

Recurrent alcoholic cirrhosis in severe alcoholic relapse after liver transplantation: a frequent and serious complication.

Objectives:Alcoholic liver disease (ALD) is a major indication for liver transplantation (LT). Recurrent alcoholic cirrhosis (RAC) after LT can occur but has not been studied. The aims of this study were to estimate the prevalence, predictive factors, and natural history of RAC after LT.Methods:All patients transplanted for ALD between 1990 and 2007 in three French centers were included. The diagnosis of RAC was based on histological evidence or a series of features combined with severe alcoholic relapse.Results:Among 1,894 adult LT patients, 712 were transplanted for alcoholic cirrhosis and survived >6 months. After a mean follow-up of 9 years, 128 patients (mean age at LT 47.2±7.1 years old, 78.9% men) experienced severe alcoholic relapse (18.0% of cases). Severe alcoholic relapse occurred after a median delay of 25 months (range 4–157) after LT. RAC was diagnosed in 41 patients with severe relapse (32%). The diagnosis of RAC was made after a median delay of 5.1 years (range 1.8–13.9) after LT and of 4.0 years (range 1.2–11.5) after relapse. RAC was significantly associated with younger age and a shorter period of pre-LT abstinence. One-, 5-, 10-, and 15-year survival was 100, 87.6, 49.7, and 21.0%, respectively, for RAC patients vs. 100, 89.4, 69.9, and 41.1%, respectively, for the patients without RAC (P<0.001).Conclusions:RAC occurs in <6% of ALD transplant patients. One-third of severe alcoholic relapse patients develop RAC <5 years after transplantation with a very poor prognosis.

Long‐term outcomes of liver transplantation: Diabetes mellitus

Key Points

Incidence of solid organ cancers after liver transplantation: comparison with regional cancer incidence rates and risk factors.

Increased rates of solid organ cancers post‐liver transplantation have been reported, but the contribution of environmental factors and immunosuppressive therapy is not clear. This studys aims were to compare the incidence of de novo solid organ cancers after liver transplantation; identify risk factors independent of immunosuppressive therapy associated with these cancers; and assess the influence of calcineurin inhibitors on the appearance of these cancers.

Tacrolimus and the risk of solid cancers after liver transplant: a dose effect relationship.

Although increased rates of solid organ cancers have been reported following liver transplantation (LT), the impact of quantitative exposure to calcineurin inhibitors (CNI) remains unclear. We have therefore probed the relationship between the development of solid organ cancers following LT and the level of CNI exposure. This prospective single‐center study was conducted between 1995 and 2008 and is based on 247 tacrolimus‐treated liver transplant recipients who survived at least 1 year following surgery. The incidence of cancer was recorded, and the mean blood concentration of tacrolimus (TC) was determined at 1 and 3 years following LT. The study results indicate that 43 (17.4%) patients developed de novo solid cancers. Mean TC during the first year after LT was significantly higher in patients who developed solid organ tumors (10.3 ± 2.1 vs. 7.9 ± 1.9 ng/mL, p < 0.0001). Independent risks factors in multivariate analysis were tobacco consumption before LT (OR = 5.42; 95% CI [1.93–15.2], p = 0.0014) and mean annual TC during the first year after LT (p < 0.0001; OR = 2.01; 95% CI [1.57–2.59], p < 0.0001). Similar effects were observed in 216 patients who received tacrolimus continuously for ≥3 years. It appears therefore that CNI should be used with caution after LT, and that new immunosuppressive therapies could deliver significant clinical benefits in this regard.

Second-line therapy for gemcitabine-pretreated advanced or metastatic pancreatic cancer

AIM To investigate second-line chemotherapy in gemcitabine-pretreated patients with advanced or metastatic pancreatic cancer [(frequency, response, outcome, course of carbohydrate antigen 19-9 (CA 19-9)]. METHODS This retrospective study included all patients with advanced or metastatic pancreatic cancer (adenocarcinoma or carcinoma) treated with second-line chemotherapy in our center between 2000 and 2008. All patients received first-line chemotherapy with gemcitabine, and prior surgery or radiotherapy was permitted. We analyzed each chemotherapy protocol for second-line treatment, the number of cycles and the type of combination used. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, response rate, grade 3-4 toxicity, dosage modifications and CA 19-9 course. RESULTS A total of eighty patients (38%) underwent a second-line therapy among 206 patients who had initially received first-line treatment with a gemcitabine-based regimen. Median number of cycles was 4 (range: 1-12) and the median duration of treatment was 2.6 mo (range: 0.3-7.4). The overall disease control rate was 40.0%. The median overall survival and progression-free survival from the start of second-line therapy were 5.8 (95% CI: 4.1-6.6) and 3.4 mo (95% CI: 2.4-4.2), respectively. Toxicity was generally acceptable. Median overall survival of patients with a CA 19-9 level declining by more than 20% was 10.3 mo (95% CI: 4.5-11.6) vs 5.2 mo (95% CI: 4.0-6.4) for others (P = 0.008). CONCLUSION A large proportion of patients could benefit from second-line therapy, and CA 19-9 allows efficient treatment monitoring both in first and second-line chemotherapy.

