Obesity and liver transplantation

The percentage of overweight and obese patients (OPs) waiting for a liver transplant continues to increase. Despite the significant advances occurred in bariatric medicine, obesity is still considered a relative contraindication to liver transplantation (LT). The main aim of this review is to appraise the literature on the outcomes of OPs undergoing LT, treatments that might reduce their weight before, during or after surgery, and discuss some of the controversies and limitations of the current knowledge with the intent of highlighting areas where future research is needed.     

Immunological aspects of liver cell transplantation

Within the field of regenerative medicine, the liver is of major interest for adoption of regenerative strategies due to its well-known and unique regenerative capacity. Whereas therapeutic strategies such as liver resection and orthotopic liver transplantation (OLT) can be considered standards of care for the treatment of a variety of liver diseases, the concept of liver cell transplantation (LCTx) still awaits clinical breakthrough. Success of LCTx is hampered by insufficient engraftment/long-term acceptance of cellular allografts mainly due to rejection of transplanted cells. This is in contrast to the results achieved for OLT where long-term graft survival is observed on a regular basis and, hence, the liver has been deemed an immune-privileged organ. Immune responses induced by isolated hepatocytes apparently differ considerably from those observed following transplantation of solid organs and, thus, LCTx requires refined immunological strategies to improve its clinical outcome. In addition, clinical usage of LCTx but also related basic research efforts are hindered by the limited availability of high quality liver cells, strongly emphasizing the need for alternative cell sources. This review focuses on the various immunological aspects of LCTx summarizing data available not only for hepatocyte transplantation but also for transplantation of non-parenchymal liver cells and liver stem cells.     

原位肝移植术后新发肿瘤三例报告并文献复习

目的总结并探讨原位肝移植术后新发肿瘤的发病特点、危险因素和防治措施。方法回顾性研究2002年4月～2008年4B间3例肝移植术后新发肿瘤患者的临床资料,并进行文献复习。结果本组资料新发肿瘤的发生率为0.3％,3例均为消化系统肿瘤（分别为肝细胞肝癌、食管癌和胰腺癌）。发病年龄平均52．7岁,肿瘤确诊时间平均为术后24个月。3例患者均死于肿瘤进展、多器官功能衰竭。结论肝移植术后新发肿瘤的发生率较高,消化系统肿瘤常见,确诊时间较晚,免疫功能低下是移植术后发生新发肿瘤的主要原因。     

Reducing transfusion requirements in liver transplantation

Liver transplantation(LT) was historically associated with massive blood loss and transfusion. Over the past two decades transfusion requirements have reduced dramatically and increasingly transfusionfree transplantation is a reality. Both bleeding and transfusion are associated with adverse outcomes in LT. Minimising bleeding and reducing unnecessary transfusions are therefore key goals in the perioperative period. As the understanding of the causes of bleeding has evolved so too have techniques to minimize or reduce the impact of blood loss. Surgical "piggyback" techniques, anaesthetic low central venous pressure and haemodilution strategies and the use of autologous cell salvage, point of care monitoring and targeted correction of coagulopathy, particularly through use of factor concentrates, have all contributed to declining reliance on allogenic blood products. Pre-emptive management of preoperative anaemia and adoption of more restrictive transfusion thresholds is increasingly common as patient blood management(PBM) gains momentum. Despite progress, increasing use of marginal grafts and transplantation of sicker recipients will continue to present new challenges in bleeding and transfusion management. Variation in practice across different centres and within the literature demonstrates the current lack of clear transfusion guidance. In this article we summarise the causes and predictors of bleeding and present the evidence for a variety of PBM strategies in LT.     

Intra-abdominal desmoid tumor after liver transplantation: A case report

We are reporting the first documented case of an abdominal desmoid tumor presenting primarily after liver transplantation. This tumor, well described in the literature as occurring both in conjunction with familial adenomatous polyposis as well as in the post-surgical patient, has never been noted after solid organ transplantation and was therefore not included in our differential upon presentation. Definitive diagnosis required the patient to undergo surgical excision and immunochemical staining of the mass for confirmation. A review of the literature showed no primary tumors after transplantation. In a population of patients who received a small bowel transplant after they developed short gut post radical resection of aggressive fibromatosis, only rare recurrences were seen. No connection of tumor development with immunosuppression or need to decrease immunosuppressant treatment has been demonstrated in these patients. Our case and the literature show the risk of this tumor presenting in the post-transplantation patient and the need for a high index of suspicion in patients who present with a complex mass after transplantation to prevent progression of the disease beyond a resectable lesion. Results of a thorough search of the literature are detailed and the medical and surgical management of both resectable and unresectable lesions is reviewed.     

