Economic Impact of European Liver and Intestine Transplantation Association (ELITA) Recommendations for Hepatitis B Prophylaxis After Liver Transplantation.

The European Liver and Intestine Transplant Association, ELITA, promoted a Consensus Conference involving 20 experts across the world which generated updated guidelines on HBV prophylaxis in liver transplant candidates and recipients. This study explores the economic impact associated with the implementation of the new ELITA guidelines. To this aim, a condition-specific cohort simulation model has been developed to compare new and historical prophylaxis, including only pharmaceutical cost and using the European perspective. The target population simulated in the model included both prevalent and incident cases, and consisted of 6,133 patients after the first year, that increased to 7,442 and 8,743 patents after 5 and 10 years from its implementation. The ELITA protocols allowed a cost saving of around € 235.65 million after 5 years and € 540.73 million after 10 years; which was mainly due to early HIBG withdrawal either after the first 4 weeks or after the first year post Liver Transplantation (LT) depending on the virological risk at transplantation. Results were confirmed by sensitivity analyses. The money saved by the implementation of the ELITA guidelines would allow healthcare decision makers and budget holders to understand where costs could be reduced and resources re-allocated to different needs.

Use of Artificial Intelligence as an Innovative Method for Liver Graft Macrosteatosis Assessment.

The worldwide implementation of a liver graft pool using marginal livers (ie, grafts with a high risk of technical complications and impaired function or with a risk of transmitting infection or malignancy to the recipient) has led to a growing interest in developing methods for accurate evaluation of graft quality. Liver steatosis is associated with a higher risk of primary nonfunction, early graft dysfunction, and poor graft survival rate. The present study aimed to analyze the value of artificial intelligence (AI) in the assessment of liver steatosis during procurement compared with liver biopsy evaluation. A total of 117 consecutive liver grafts from brain-dead donors were included and classified into 2 cohorts: ≥30 versus <30% hepatic steatosis. AI analysis required the presence of an intraoperative smartphone liver picture as well as a graft biopsy and donor data. First, a new algorithm arising from current visual recognition methods was developed, trained, and validated to obtain automatic liver graft segmentation from smartphone images. Second, a fully automated texture analysis and classification of the liver graft was performed by machine-learning algorithms. Automatic liver graft segmentation from smartphone images achieved an accuracy (Acc) of 98%, whereas the analysis of the liver graft features (cropped picture and donor data) showed an Acc of 89% in graft classification (≥30 versus <30%). This study demonstrates that AI has the potential to assess steatosis in a handy and noninvasive way to reliably identify potential nontransplantable liver grafts and to avoid improper graft utilization.

Physiological assessment of high glucose neurotoxicity in mouse and rat retinal explants.

One of the tissues of the central nervous system most affected by diabetes is the retina. Despite a growing understanding of the biochemical processes involved in glucose toxicity, little is known about the physiological consequences of chronic high glucose (HG) on individual neurons and neuronal circuits. Electroretinogram recordings suggest that retinal bipolar cells (BCs), which filter and transmit photoreceptor output to the inner retina, are among the first cells affected by diabetic conditions, and may therefore serve as sensitive early biomarkers for incipient neuronal damage caused in diabetes. Here, we comparatively assessed retinal integrity, calcium responses, and the electrophysiological profiles of specific BC types of mouse and rat organotypic retinal explants after 1 to 3 weeks in tissue culture, under moderate glucose (MG) and HG conditions. While the retinal layers of both rodent species displayed a progressively reduced thickness in culture, BCs retained their electrophysiological profiles and remained morphologically identifiable for up to 2 weeks. Responses to glutamate and endogenous inhibitory responses were routinely observed, indicating that the retinal circuitry remained intact during this period. Significant physiological differences between MG and HG conditions were evident in calcium signals and in the time course of responses to glutamate, but the voltage-gated current profiles of BCs displayed only minor variations. Overall, rat retina appeared slightly more sensitive to HG levels compared with mouse. In conclusion, electrophysiological analysis of neuronal function in rodent retinal explants is useful for the study of early damage due to HG neurotoxicity.

Liver Transplantation in France.

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.

Assessment of adrenal function in patients with acute hepatitis using serum free and total cortisol.

