K.I. Rodriguez-Castro

Management of Nonneoplastic Portal Vein Thrombosis in the Setting of Liver Transplantation: A Systematic Review

Background Nonneoplastic portal vein thrombosis (PVT) is frequent in patients with cirrhosis who undergo liver transplantation (LT); however, data on its impact on outcome and strategies of management are sparse. Methods A systematic review of the literature was performed by analyzing studies that report on PVT in LT recipients and were published between January 1986 and January 2012. Results Of 25,753 liver transplants, 2004 were performed in patients with PVT (7.78%), and approximately half presented complete thrombosis. Thrombectomy/thromboendovenectomy was employed in 75% of patients; other techniques included venous graft interposition and portocaval hemitransposition. Overall, the presence of PVT significantly increased 30-day (10.5%) and 1-year (18.8%) post-LT mortality when compared to patients without PVT (7.7% and 15.4%, respectively). However, only complete PVT accounted for this increased mortality. Rethrombosis occurred in up to 13% of patients with complete PVT and in whom no preventative strategies were used, and was associated with increased morbidity and mortality. Conclusions PVT is common in patients with cirrhosis undergoing LT, and it affects survival when it is complete, at least in the short term after transplant. Therefore, screening for this condition is essential, alongside adequate treatment strategies to attempt repermeation of the PV and prevent thrombosis extension.

Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review

Calcineurin inhibitors (CNIs) have been associated in a dose‐dependent fashion with an increased risk of post‐transplant hepatocellular carcinoma (HCC) recurrence. The mammalian target of rapamycin inhibitors (mTORi) (sirolimus/everolimus) might represent an alternative immunosuppressive regimen with antineoplastic effect. In the present systematic review, the association between mTORi and HCC recurrence after liver transplantation (LT) was evaluated and compared against that of CNIs‐treated patients. In total, 3666 HCC liver transplant recipients from 42 studies met the inclusion criteria. Patients under CNIs developed HCC recurrence significantly more frequently, compared with patients under mTORi (448/3227 or 13.8% vs. 35/439 or 8%, P < 0.001), although patients treated with CNIs had a higher proportion of HCC within Milan criteria (74% vs. 69%) and lower rates of microvascular invasion, compared with mTORi‐treated patients (22% vs. 44%) (P < 0.05). Patients on everolimus had significantly lower recurrence rates of HCC, compared with those on sirolimus or CNIs (4.1% vs. 10.5% vs. 13.8%, respectively, P < 0.05), but everolimus‐treated recipients had shorter follow‐up period (13 vs. 30 vs. 43.2 months, respectively) and more frequently been transplanted for HCC within Milan criteria (84% vs. 60.5% vs. 74%, respectively, P < 0.05). Our findings favor the use of mTORi instead of CNIs to control HCC recurrence after LT, but comparative studies with longer follow‐up are needed for final conclusions.

Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced cirrhosis

Summary.  Introduction:  Cirrhotic patients may present thrombotic complications that warrant anticoagulant therapy. However, the efficacy of low‐molecular‐weight heparin (LMWH) in this clinical setting is still unclear.

Anticoagulation for the treatment of thrombotic complications in patients with cirrhosis

Cirrhotic patients can develop thrombotic complications, which in this group of patients occur with a greater frequency than in the general population. Portal vein thrombosis (PVT) is the most common thrombotic phenomenon, although deep venous thrombosis and pulmonary embolism can also occur. Risk factors for thrombosis include inherited and acquired deficiency of factors involved in anticoagulation mechanisms, venous stasis of the portal vein owing to architectural derangement of the liver and possibly local factors related to the endothelium. Clinical manifestations of PVT range from asymptomatic disease to a life‐threatening complication, and although it is no longer considered an absolute contraindication for liver transplant, its presence may require challenging surgical techniques, which entail greater morbidity. Anticoagulation therapy is henceforth an important strategy to treat cirrhotic patients with PVT, although experience in this group of patients is limited. Vitamin K antagonists and low‐molecular‐weight heparin have been used successfully, achieving recanalization of the thrombosed vessel in patients with cirrhosis; however, the precise drug regimen management and monitoring has not be fully explored in this group of patients.

Markers of acute rejection and graft acceptance in liver transplantation

The evaluation of the immunosuppression state in liver transplanted patients is crucial for a correct post-transplant management and a major step towards the personalisation of the immunosuppressive therapy. However, current immunological monitoring after liver transplantation relies mainly on clinical judgment and on immunosuppressive drug levels, without a proper assessment of the real suppression of the immunological system. Various markers have been studied in an attempt to identify a specific indicator of graft rejection and graft acceptance after liver transplantation. Considering acute rejection, the most studied markers are pro-inflammatory and immunoregulatory cytokines and other proteins related to inflammation. However there is considerable overlap with other conditions, and only few of them have been validated. Standard liver tests cannot be used as markers of graft rejection due to their low sensitivity and specificity and the weak correlation with the severity of histopathological findings. Several studies have been performed to identify biomarkers of tolerance in liver transplanted patients. Most of them are based on the analysis of peripheral blood samples and on the use of transcriptional profiling techniques. Amongst these, NK cell-related molecules seem to be the most valid marker of graft acceptance, whereas the role CD4+CD25+Foxp3+ T cells has still to be properly defined.