Surgical chest complications after liver transplantation

Liver transplantation is a major abdominal operation and the intimate anatomic relation of the liver with the right hemidiaphragm predisposes the patient to various manifestations in the chest cavity. Furthermore, chronic liver disease affects pulmonary function before and after liver transplantation resulting in a considerable percentage of patients presenting with morbidity related to chest complications. This review aims to identify the potential chest complications of surgical interest during or after liver transplantation. Complications of surgical interest are defined as those conditions that necessitate an invasive procedure (such as thoracocentesis or a chest tube placement) in the chest or a surgical intervention performed by a thoracic surgeon. These complications will be classified as perioperative and postoperative; the latter will be categorized as early and late. Although thoracocentesis or a chest tube placement is usually sufficient when invasive measures are deemed necessary, in some patients, thoracic surgical interventions are warranted. A high index of suspicion is needed to recognize and treat these conditions promptly. A close collaboration between abdominal surgeons, intensive care unit physicians and thoracic surgeons is of paramount importance.     

In memoriam of Thomas Earl Starzl,the pioneer of liver transplantation

Starzl’s nearly 3000 publications that contribute to the science of transplantation in every field have been the most important resources for every scientist working in this field. For those of us who work in the liver transplant field, his contributions throughout his life have shaped our career and passion, even for those who have never met, spoken to, or worked with him. If we are able to help patients with liver failure today by offering them the chance of transplantation, it is because of Starzl’s passionate work and efforts. Thanks to Starzl’s scientific legacy, hundreds of scientists serve humanity and thousands of patients can hold on to life. It has been an honor for us to write this article about Professor Starzl.     

Torque teno virus in liver diseases and after liver transplantation

Torque teno virus (TTV) has been proposed as a surrogate biomarker for immune monitoring in different patient cohorts. Historically, TTV has been associated with different liver diseases such as post-transfusion hepatitis, hepatitis B, and hepatitis C, but the virus's pathogenicity is controversial. TTV is a ubiquitous DNA virus, highly prevalent and mostly indolent in the general population. Thus, TTV viral load is more relevant than prevalence to understand TTV infection. In the context of liver transplantation, TTV viral load is modulated by the immune, viral, and inflammatory status. After liver transplantation, the TTV viral load positively correlates with the intensity of immunosuppression (IS), and low TTV viral burden is a predictor of acute rejection episodes, making it an attractive marker for the efficacy of IS. However, the TTV role as a single or a panel biomarker needs to be evaluated in further independent prospective trails.     

Massive haemorrhage in liver transplantation: Consequences,prediction and management

From its inception the success of liver transplantation has been associated with massive blood loss. Massive transfusion is classically defined as > 10 units of red blood cells within 24 h, but describing transfusion rates over a shorter period of time may reduce the potential for survival bias. Both massive haemorrhage and transfusion are associated with increased risk of mortality and morbidity (need for dialysis/surgical site infection) following liver transplantation although causality is difficult to prove due to the observational design of most trials. The blood loss associated with liver transplantation is multifactorial. Portal hypertension secondary to cirrhosis results in extensive collateral circulation, which can bleed during hepatectomy particular if portal pressures are increased. Avoiding volume loading and maintenance of a low central venous pressure together with the use of vasopressors have been shown to reduce blood loss and transfusion during liver transplantation, but may increase the risk of renal impairment post-operatively. Coagulation defects may be present pre-transplant, but haemostasis is often re-balanced due to a deficit in both pro- and anti-coagulation factors. Further derangement of haemostasis may develop in the anhepatic and neohepatic phases due to absent hepatic metabolic function, hyperfibrinolysis and platelet sequestration in the donor liver. Point-of-care tests of coagulation such as the viscoelastic tests rotation thromboelastometry/thromboelastometry allow and more accurate and rapid assessment of these derangements in coagulation and guide the use of factor replacement and antifibrinolytics. Transfusion protocols guided by these tests have been shown to reduce transfusion rates compared with conventional coagulation tests, but have not shown improvements in mortality or morbidity. Pre-operative factors associated with massive transfusion include previous surgery, re-do transplantation, the aetiology and severity of liver disease. Intra-operatively the use of piggy-back technique and avoiding veno-veno bypass has been shown to reduced blood loss.     

Assessment of advanced age candidates for liver transplantation warrants more caution

For patients with fulminant liver failure and end-stage liver disease, liver transplantation remains the only effective treatment. Over the years, as a result of the ageing population, the average age of liver transplant donors and recipients has increased and currently about one quarter of patients receiving transplantation in the United States are above the age of 65. Recently, a study reported that patients aged 65 years or older had lower one-year survival compared to a younger cohort. Herein, we express our opinion about this interesting publication.     