BACKGROUND: Adrenal dysfunction is frequently reported in severe acute hepatitis using serum total cortisol. AIMS: Because 90% of serum cortisol is bound to proteins that are altered during stress, we investigated the effect of decreased cortisol-binding proteins on serum total and free cortisol in severe acute hepatitis. METHODS: 43 severe and 31 non-severe acute hepatitis and 29 healthy controls were enrolled consecutively and studied prospectively. Baseline (T0) and cosyntropin-stimulated (T60) serum total and free cortisol concentrations were measured. RESULTS: T0 and T60 serum total cortisol did not differ significantly between severe, non-severe hepatitis and healthy controls. Conversely, serum free cortisol (T0p=0.012; T60p<0.001) concentrations increased from healthy controls to severe hepatitis, accompanied by a decrease in corticosteroid-binding globulin and albumin (all p<0.001). In acute hepatitis (n=74), patients with "low" corticosteroid-binding globulin (<28mg/L) had higher T0 serum free cortisol than others (103.1 [61.2-157] vs. 56.6 [43.6-81.9]nmol/L, p=0.0024). Analysis of covariance showed that at equal concentration of total cortisol, the free cortisol concentration was significantly higher in severe than in non-severe hepatitis (p<0.001) or healthy controls (p<0.001). CONCLUSIONS: In severe hepatitis, the decrease in cortisol-binding proteins impairs correct diagnosis of adrenal dysfunction. This could be corrected by measuring or estimating free cortisol.

Inhibition of mitochondrial pyruvate transport by zaprinast causes massive accumulation of aspartate at the expense of glutamate in the retina.

Transport of pyruvate into mitochondria by the mitochondrial pyruvate carrier is crucial for complete oxidation of glucose and for biosynthesis of amino acids and lipids. Zaprinast is a well known phosphodiesterase inhibitor and lead compound for sildenafil. We found Zaprinast alters the metabolomic profile of mitochondrial intermediates and amino acids in retina and brain. This metabolic effect of Zaprinast does not depend on inhibition of phosphodiesterase activity. By providing (13)C-labeled glucose and glutamine as fuels, we found that the metabolic profile of the Zaprinast effect is nearly identical to that of inhibitors of the mitochondrial pyruvate carrier. Both stimulate oxidation of glutamate and massive accumulation of aspartate. Moreover, Zaprinast inhibits pyruvate-driven O2 consumption in brain mitochondria and blocks mitochondrial pyruvate carrier in liver mitochondria. Inactivation of the aspartate glutamate carrier in retina does not attenuate the metabolic effect of Zaprinast. Our results show that Zaprinast is a potent inhibitor of mitochondrial pyruvate carrier activity, and this action causes aspartate to accumulate at the expense of glutamate. Our findings show that Zaprinast is a specific mitochondrial pyruvate carrier (MPC) inhibitor and may help to elucidate the roles of MPC in amino acid metabolism and hypoglycemia.

Model for end-stage liver disease exceptions in the context of the French model for end-stage liver disease score-based liver allocation system.

Model for End-Stage Liver Disease (MELD) score-based allocation systems have been adopted by most countries in Europe and North America. Indeed, the MELD score is a robust marker of early mortality for patients with cirrhosis. Except for extreme values, high pretransplant MELD scores do not significantly affect posttransplant survival. The MELD score can be used to optimize the allocation of allografts according to a sickest first policy. Most often, patients with small hepatocellular carcinomas (HCCs) and low MELD scores receive extra points, which allow them appropriate access to transplantation comparable to the access of patients with advanced cirrhosis and high MELD scores. In addition to patients with advanced cirrhosis and HCC, patients with a number of relatively uncommon conditions have low MELD scores and a poor prognosis in the short term without transplantation but derive excellent benefits from transplantation. These conditions, which correspond to the so-called MELD score exceptions, justify the allocation of a specific score for appropriate access to transplantation. Here we report the conclusions of the French consensus meeting. The goals of this meeting were (1) to identify which conditions merit MELD score exceptions, (2) to list the criteria needed for defining each of these conditions, and (3) to define a reasonable time interval for organ allocation for each MELD exception in the general context of organ shortages. MELD exceptions were discussed in an attempt to reconcile the concepts of transparency, equity, justice, and utility.

A randomized study comparing IGL-1 to the University of Wisconsin preservation solution in liver transplantation.

BACKGROUND: Institut Georges Lopez-1 (IGL-1) is a new preservation solution with lower potassium and lower viscosity than University Wisconsin solution (UW). These characteristics which improve liver preservation lead us to evaluate clinical effects of IGL-1 in a randomized controlled study with UW. MATERIAL/METHODS: From June 2007 to July 2009, after exclusion of partial graft, combined transplantation and fulminant hepatic failure, 140 deceased donor allografts were randomly assigned to IGL-1 (n=48) or UW (n=92) solution. Variables concerning donors and recipients were collected including liver tests (total serum bilirubin, prothrombin time and transaminases) were analyzed until postoperative day 30. Incidences of hepatic artery thrombosis (HAT), primary non function (PNF) and biliary non anastomotic strictures (NAS) were analyzed. The comparative analysis of costs was realized. RESULTS: Donor and recipients characteristics were similar in both groups. Volume of preservation solution utilized for harvesting was identical. Duration of cold ischemia (472±142 vs. 477±122 min), surgery (427±97 vs. 437±94 min) and proportion of extended criteria donor was similar. Postoperative kinetic and level liver tests were similar. Rate of PNF (2% vs. 4%), early retransplantation (6% vs. 7%), incidence of biliary NAS (2% vs. 3%) and HAT (6% vs. 4%) were similar. Mean intensive care unit (ICU) stay was similar (5.6 vs. 6.1 days). However costs related to preservation solution for one liver procurement were 992.0 for IGL-1 vs. 1609.0 Euros for UW. CONCLUSIONS: Results of this randomized study shows that the efficacy and safety of IGL-1 are comparable to those of the reference UW with a lower cost.

Inaccuracies of creatinine and creatinine-based equations in candidates for liver transplantation with low creatinine: impact on the model for end-stage liver disease score.

Renal function has a significant impact on early mortality in patients with cirrhosis. However, creatinine and creatinine-based equations are inaccurate markers of renal function in cirrhosis. The aim of this study was to reassess correlations between creatinine-based equations and measured glomerular filtration rate (GFR) and to investigate the impact of inaccuracies on the Model for End-Stage Liver Disease (MELD) score. GFR was measured using iohexol clearance and calculated with creatinine-based equations in 157 patients with cirrhosis during pretransplant evaluation. We compared the accuracy of creatinine to that of true GFR in a prognostic score also including bilirubin and the international normalized ratio. In patients with creatinine below 1 mg/dL, true GFR ranged from 34-163 mL/minute/1.73 m(2). Cockcroft and Modification of Diet in Renal Disease (MDRD) significantly overestimated true GFR. On multivariate analysis, younger age and ascites were significantly correlated with the overestimation of true GFR by 20% or more. Body mass index was an independent risk factor of overestimation of GFR with Cockcroft but not with MDRD. The accuracy of a prognostic score combining bilirubin, international normalized ratio, and true GFR was superior to that of MELD, whether creatinine was rounded to 1 mg/dL when lower than 1 mg/dL or not (c-statistic of 0.8 versus 0.75 and 0.73, respectively). Creatinine-based formulas overestimate true GFR, especially in patients younger than 50 years or with ascites. In patients with serum creatinine below 1 mg/dL, the spectrum of true GFR is large. True GFR seems to have a better prognostic value than creatinine and creatinine-based equations. Specific equations are needed in patients with cirrhosis to improve prognostic scores.

Assessment of prognosis of cirrhosis.

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.

Indications of liver transplantation in patients with complications of cirrhosis.

Transplantation is the only option for reversing liver insufficiency and its complications in patients with end-stage cirrhosis. Transplantation is generally considered after the first episode of decompensation of cirrhosis, provided no specific intervention can result in a longstanding return to the compensated state. Alcohol abuse and hepatitis C virus infection are the predominant causes leading to transplantation in Western countries. In cases of alcoholic cirrhosis, a 6-month period of abstinence is needed before transplantation. Patients with hepatitis C virus infection are considered independent of viral replication, even if post-transplantation recurrence is almost constant. Conversely, in cases of hepatitis B infection, only patients without viral replication (or with extremely low viral load) are suitable candidates. Hepatocellular carcinoma represents an increasing proportion of the indications and offers excellent long-term survival. However, transplantation should be limited to patients with small tumours. HIV infection no longer represents a definitive contraindication.