Cirrhotic patients with portal hypertension-related bleeding and an indication for early-TIPS: A large multicentre audit with real-life results

BACKGROUND The Baveno VI consensus meeting concluded that an early TIPS must be considered in high-risk cirrhotic patients presenting with variceal bleeding (VB) (Child B + active bleeding at endoscopy or Child C10-13 patients). Whether this therapeutic approach is feasible in a real-life setting remains unclear. AIMS To determine (1) the proportion of patients eligible for early-TIPS among cirrhotic patients with VB, (2) the proportion of these patients who underwent early-TIPS placement and the main reasons for discarding TIPS, and (3) the outcomes of patients who experienced early-TIPS placement in a large, national, prospective, multicentre audit including academic and non-academic centres. MATERIALS AND METHODS All French centres recruiting gastrointestinal bleeding were invited to participate. All consecutive patients with cirrhosis and PHT-related bleeding were included. RESULTS 964 patients were included (58 centres: 26 academic, 32 non-academic; patient characteristics: male sex, 77%; age, 59.6 ± 12.1 years; aetiologies of cirrhosis (alcoholic,viral/other, 67%/15%/18%); source of bleeding (EV/GV/other, 80/11/9%); active bleeding at endoscopy 34%; Child A 21%/B 44%/C 35%. Overall, 35% of the patients were eligible for early-TIPS, but only 6.8%, displaying less severe cirrhosis underwent early-TIPS placement. The main reason for discarding TIPS was a lack of availability. The actuarial probability of survival at one year was significantly increased in early-TIPS patients (85.7±0.07% vs 58.9±0.03%, p=0.04). The severity of liver disease was the only parameter independently associated with improved one-year survival. CONCLUSION In this real-life study, one-third of the cirrhotic patients admitted for VB fulfilled the criteria for early-TIPS placement, whereas only 7% had access to TIPS. TIPS was restricted to patients displaying less severe cirrhosis. The severity of liver disease was the only parameter that influenced survival.

Solid, non-skin, post-liver transplant tumors: Key role of lifestyle and immunosuppression management

Liver transplantation has been the treatment of choice for end-stage liver disease since 1983. Cancer has emerged as a major long-term cause of death for liver transplant recipients. Many retrospective studies that have explored standardized incidence ratio have reported increased rates of solid organ cancers post-liver transplantation; some have also studied risk factors. Liver transplantation results in a two to five-fold mean increase in the rate of solid organ cancers. Risk of head and neck, lung, esophageal, cervical cancers and Kaposis sarcoma is high, but risk of colorectal cancer is not clearly demonstrated. There appears to be no excess risk of developing breast or prostate cancer. Environmental risk factors such as viral infection and tobacco consumption, and personal risk factors such as obesity play a key role, but recent data also implicate the role of calcineurin inhibitors, whose cumulative and dose-dependent effects on cell metabolism might play a direct role in oncogenesis. In this paper, we review the results of studies assessing the incidence of non-skin solid tumors in order to understand the mechanisms underlying solid cancers in post-liver transplant patients and, ultimately, discuss how to prevent these cancers. Immunosuppressive protocol changes, including a calcineurin inhibitor-free regimen, combined with dietary guidelines and smoking cessation, are theoretically the best preventive measures.

Addictive behaviors in liver transplant recipients: The real problem?

Liver transplantation (LT) is the gold standard treatment for end-stage liver disease. Whatever the primary indication of LT, substance abuse after surgery may decrease survival rates and quality of life. Prevalence of severe alcohol relapse is between 11 and 26%, and reduces life expectancy regardless of the primary indication of LT. Many patients on waiting lists for LT are smokers and this is a major risk factor for both malignant tumors and cardiovascular events post-surgery. The aim of this review is to describe psychoactive substance consumption after LT, and to assess the impact on liver transplant recipients. This review describes data about alcohol and illicit drug use by transplant recipients and suggests guidelines for behavior management after surgery. The presence of an addiction specialist in a LT team seems to be very important.

Alcohol use and smoking after liver transplantation; complications and prevention

The last thirty years have been very prosperous in the field of liver transplantation (LT), with great advances in organ conservation, surgical techniques, peri-operative management and long-term immunosuppression, resulting in improved patient and graft survival rates as well as quality of life. However, substance addiction after LT, namely alcohol and tobacco, results in short term morbidity together with medium and long-term mortality. The main consequences can be vascular (increased risk of hepatic artery thrombosis in smokers), hepatic (recurrent alcoholic cirrhosis in alcohol relapsers) and oncological (increased risk of malignancy in patients consuming tobacco and/or alcohol after LT). This issue has thus drawn attention in the field of LT research. The management of these two at-risk behaviors addictions need the implication of hepatologists and addiction specialists, before and after LT. This review will summarize our current knowledge in alcohol use and cigarette smoking in the setting of LT, give practical tools for identification of high risk patients and treatment options.