Cutaneous lesions as the presenting sign of acute graft-versus-host disease following liver transplantation

Acute graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation but is only rarely observed after solid organ transplantation. We describe a 68-year-old man who developed a maculopapular eruption 7 days following orthotopic liver transplantation for cirrhosis with malignant transformation due to haemochromatosis. At day 20, the patient complained of nausea, vomiting, diarrhoea and fever. Skin biopsy revealed a lymphocytic infiltrate at the dermoepidermal interface, vacuolization of basal cells and epidermal dyskeratosis. Immunohistochemistry showed HLA-DR and intercellular adhesion molecule-1 expression of lesional keratinocytes. HLA-typing of peripheral blood lymphocytes demonstrated circulating lymphocytes of donor origin. Endoscopy revealed extensive erosions of the oesophagus, stomach and duodenum that on histology disclosed multifocal loss of crypts, lymphocytic infiltrates and epithelial cell death. A diagnosis of acute GVHD was made, and high-dose immunosuppressive therapy with azathioprine and methylprednisolone was instituted. The skin and gastrointestinal symptoms subsided within 4 weeks, but the patient died from severe infectious complications 105 days after transplantation. We conclude that acute GVHD is a rare but potentially fatal complication of liver transplantation. Skin lesions are an early sign of acute GVHD and thus represent an important tool for early diagnosis.     

Pediatric metabolic liver diseases: Evolving role of liver transplantation

Metabolic liver diseases (MLD) are the second most common indication for liver transplantation (LT) in children. This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation. LT is also performed in metabolic disorders for end-stage liver disease, its sequelae including hepatocellular cancer. It is also performed for preventing metabolic crisis’, arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia. Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis, cholestasis, inflammation, variable amount of fibrosis, and cirrhosis. The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT. A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters. Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver. The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.     

Multiple indications for everolimus after liver transplantation in current clinical practice

AIM: To assess our experience with the use and management of everolimus-based regimens post-liver transplantation and to redefine the potential role of this drug in current clinical practice.METHODS: From October 1988 to December 2012, 1023 liver transplantations were performed in 955 patients in our Unit. Seventy-four patients (7.74%) received immunosuppression with everolimus at some time post-transplantation. Demographic characteristics, everolimus indication, time elapsed from transplantation to the introduction of everolimus, doses and levels administered, efficacy, side effects, discontinuation and post-conversion survival were analyzed.RESULTS: Mean age at the time of conversion to everolimus was 57.7 ± 10 years. Indications for conversion were: refractory rejection 31.1%, extended hepatocellular carcinoma in explanted liver 19%, post-transplant hepatocellular carcinoma recurrence 8.1%, de novo tumour 17.6%, renal insufficiency 8.1%, severe neurotoxicity 10.8%, and others 5.4%. Median time from transplantation to introduction of everolimus was 6 mo (range: 0.10-192). Mean follow-up post-conversion was 22 ± 19 mo (range: 0.50-74). The event for which the drug was indicated was resolved in 60.8% of patients, with the best results in cases of refractory rejection, renal insufficiency and neurotoxicity. Results in patients with cancer were similar to those of a historical cohort treated with other immunosuppressants. The main side effects were dyslipidemia and infections. Post-conversion acute rejection occurred in 14.9% of cases. The drug was discontinued in 28.4% of patients.CONCLUSION: Everolimus at low doses in combination with tacrolimus is a safe immunosuppressant with multiple early and late indications post-liver transplantation.     

Orthotopic liver transplantation for giant liver haemangioma: A case report

In liver haemangiomas, the risk of complication rises with increasing size, and treatment can be obligatory. Here we present a case of a 46-year-old female who suffered from a giant haemangioma causing severe portal hypertension and vena cava compression, leading to therapy refractory ascites, hyponatremia and venostasis-associated thrombosis with pulmonary embolism. The patients did not experience tumour rupture or consumptive coagulopathy. Surgical resection was impossible because of steatosis of the non-affected liver. Orthotopic liver transplantation was identified as the only treatment option. The patient's renal function remained stable even though progressive morbidity and organ allocation were improbable according to the patient's lab model for end-stage liver disease(lab MELD) score. Therefore, non-standard exception status was approved by the European organ allocation network "Eurotransplant". The patient underwent successful orthotopic liver transplantation 16 mo after admission to our centre. Our case report indicates the underrepresentation of morbidity associated with refractory ascites in the lab MELD-based transplant allocation system, and it indicates the necessity of promptly applying for non-standard exception status to enable transplantation in patients with a severe clinical condition but low lab MELD score. Our case highlights the fact that liver transplantation should be considered early in patients with non-resectable, symptomatic benign liver tumours.     