Whole blood rotation thromboelastometry (ROTEM®) profiles in subjects with non-neoplastic portal vein thrombosis

The coagulation pattern and the determinants of portal vein thrombosis (PVT), both in patients with and without cirrhosis, are still largely unknown. The aim of this study was to evaluate whole blood thromboelastometry profile, performed by ROTEM®, of both cirrhotic and non-cirrhotic subjects with PVT. Two different groups were considered: i) 14 non-cirrhotic PVT patients, ii) 35 cirrhotic patients with PVT. Controls were sex- and age-matched healthy volunteers and cirrhotic subjects without PVT, respectively. ROTEM® assays (i.e. INTEM, EXTEM, NATEM, and FIBTEM) and traditional coagulative parameters (i.e. platelet count, PT/INR, aPTT, and fibrinogen) were performed on blood samples from each subject. There were no significant differences in ROTEM® profile, as for INTEM, EXTEM, and NATEM assays, and in traditional coagulative parameters, between PVT patients, both with and without cirrhosis, and control groups. Interestingly, Maximum Clot Firmness (MCF) in FIBTEM was significantly higher in non-cirrhotic PVT patients (19 mm) than in healthy volunteers (11 mm, p<0.05). The amplitude of MCF in FIBTEM revealed to be a useful tool to discriminate non-cirrhotic subjects with PVT from those without thrombotic events. Larger prospective studies are needed to evaluate the relevance of the association between the alterations of ROTEM® profiles and PVT in cirrhotic patients.

Neoplastic disease after liver transplantation: Focus on de novo neoplasms

De novo neoplasms account for almost 30% of deaths 10 years after liver transplantation and are the most common cause of mortality in patients surviving at least 1 year after transplant. The risk of malignancy is two to four times higher in transplant recipients than in an age- and sex-matched population, and cancer is expected to surpass cardiovascular complications as the primary cause of death in transplanted patients within the next 2 decades. Since exposure to immunosuppression is associated with an increased frequency of developing neoplasm, long-term immunosuppression should be therefore minimized. Promising results in the prevention of hepatocellular carcinoma (HCC) recurrence have been reported with the use of mTOR inhibitors including everolimus and sirolimus and the ongoing open-label prospective randomized controlled SILVER. Study will provide more information on whether sirolimus-containing vs mTOR-inhibitor-free immunosuppression is more efficacious in reducing HCC recurrence.

Infections and organ transplantation: new challenges for prevention and treatment--a colloquium

Paolo A. Grossi, Alessandro Nanni Costa, Deirdre Fehily, Emily A. Blumberg, Matthew J. Kuehnert, Jay A. Fishman, Michael G. Ison, Roberta Lattes, Camille N. Kotton, Daniele Lilleri, Anne Kabanova, Antonio Lanzavecchia, Giuseppi Gerna, Raymund R. Razonable, Patrizia Comoli, Marco Zecca, Sabrina Basso, Fabrizio Ginevri, Alessandra Grossi, Francesco P. Schena, Antoni Rimola, Patrizia Burra, Elenora De Martin, Kryssia Isabel Rodriguez-Castro, Stefano Fagiuoli, Luisa Pasulo, Raffaele Bruno, Pietro Andreone, Elisabetta Loggi, Fabio Arena, Gian Maria Rossolini, Gabriele Sganga, and Valerio Cozza

Female gender in the setting of liver transplantation.

The evolution of liver diseases to end-stage liver disease or to acute hepatic failure, the evaluation process for liver transplantation, the organ allocation decision-making, as well as the post-transplant outcomes are different between female and male genders. Womens access to liver transplantation is hampered by the use of model for end-stage liver disease (MELD) score, in which creatinine values exert a systematic bias against women due to their lower values even in the presence of variable degrees of renal dysfunction. Furthermore, even when correcting MELD score for gender-appropriate creatinine determination, a quantifiable uneven access to transplant prevails, demonstrating that other factors are also involved. While some of the differences can be explained from the epidemiological point of view, hormonal status plays an important role. Moreover, the pre-menopausal and post-menopausal stages imply profound differences in a womans physiology, including not only the passage from the fertile age to the non-fertile stage, but also the loss of estrogens and their potentially protective role in delaying liver fibrosis progression, amongst others. With menopause, the tendency to gain weight may contribute to the development of or worsening of pre-existing metabolic syndrome. As an increasing number of patients are transplanted for non-alcoholic steatohepatitis, and as the average age at transplant increases, clinicians must be prepared for the management of this particular condition, especially in post-menopausal women, who are at particular risk of developing metabolic complications after menopause.

Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease.

Hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B (CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma (HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation.