The role of liver sinusoidal endothelial cells in liver remodeling after injury

Liver transplantation is the optimal treatment for patients with end-stage liver disease, metabolic liver diseases, and hepatic malignancies that are not amenable to resection. Hepatic ischemia-reperfusion injury (IRI) is the main problem in liver transplantation and liver resection, leading to parenchymal cell injury and organ dysfunction. The damage of liver sinusoidal endothelial cells (LSECs) is a critical event in IRI. LSECs work as an important regulating factor of liver regeneration after partial hepatectomy. This review primarily describes the mechanisms of LSECs injury in IRI and explores the roles of LSECs in liver regeneration, and briefly introduces the protective strategies targeting LSECs damaged in IRI.     

Hyperbaric oxygen therapy and liver transplantation

Liver transplantation is the treatment of choice for end stage liver disease and is often used for primary liver malignancies. The main limitation of its wider application is the availability of suitable donor organs. The use of marginal donor organs, split-liver transplantation and living-related liver transplantation techniques contribute to increase the donor pool. However, the use of these techniques is associated with a higher risk of post transplantation organ dysfunction, predominantly due to ischaemia, preservation and reperfusion injury (IPRI). A number of studies have demonstrated that hyperbaric oxygen (HBO) therapy influences IPRI and consequential acute cellular rejection. This article reviews the rationale of HBO therapy in the field of transplantation with particular emphasis on liver transplantation.     

Polyethylene glycols: An effective strategy for limiting liver ischemia reperfusion injury

Liver ischemia-reperfusion injury(IRI) is an inherent feature of liver surgery and liver transplantation in which damage to a hypoxic organ(ischemia) is exacerbated following the return of oxygen delivery(reperfusion). IRI is a major cause of primary nonfunction after transplantation and may lead to graft rejection, regardless of immunological considerations. The immediate response involves the disruption of cellular mitochondrial oxidative phosphorylation and the accumulation of metabolic intermediates during the ischemic period, and oxidative stress during blood flow restoration. Moreover, a complex cascade of inflammatory mediators is generated during reperfusion, contributing to the extension of the damage and finally to organ failure. A variety of pharmacological interventions(antioxidants, anticytokines, etc.) have been proposed to alleviate graft injury but their usefulness is limited by the local and specific action of the drugs and by their potential undesirable toxic effects. Polyethylene glycols(PEGs), which are non-toxic water-soluble compounds approved by the FDA, have been widely used as a vehicle or a base in food, cosmetics and pharmaceuticals, and also as adjuvants for ameliorating drug pharmacokinetics. Some PEGs are also currently used as additives in organ preservation solutions prior to transplantation in order to limit the damage associated with cold ischemia reperfusion. More recently, the administration of PEGs of different molecular weights by intravenous injection has emerged as a new therapeutic tool to protect liver grafts from IRI. In this review, we summarize the current knowledge concerning the use of PEGs as a useful target for limiting liver IRI.     

Liver‐specific deceased donor risk indices

In order to assess the quality of the donor liver, procuring surgeons should accurately evaluate not only general donor risk indices, such as donor age, causes of brain death and cold ischemic time, but also consider the specific donor risk indices. In this review, we focus on liver‐specific deceased donor risk indices, including liver steatosis, anti‐hepatitis B core (HBc) positive or hepatitis C virus (HCV) positive donors, hypernatremia and anatomical variations. Liver steatosis is strongly associated with poor graft function after liver transplantation. Liver with more than 40–50% macrosteatosis should not be used. However, at present the quantity of fatty livers lack accepted standards. The computerized image analysis programs should be used to automate the determination of fat content in liver biopsy specimens. Liver grafts from anti‐HBc positive donors can be safely used, preferentially in hepatitis B surface antigen (HBsAg) positive or anti‐HBc/anti‐HBs positive recipients. HCV positive allografts free from fibrosis or severe inflammation are a safe option for HCV positive recipients. The procurement team should consider liver biopsy to evaluate these HCV positive allografts. Donor serum sodium over 150 mm may predict a higher rate of graft primary non‐functions. Recently, however, some investigators reported the sodium level likely has little clinical impact on post‐transplant liver function. The incidence of hepatic artery variations has been reported to be approximately 30%. To avoid injuries, it is very important to know and identify these variations with precision at the time of organ procurement.     

