Digestive and Liver Disease Supplements最新文献

Recurrent hepatitis C after liver transplantation is a rapidly evolving condition in which fibrosis deposition is accelerated, with 30% of patients developing graft cirrhosis within the first 5 years after transplantation. Antiviral therapy after transplantation achieves sustained virological response (SVR) in approximately 30% of patients, and a milder fibrosis stage at treatment seems to increase the probabilities of response to treatment. Importantly, SVR to antiviral therapy in this setting has been shown to modify the natural history of the disease, given the excellent prognosis of patients who are able to clear the virus. In this regard, an early recognition of these patients can help to start antiviral therapy in less advanced stages of the recurrence, with higher probabilities of achieving SVR. Non-invasive methods, and especially Fibroscan™, have been shown to significantly correlate with fibrosis stage and, more importantly, to permit early identification of those patients at higher risk of presenting worse outcomes. In addition, they can also confidently distinguish those patients who will present a good outcome and in which a significant number of protocol liver biopsies may be avoided.

In western countries, about 10–25% of patients undergoing liver transplantation (LT) are HBsAg carriers. In Asia, HBV-related liver disease is the leading indication to LT. After surgery hepatitis B can develop in patients transplanted for HBV-related disease or in HBsAg-negative recipients of anti-HBc positive grafts. In the last years prophylaxis with HBIG and/or antivirals has been proposed in both conditions with excellent results. However, lack of efficacy of prophylaxis is frequently associated with the selection of HBV mutants resistant to the different drugs.

Cirrhosis with/without hepatocellular carcinoma is the primary indication for liver transplantation (LT) in many countries. Hepatitis C virus (HCV) reinfection occurs universally resulting in HCV-graft disease with progression to cirrhosis in about one third of cases after 5 years. Graft failure secondary to recurrent HCV is now the most frequent cause of death, graft failure and need for retransplantation in these patients, with a cumulative risk of allograft failure due to recurrent disease at 10–13 years of 25–30%. The use of suboptimal quality organs, particularly from old donors, has a negative impact on disease severity and transplant outcome, which may explain the increasing rate of severe recurrent disease reported in some centers in recent years, paralleling the increasing donor age. Antiviral therapy, on the other hand, particularly among patients who achieve a sustained viral response (SVR), is associated with improved histology, reduced rate of graft decompensation and better graft and patient survival. Peginterferon (pegIFN) with ribavirin (RBV) is currently the treatment of choice, with SVR achieved in 25–40% of cases. Side effects, particularly anaemia, are extremely frequent and sometimes severe (rejection, de novo autoimmune hepatitis). Baseline factors associated with SVR include genotype non-1, donor and recipient CC IL28B polymorphism, low baseline viraemia, young donor age or mild disease severity. In turn, on-treatment factors predictive of SVR include viral kinetics and treatment adherence.

Despite its widespread diffusion, liver transplantation (LT) still remains one of the most resource consuming surgical procedures. In times of economic constraints, the entire medical community is discussing the strategies necessary to allow a sustainable development of LT. Sustainability is the capacity to endure and, in ecology, the word describes how biological systems remain diverse and productive over time. In clinical practice, sustainability is the potential for long-term maintenance of human well-being, which has environmental, economic and social dimensions. Making LT a sustainable clinical practice entails a multidimensional, multilevel approach balancing patients' needs with those of the entire society. Consumption of resources is pivotal to a sustainable LT practice, and the strategies to adopt should focus on increasing deceased donor availability as well as on reducing current long-term graft attrition rates. It is our duty to rethink the way we are currently performing LT and our major commitment is to transfer our capacities to future generations, without wasting resources and to invest in research. This calls for urgent action to be taken at the care-provider-to-patient, social and political levels, and for networking of all professionals involved in care of liver disease patients.

In Liver Transplantation (LT) units the clinicians routinely deal with complex decision making situations that cannot always be solved with the available scientific evidence. They include selection of the best candidates for LT, minimizing mortality and drop-out rates within the waiting list (WL) and rationalizing donor–recipient matching. These topics constitute some of the current challenges in LT and they may drive a number of future research trends. Since the MELD implementation the organ allocation model has moved from a system based on length of time on the WL to a disease severity based policy, and thus to a more rational use of LT and a decrease in WL mortality. However, during the last decade several limitations of this system have been highlighted, and modifications of the MELD score have been proposed. Furthermore, patients with hepatocellular carcinoma do not fit inside the MELD system and the current strategy of prioritization based on number and size of nodules has not eliminated the drop-out risk, despite the use of locoregional ablative treatment while on the WL. A better understanding of tumour behavior, especially concerning microvascular invasion, is urgently needed to improve management of patients with hepatocellular carcinoma. Finally, the donor and recipient features maintain a complex relationship that affects outcome. The use of artificial neural network to find the most adequate recipient to each graft, may allow a more rationalized allocation policy.

End-stage liver disease related to HCV infection is the most common indication for liver transplantation both in Europe and in USA (http://www.UNOS.org; http://www.ELTR.org). The results of liver transplantation for this indication are negatively affected by the high rate of viral recurrence which, through an accelerated rate of disease progression, significantly impairs patient and graft survival.

Given this scenario, post-transplant viral eradication should be identified as a primary goal. At present, a combined regimen with pegylated interferon and ribavirin leads to sustained virological response (SVR) in approximately 30% of transplanted patients, which is significantly lower than in immunocompetent subjects. The main problem lies in the high rate of side effects which leads a significant proportion of patients to not receive appropriate therapy. Moreover, in view of the immunological activity of interferon, transplanted patients are exposed to additional immunological risks. Thus, role and efficacy of antiviral therapy in HCV recurrent hepatitis is still under debate. Nevertheless, a progressive amount of data from field practice are now demonstrating that SVR after post-transplant antiviral treatment is associated with a significant benefit on patient and graft survival and is the most relevant modifier of the natural history of HCV recurrent disease after liver transplantation.

A combination of hepatitis B immunoglobulins (HBIg) and nucleos(t)ide analogues (NA) is currently recommended for HBV prophylaxis after liver transplantation (LT), but the optimal regimen is still controversial. Several issues concerning use of HBIg after LT still await definitive clarification, such as dosage (high vs. low); timing (ab initio vs. delayed); schedule (on demand vs. fixed-dose); route of administration (intravenous vs. intramuscular vs. subcutaneous), and duration (short-term vs. long-term vs. lifelong). Alongside efficacy, issues concerning patients' safety and adherence, costs, and resource consumption should be part of the post-transplant decision algorithm to achieve optimization of anti-HBV prophylaxis and maximization of graft and patient survival. Based on the available data, HBIg withdrawal after LT needs to be validated in the long term. On the other hand, a monthly, fixed, low-dose HBIg schedule currently seems the solution to increase the cost–benefit ratio of combination prophylaxis regimens post-transplantation.

Liver transplantation remains the ultimate cure for patients with hepatitis B virus-related end-stage liver disease. Clinical Practice Guidelines currently recommend that patients with decompensated HBV cirrhosis should be treated without delay with nucleos(t)ide analogues regardless of the patient's serum ALT, HBV DNA level, and HBeAg status. The main goal of pre-transplantation antiviral therapy is to achieve a rapid and prolonged suppression of viral replication and thus decrease the risk of hepatitis B virus reinfection of the graft. In addition, sustained negativization of serum HBV DNA may also result in clinical stabilization which can decrease the mortality rate while on the waiting list and delay or avoid liver transplantation in some cases. Clinical improvement may take from 3 to 6 months to become evident. Lamivudine and adefovir are no longer considered first-line therapy in these patients. Potent nucleos(t)ide analogues with good resistance profiles such as entecavir or tenofovir should be used instead. Preliminary data suggest that these agents are effective and have a good safety profile in patients with decompensated cirrhosis. More safety data, however, are needed, particularly in patients with severe impairment of liver function. More data are needed to determine which of the newer antiviral agents offer the best risk–benefit ratio in this challenging patient population. Although a tenofovir-based regimen may be preferred in decompensated patients with lamivudine-resistant hepatitis B virus, there are some concerns about the long-term safety of tenofovir including nephrotoxicity and metabolic bone disease.