The outcome of liver transplantation has markedly improved in the last 3 decades. Although early post‐transplantation outcomes have improved over time, this is not true of the long‐term outcome. The ...majority of late deaths are not related to graft dysfunction, and with the advent of new antiviral agents, recurrence of hepatitis B and hepatitis C after transplantation may no longer represent a source of graft loss and patient's death in the long term. The complications of metabolic syndrome may represent an increasing source of morbidity and mortality after transplantation. This study discusses these modifiable factors associated with late mortality to improve the long‐term results of transplantation.
Abstract Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells representing the interface between blood cells on the one side and hepatocytes and hepatic stellate cells ...on the other side. LSECs represent a permeable barrier. Indeed, the association of fenestrae , absence of diaphragm and lack of basement membrane make them the most permeable endothelial cells of the mammalian body. They also have the highest endocytosis capacity of human cells. In physiological conditions, LSECs regulate hepatic vascular tone contributing to the maintenance of a low portal pressure despite the major changes in hepatic blood flow occurring during digestion. LSECs maintain hepatic stellate cell quiescence, thus inhibiting intrahepatic vasoconstriction and fibrosis development. In pathological conditions, LSECs play a key role in the initiation and progression of chronic liver diseases. Indeed, they become capillarized and lose their protective properties, and they promote angiogenesis and vasoconstriction. LSECs are implicated in liver regeneration following acute liver injury or partial hepatectomy since they renew from LSECs and/or LSEC progenitors, they sense changes in shear stress resulting from surgery, and they interact with platelets and inflammatory cells. LSECs also play a role in hepatocellular carcinoma development and progression, in aging, and in liver lesions related to inflammation and infection. This review also presents a detailed analysis of the technical aspects relevant for LSEC analysis including the markers these cells express, the available cell lines and the transgenic mouse models. Finally, this review provides an overview of the strategies available for a specific targeting of LSECs.
Using computer simulations based on empirical data, we show that seven voting rules that we call the
IRV family
(Instant-runoff voting, exhaustive ballot, Condorcet-IRV, Benham, Smith-IRV, Tideman ...and Woodall) are less sensitive to coalitional manipulation than a large selection of prominent voting rules. While the relative performances of these seven rules still deserve further investigation, we show that the differences are at most marginal.
Age and liver transplantation Durand, François; Levitsky, Josh; Cauchy, François ...
Journal of hepatology,
04/2019, Letnik:
70, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The average age of liver transplant donors and recipients has increased over the years. Independent of the cause of liver disease, older candidates have more comorbidities, higher waitlist mortality ...and higher post-transplant mortality than younger patients. However, transplant benefit may be similar in older and younger recipients, provided older recipients are carefully selected. The cohort of elderly patients transplanted decades ago is also increasingly raising issues concerning long-term exposure to immunosuppression and aging of the transplanted liver. Excellent results can be achieved with elderly donors and there is virtually no upper age limit for donors after brain death liver transplantation. The issue is how to optimise selection, procurement and matching to ensure good results with elderly donors. The impact of old donor age is more pronounced in younger recipients and patients with a high model for end-stage liver disease score. Age matching between the donor and the recipient should be incorporated into allocation policies with a multistep approach. However, age matching may vary depending on the objectives of different allocation policies. In addition, age matching must be revisited in the era of direct-acting antivirals. More restrictive limits have been adopted in donation after circulatory death. Perfusion machines which are currently under investigation may help expand these limits. In living donor liver transplantation, donor age limit is essentially guided by morbidity related to procurement. In this review we summarise changing trends in recipient and donor age. We discuss the implications of older age donors and recipients. We also consider different options for age matching in liver transplantation that could improve outcomes.
Summary Portal vein thrombosis is not uncommon in candidates for transplantation. Partial thrombosis is more common than complete thrombosis. Despite careful screening at evaluation, a number of ...patients are still found with previously unrecognized thrombosis per-operatively. The objective is to recanalize the portal vein or, if recanalization is not achievable, to prevent the extension of the thrombus so that a splanchnic vein can be used as the inflow vessel to restore physiological blood flow to the allograft. Anticoagulation during waiting time and transjugular intrahepatic portosystemic shunt (TIPS) are two options to achieve these goals. TIPS may achieve recanalization in patients with complete portal vein thrombosis. However, a marked impairment in liver function, which is a characteristic feature of most candidates for transplantation, may be a contraindication for TIPS. Importantly, the MELD score is artificially increased by the administration of vitamin K antagonists due to prolonged INR. When patency of the portal vein and/or superior mesenteric vein is not achieved, only non-anatomical techniques (renoportal anastomosis or cavoportal hemitransposition) can be performed. These techniques, which do not fully reverse portal hypertension, are associated with higher morbidity and mortality risks. Multivisceral transplantation including the liver and small bowel needs to be evaluated. In the absence of prothrombotic states that may persist after transplantation, there is no evidence that pre-transplant portal vein thrombosis justifies long term anticoagulation post-transplantation, provided portal flow has been restored through conventional end-to-end portal anastomosis.
Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is ...energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF.
We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals.
Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins.
In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures.
Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.
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•Metabolomics performed in sera of a large series of patients with acute decompensation (AD) of cirrhosis, with/without ACLF.•Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF relative to those with AD.•38 metabolites comprised a distinctive ACLF fingerprint, whose intensity correlated with systemic inflammation.•The ACLF fingerprint represented increases in glycolysis and related pathways.•Fingerprint indicated reduced mitochondrial ATP-producing fatty acid β-oxidation which may contribute to organ failure(s).