Ischemic post-conditioning to counteract intestinal ischemia/reperfusion injury

Intestinal ischemia is a severe disorder with a variety of causes. Reperfusion is a common occurrence during treatment of acute intestinal ischemia but the injury resulting from ischemia/reperfusion (IR) may lead to even more serious complications from intestinal atrophy to multiple organ failure and death. The susceptibility of the intestine to IR-induced injury (IRI) appears from various experimental studies and clinical settings such as cardiac and major vascular surgery and organ transplantation. Whereas oxygen free radicals, activation of leukocytes, failure of microvascular perfusion, cellular acidosis and disturbance of intracellular homeostasis have been implicated as important factors in the pathogenesis of intestinal IRI, the mechanisms underlying this disorder are not well known. To date, increasing attention is being paid in animal studies to potential pre- and post-ischemia treatments that protect against intestinal IRI such as drug interference with IR-induced apoptosis and inflammation processes and ischemic pre-conditioning. However, better insight is needed into the molecular and cellular events associated with reperfusion-induced damage to develop effective clinical protection protocols to combat this disorder. In this respect, the use of ischemic post-conditioning in combination with experimentally prolonged acidosis blocking deleterious reperfusion actions may turn out to have particular clinical relevance.     

Apheresis Therapy for Living‐Donor Liver Transplantation

Abstract: Liver transplantation is a fundamental treatment for patients with end‐stage hepatic failure. In order to perform living‐donor liver transplantations under safer conditions, apheresis plays a major role in Japan due to the prevalence of living‐donor liver transplantation wherein later retransplantation is difficult. In our department, the roles of apheresis in liver transplantation are as follows: as bridge therapy to liver transplantation (n = 45); as a supplement to the graft liver until the recovery of hepatic function (n = 77); as treatment for multiple organ failure including posttransplantation renal failure (n = 15); and as a means with which to reduce antibody titers for antibodies such as anti‐A or anti‐B in persons with ABO blood type = incompatible liver transplantation (n = 23). In our department, we have performed 822 liver transplantations at present. Of those cases, 183 were selected wherein apheresis was performed around the time of the operation. In all cases, transplantation with sufficient apheresis was performed before the surgical operation, however, 22 patients (48.9%) died after undergoing surgery. Among the patients who underwent the postoperative apheresis, those in the nonsurvivor group had lower grafted liver weights compared to those of the survivor group. The kidney was the organ that most frequently failed due to postoperative complications. In cases of ABO blood type‐incompatible liver transplantations, patients with high preoperative anti‐A/B IgM antibody titers sustained bile duct complications, patients with high preoperative anti‐IgG antibody titers sustained hepatic necrosis, and patients with high postoperative anti‐A/B IgM and anti‐IgG antibody titers sustained hepatic necrosis most frequently.     

Hepatic fibrogenesis in response to chronic liver injury: novel insights on the role of cell‐to‐cell interaction and transition

Hepatic fibrosis represents the wound‐healing response process of the liver to chronic injury, independently from aetiology. Advanced liver fibrosis results in cirrhosis that can lead to liver failure, portal hypertension and hepatocellular carcinoma. Currently, no effective therapies are available for hepatic fibrosis. After the definition of hepatic stellate cells (HSCs) as the main liver extracellular matrix‐producing cells in the 1980s, the subsequent decade was dedicated to determine the role of specific cytokines and growth factors. Fibrotic progression of chronic liver diseases can be nowadays considered as a dynamic and highly integrated process of cellular response to chronic liver injury. The present review is dedicated to the novel mechanisms of cellular response to chronic liver injury leading to hepatic myofibroblasts' activation. The understanding of the cellular and molecular pathways regulating their function is crucial to counteract therapeutically the organ dysfunction caused by myofibroblasts' activation.     

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 Kaposi’s 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.     

Living related liver transplantation in an adult patient with hepatocellular adenoma and carcinoma 13 years after bone marrow transplantation for Fanconi anemia: A case report

Fanconi anemia (FA) is an inherited bone marrow failure syndrome due to defective DNA inter‐strand cross‐link repair. Hematopoietic stem cell transplantation (HSCT) is curative for pancytopenia, but may not prevent the development of non‐hematological malignancies. We describe a 26‐year‐old male patient with FA and Marfan syndrome who in 1994 underwent successful HSCT with bone marrow stem cells from his human leukocyte antigen (HLA)‐identical sister. In 2006, three lesions in the liver were detected and resected. The three lesions all showed activation of the β‐catenin pathway and were histologically characterized by a highly differentiated steatotic hepatocellular carcinoma (HCC) with remnants of the underlying adenoma from which it arose, a hepatocellular adenoma with foci of well‐differentiated HCC, and a cholestatic adenoma. Risk factors for the emergence of HCC included FA itself, the use of androgens for a period of 3 years preceding HSCT and toxicity of the conditioning regimen. Because of the danger of developing additional HCC, liver transplantation was proposed, taking into consideration that immunosuppression would increase the risk of other malignancies. By using part of the liver of the sister, who already acted as bone marrow donor 13 years earlier, immunosuppression could be avoided. Liver transplantation was performed in 2007 without complication. Five years after liver transplantation the patient is doing well. This case is twofold special being the first case reporting FA co‐occurring with Marfan syndrome and being the first reported case of FA treated for HCC by liver transplantation from a HLA‐identical sibling donor without the use of immunosuppression.     