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. Women’s 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 woman’s 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.     

Interrelationship between Toll-like receptors and infection after orthotopic liver transplantation

Early microbial recognition by the innate immune system is accomplished by Toll-like receptors (TLRs), with resultant initiation of a pro-inflammatory response against infecting organisms. In spite of presence of an abundance of Toll-like receptors on the surface of the liver, gut bacteria does not elicit an inflammatory reaction in healthy individuals due to tolerance to these TLRs, suggesting that the inflammatory responses seen in the liver are the result of breakdown of this tolerance. While orthotopic liver transplantation is often life saving in many instances, death following this procedure is most commonly due to infection that occurs in up to 80% of transplant recipients, most commonly due to microbial causes in up to 70% of cases and viral infections in 20%, while fungal infections affect only 8% of cases. The probability of acquiring infection following hepatic transplantation is heightened due to affection of the innate immune defense mechanisms of the host following this procedure. Single nucleotide polymorphisms of TLRs have been associated with increased likelihood of either development of post-transplant infection or eradication of infecting organism. However, conflicting reports from other studies reveal that prevalence of this single nucleotide polymorphism is not increased in infected patients.     

Growing challenge of post-liver transplantation non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide, with an estimated prevalence of 25%. Post-liver transplantation (LT) recurrent or de novo hepatic steatosis is a common complication in recipients, irrespective of transplantation indication. Risk factors for graft steatosis mainly include obesity, immunosuppression, donor steatosis, and genetic factors. Liver transplant recipients are at high risk of developing insulin resistance, new-onset diabetes, and post-transplantation metabolic syndrome that is highly associated with immunosuppressive treatment. Post-LT NAFLD is often underdiagnosed due to the poor sensitivity of most routine imaging methods. The gold standard for the diagnosis of hepatic steatosis is liver biopsy, which is, however, limited to more complex cases due to its invasive nature. There is no approved pharmacotherapy in NAFLD. Lifestyle modification remains the cornerstone in NAFLD treatment. Other treatment strategies in post-LT NAFLD include lifestyle modifications, pharmacotherapy, bariatric surgery, and tailored immunosuppression. However, these approaches originate from recommendations in the general population, as there is scarce data regarding the safety and efficacy of current management strategies for NAFLD in liver transplant patients. Future prospective studies are required to achieve tailored treatment for these patients.     

Two cases of pressure ulcer healing after liver transplantation in cirrhosis patients

We report two cases of pressure ulcers in liver cirrhosis patients. In case 1, a 64-year-old Japanese woman had suffered from liver cirrhosis caused by hepatitis C virus and developed a pressure ulcer on her sacral and coccygeal area due to long-term bedrest. After she received a living donor liver transplantation from her child, the ulcer healed synchronizing with improvement of serum cholinesterase and bilirubin. Likewise, her systemic condition also got much better after the transplantation. In case 2, a 53-year-old Japanese man with hepatitis B virus cirrhosis and hepatocellular carcinoma developed a pressure ulcer on his sacral area. Although he received a living donor liver transplantation from his brother, his general status and pressure ulcer were fluctuating in conformity with the variance of serum bilirubin. However, at 5 weeks after the transplantation, the ulcer gradually started improving, entrained to serum bilirubin decrease. From these findings, the condition of the pressure ulcer in liver cirrhosis patients synchronized with serum bilirubin as well as systemic condition, suggesting a possible influence of bilirubin for wound healing.     

Current techniques for AB0-incompatible living donor liver transplantation

For a long time, it was considered medical malpractice to neglect the blood group system during transplantation. Because there are far more patients waiting for organs than organs available, a variety of attempts have been made to transplant AB0-incompatible (AB0i) grafts. Improvements in AB0i graft survival rates have been achieved with immunosuppression regimens and plasma treatment procedures. Nevertheless, some grafts are rejected early after AB0i living donor liver transplantation (LDLT) due to antibody mediated rejection or later biliary complications that affect the quality of life. Therefore, the AB0i LDLT is an option only for emergency situations, and it requires careful planning. This review compares the treatment possibilities and their effect on the patients’ graft outcome from 2010 to the present. We compared 11 transplant center regimens and their outcomes. The best improvement, next to plasma treatment procedures, has been reached with the prophylactic use of rituximab more than one week before AB0i LDLT. Unfortunately, no standardized treatment protocols are available. Each center treats its patients with its own scheme. Nevertheless, the transplant results are homogeneous. Due to refined treatment strategies, AB0i LDLT is a feasible option today and almost free of severe complications.