Liver resection (LR) for hepatocellular carcinoma (HCC) as the first‐line treatment in transplantable patients followed by “salvage transplantation” (ST) in case of recurrence is an attractive ...concept. The aim was to identify patients who gain benefit from this approach in an intention‐to‐treat study. From 1998 to 2008, among 329 potential candidates for liver transplantation (LT) with HCC within the Milan criteria (MC), 138 with good liver function were resected (LR group) from a perspective of ST in case of recurrence, and 191 were listed for LT first (LT group). The two groups were compared on an intention‐to‐treat basis with special reference to management of recurrences and transplantability after LR. Univariate and multivariate analyses were performed to identify resected patients who developed recurrence beyond MC. Five‐year overall and disease‐free survival was similar in both groups: LT versus LR group, 60% versus 77% and 56% versus 40%, respectively. Among the 138 patients in the LR group, 20 underwent LT before recurrence, 39 (28%) had ST, and 51 (37%) with recurrence were not transplanted including 21 within MC who were excluded for advanced age, acquired comorbidities, or refusal and 30 (22%) with recurrence beyond MC. Predictive factors for nontransplantability due to recurrence beyond MC included microscopic vascular invasion (hazard ratio HR 2.38 range, 1.10‐7.29), satellite nodules (HR 2.46 range, 1.01‐6.68), tumor size > 3 cm (HR 1.34 range, 1.03‐3.12), poorly differentiated tumor (HR 3.18 range, 1.31‐7.70), and liver cirrhosis (HR 1.90 range, 1.04‐3.12). Conclusion: The high risk of failure of ST after initial LR for HCC within MC suggests the use of tissue analysis as a selection criterion. The salvage LT strategy should be restricted to patients with favorable oncological factors. (HEPATOLOGY 2012;;55:132–140)
Once patients with cirrhosis experience decompensation, early mortality risk increases sharply. Liver transplantation has transformed the prognosis of decompensated cirrhosis. Child-Pugh score has ...been the reference for many years for assessing the prognosis of cirrhosis. However, Child-Pugh score has important limitations among which is subjective interpretation of some of its variables, making it difficult to categorize patients according to their own disease severity. The model for end-stage liver disease (MELD) score, which was originally designed for assessing the prognosis of cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS), is a continuous score relying on three objective variables. Along with TIPS, MELD score proved to be a robust marker of early mortality across a wide spectrum of causes of cirrhosis, even though 10 to 20% of patients are still misclassified. MELD is especially useful for prioritizing candidates for transplantation according to a "sickest first" policy. However, MELD is not a universal prognostic marker of cirrhosis and several MELD exceptions require more specific approaches.
Liver Transplantation in France Durand, François; Antoine, Corinne; Soubrane, Olivier
Liver transplantation,
20/May , Letnik:
25, Številka:
5
Journal Article
Recenzirano
In France, the main indications for liver transplantation are hepatocellular carcinoma (HCC) and alcoholic cirrhosis. The number of candidates for decompensated hepatitis C virus–related cirrhosis ...has markedly decreased since the advent of direct‐acting antiviral agents. Nonalcoholic steatohepatitis represents a lower proportion of candidates as compared with the United States. The main source of donors is donation after brain death, but the program of transplantation using donation after circulatory death is growing with excellent results. The deceased donation rate was 28.8 per million people in 2017, which has increased over the last few years. Adult‐to‐adult living donor liver transplantation has been almost completely abandoned. Donors are allocated on a national basis, and there is no longer local or regional priority. In patients with decompensated cirrhosis, prioritization is based on the Model for End‐Stage Liver Disease (MELD) score. The distance between the donor and the recipient is taken into account according to an original gravity model. In patients with HCC, prioritization depends on the alfa‐fetoprotein (AFP) score, the MELD score, and waiting time. Only patients with HCC tumor‐node‐metastasis ≥2 and AFP score ≤2 are eligible for the HCC score. A list of MELD exceptions, consisting of uncommon complications where mortality risk is not adequately predicted by the MELD score and conditions other than cirrhosis, has been established. MELD exceptions must be individually validated by a college of experts mandated by the French Regulatory Agency of Transplantation (Agence de la Biomédecine). The most common MELD exception is refractory ascites with a low MELD score. A major challenge is to reduce the rate of refusal of donation through information campaigns.
Acute‐on‐chronic liver failure (ACLF) in cirrhosis is characterized by acute decompensation (AD), organ failure(s), and high short‐term mortality. Recently, we have proposed (systemic inflammation SI ...hypothesis) that ACLF is the expression of an acute exacerbation of the SI already present in decompensated cirrhosis. This study was aimed at testing this hypothesis and included 522 patients with decompensated cirrhosis (237 with ACLF) and 40 healthy subjects. SI was assessed by measuring 29 cytokines and the redox state of circulating albumin (HNA2), a marker of systemic oxidative stress. Systemic circulatory dysfunction (SCD) was estimated by plasma renin (PRC) and copeptin (PCC) concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. The main findings of this study were: (1) Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC. Patients with ACLF showed significantly higher levels of these markers than those without ACLF; (2) different cytokine profiles were identified according to the type of ACLF precipitating event (active alcoholism/acute alcoholic hepatitis, bacterial infection, and others); (3) severity of SI and frequency and severity of ACLF at enrollment were strongly associated. The course of SI and the course of ACLF (improvement, no change, or worsening) during hospitalization and short‐term mortality were also strongly associated; and (4) the strength of association of ACLF with SI was higher than with SCD. Conclusion: These data support SI as the primary driver of ACLF in cirrhosis. (Hepatology 2016;64:1249‐1264).
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