Cardiovascular risk factors following orthotopic liver transplantation: predisposing factors,incidence and management

Background: Liver transplantation is the standard of care for acute and chronic causes of end‐stage liver disease. Advances in medical therapy and surgical techniques have led to improvement of patient and graft survival rates following orthotopic liver transplantation. However, the prevalence of post‐transplant cardiovascular complications has been rising with increased life expectancy after liver transplantation. Aims: To determine the incidences, risk factors, and treatment for hypertension, hyperlipidaemia, diabetes, and obesity in the post‐liver transplantation population. Methods: We performed a review of relevant studies available on the PubMed database that provided information on the incidence, risk factors and treatment for cardiovascular complications that develop in the post‐liver transplantation population. Results: Current immunosuppressive agents have improved patient and graft survival rates. However, long‐term exposure to these agents has been associated with development of systemic and metabolic complications including hypertension, hyperlipidaemia, diabetes mellitus and obesity. Cardiovascular disease remains one of the most common causes of death in liver transplant patients with functional grafts. Conclusions: Liver transplant recipients have a higher risk of cardiovascular complications compared with the nontransplant population. Post‐transplant cardiac risk stratification and aggressive treatment of cardiovascular complications, including modification of risk factors and tailoring of immunosuppressive regimen, is imperative to prevent serious complications.     

我国心脏死亡器官捐献供肝现状及其肝移植的临床进展

肝移植是治疗终末期肝病的重要手段,但是供体短缺的问题日益显现,因此适合我国国情,同时符合国际标准的心脏死亡器官捐献(DCD)应该是现阶段缓解器官短缺的一种重要手段。本文回顾了国际上DCD肝移植的曲折发展历程,通过对DCD肝移植的定义与分类、伦理原则、适应证、获取方案、捐献情况和临床效果进行综述,认为DCD供肝是目前我国肝移植供体极度短缺大环境下的一支"生力军"。随着其工作的深入开展,必将成为我国肝移植的重要组成部分。     

The liver: a special case in transplantation tolerance

Liver transplants are not often rejected in patients weaned from immunosuppression and are spontaneously accepted in some animal models. We review past and recent findings of liver transplantation and propose a unified model in which several mechanisms act in concert to induce and maintain tolerance in both na?ve and effector T cell compartments. First, passenger leukocytes migrate to lymphoid tissues and induce apoptosis of alloreactive na?ve T cells. Second, antigen-specific activation and subsequent deletion of na?ve and effector cells within the liver itself purge the repertoire of alloreactive T cells. Other mechanisms such as microchimerism and migration of donor dendritic cells to the thymus may play a predominant role in maintaining tolerance, and soluble major histocompatibility complex molecules, donor peptides, and regulatory T cells may participate in the induction and maintenance phases. Thus, the major challenge in liver transplantation will be to favor these tolerogenic processes while developing strategies that specifically inhibit alloreactive memory T cells.     

Liver transplantation in the era of model for end‐stage liver disease

Abstract: Liver transplantation is challenged by organ shortage and prolonged waiting list time. The goal of the ideal organ allocation system is to transplant individuals least likely to survive without a liver transplantation, and maintain appropriate rates of postoperative survival. Currently, liver allocation in the United States is based on the model for end‐stage liver disease (MELD). Studies have shown MELD to be objective and accurate in predicting short‐term survival in patients with cirrhosis.     

Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: the controversies continue

Liver transplantation has now become a favored option for patients with early-stage hepatocellular carcinoma (HCC) with or without impaired hepatic function as a complication of underlying cirrhosis. To overcome the persistent donor organ shortage, the use of adult-to-adult living donor liver transplantation (LDLT) has recently increased, especially in Asian countries. In the use of LDLT, several controversies remain including the safety of living donation and expanding the current Milan criteria. Most physicians agree that criteria for transplanting patients with HCC should be expanded beyond the Milan criteria because the Milan criteria miss a number of patients who may benefit from LDLT; however, the expanded criteria proposed were different (the size and number of HCCs and the biologic markers) from one center to the other. When we consider LDLT as a treatment option for patients with HCC, donor safety should be kept in mind first, and the wishes of both patient and donor should be weighed against the potential (if small) risk for the donor. In contrast to deceased donor liver transplantation, the benefit of LDLT is better appreciated in terms of gain in life expectancy than in terms of survival when the wishes of both patient and donor outweigh the donor risk. Further research on the predictors of benefit of LDLT to HCC patients other than the size and number of HCC such as molecular profiling of HCC are necessary to finally reach a consensus.     

Living-donor liver transplantation in the new decade: perspective from the twentieth to the twenty-first century

Liver transplantation from living donors developed rapidly in the last decade of the twentieth century and is now an important option in the treatment of patients with end stage and/or irreversible liver diseases. Although the disadvantages of small‐for‐size grafts are being significantly mitigated by the repertoire of left lobe, while left liver, and right lobe grafts, the struggle for graft size matching has disclosed not a few problems, such as small grafts for advanced disease, anatomical variations in donor livers, and, above all, the increasing importance of donor safety. The range of donor candidates is also an important point of discussion in regard to the social significance of this treatment modality. Apart from the surgical aspects, many medical aspects, including the indications and timing of transplantation specific to this technique, the prevention of disease transmission in family members, and immunological aspects, including the risk of graft‐versus‐host disease, remain to be clarified. Social and economic questions, as well as surgical and medical issues, will be the theme in the second decade, and the new century, of this newborn treatment modality.     

Liver transplantation and cell therapies for inborn errors of metabolism

Liver transplantation is now very successful with >85 % long term survival into adult life. When considering the impact of liver transplantation for metabolic disease two independent factors need to be considered; whether or not the defect causes liver disease and whether or not it is confined to the liver. When considering transplantation many factors need to be considered including the local success of transplantation, the impact of the metabolic disease on the patient and family and the potential for future therapeutic developments. Where transplantation is undertaken for a liver based defect there is a lifelong complete correction of the defect. Where there is a residual extrahepatic defect this will have an impact on the outcome of liver transplantation and the severity of this defect must be considered as part of the transplant assessment process. Access to a multi-disciplinary team with expertise in metabolic disease, liver disease and other relevant organ based specialists is crucial. Most children will receive transplantation from cadaveric donor but living related transplantation from a heterozygote parent is usually safe and effective. Auxiliary liver transplantation has a small but useful role where partial correction of the defect is helpful and there is a future prospect of gene therapy. The first-generation of hepatocyte transplants have shown proof of principle but to date have had a rather modest and temporary metabolic effect. Stem cells may have the potential to produce a more sustained and significant metabolic correction, but must be shown to be effective in controlled trials.     

Early postoperative complications following liver transplantation

Liver transplantation is a highly successful treatment for patients with end-stage liver disease and acute liver failure. However, serious postoperative complications can significantly compromise patient survival. Complications can be technical, medical, or immunological in nature. The risk of developing early postoperative complications is associated with the patient's preoperative condition, the quality of the donor liver, the quality of the donor and recipient procedure, initial graft function, and perioperative anaesthesiological and intensive care management. The patient's preoperative condition can include gastrointestinal bleeding, acute renal failure, a requirement for cathecholamines or mechanical ventilation, and prolonged encephalopathy for the most detrimental risk factors for developing early postoperative complications. The necessity for prolonged mechanical ventilation or the requirement for reintubation after transplantation can significantly increase the risk of developing pneumonia, sepsis, and multiple organ dysfunction. A decrease in infectious and other complications can be achieved by early postoperative enteral nutition, including the application of probiotics.     

Platelet activation and increased tissue factor expression on monocytes in reperfusion injury following orthotopic liver transplantation

Platelets have been implicated in the pathogenesis of liver damage after orthotopic liver transplantation (OLT). Early graft dysfunction is frequently caused by reperfusion injury subsequent to cold ischemia (IRI). Therefore, we investigated activation of the pivotal haemostatic cells, platelets and monocytes, from patients with elevated markers of IRI and from patients with uneventful course (control-group), respectively during the first week after OLT. Flow cytometry analysis of citrate anticoagulated blood samples revealed that platelets from IRI patients became significantly activated within 48 h after OLT in vivo, with increased surface presentation of P-selectin, CD40L, thrombospondin-1 and tissue-factor. Platelet activation in IRI patients on post-transplant day 2 was accompanied by significantly enhanced tissue-factor expression on peripheral blood monocytes, significant elevated levels of C-reactive protein and hepatocellular damage. Towards post-transplant day 4, levels of platelet-derived microparticles rose significantly in IRI patients if contrasted to control patients. Thus, activated cellular haemostasis is involved in the early inflammatory response of hepatocellular damage subsequent to reperfusion of the transplanted liver. Targeting distinct activation patterns of platelets and monocytes in an early phase of hepatic grafting may counteract the extent of IRI via inhibition of micro-thrombus formation and inflammation without exacerbating the existing bleeding risk.