A plasmatic score using a miRNA signature and CXCL-10 for accurate prediction and diagnosis of liver allograft rejection.

Introduction: The use of noninvasive biomarkers may avoid the need for liver biopsy (LB) and could guide immunosuppression adjustment in liver transplantation (LT). The aims of this study were: to confirm the predictive and diagnostic capacity of plasmatic expression of miR-155-5p, miR-181a-5p, miR-122-5p and CXCL-10 for assessing T-cell mediated rejection (TCMR) risk; to develop a score based on a panel of noninvasive biomarkers to predict graft rejection risk and to validate this score in a separate cohort. Methods: A prospective, observational study was conducted with a cohort of 79 patients followed during the first year after LT. Plasma samples were collected at predetermined time points for the analysis of miRNAs and the CXCL-10. Patients with LFTs abnormalities were submitted to a LB to rule out rejection, assessing previous and concurrent expression of the biomarkers to evaluate their predictive and diagnostic ability. Information from 86 patients included in a previous study was collected and used as a validation cohort. Results: Twenty-four rejection episodes were diagnosed in 22 patients. Plasmatic CXCL-10 concentration and the expression of the three miRNAs were significantly elevated prior to and at the moment of the diagnosis of rejection. We developed a logistic model for rejection prediction and diagnosis, which included CXCL-10, miR-155-5p and miR-181a-5p. The area under the ROC curve (AUROC) for rejection prediction was 0.975 (79.6% sensitivity, 99.1% specificity, 90,7% PPV; 97.7% NPV; 97.1% correctly classified) and 0.99 for diagnosis (87.5% sensitivity, 99.5% specificity, 91.3% PPV; 99.3% NPV; 98.9% correctly classified). In the validation cohort (n=86; 14 rejections), the same cut-off points were used obtaining AUROCs for rejection prediction and diagnosis of 0.89 and 0.92 respectively. In patients with graft dysfunction in both cohorts the score could discriminate those with rejection regarding other causes with an AUROC of 0.98 (97.3% sensitivity, 94.1%specificity). Conclusion: These results suggest that the clinical implementation of the monitoring of this noninvasive plasmatic score may allow the prediction and diagnosis of rejection and identify patients with graft dysfunction due to rejection, helping with a more efficient guide for immunosuppressive therapy adjustment. This finding warrants the development of prospective biomarker-guided clinical trials.

Posttransplant Hepatocellular Carcinoma Surveillance: A Cost-effectiveness and Cost-utility Analysis.

OBJECTIVE: Assess cost-effectiveness and -utility associated with posttransplant HCC surveillance compared to standard follow-up. SUMMARY OF BACKGROUND DATA: Despite lack of prospective clinical data, expert consensus recommends posttransplant surveillance to detect HCC recurrence in a latent phase, while it might be amenable to curative-intent therapy. METHODS: A Markov-based transition model was created to estimate life expectancy and quality-of-life among liver transplant patients undergoing HCC surveillance. Models were built for 2 cohorts: 1 undergoing HCC surveillance with contrast-enhanced computed tomography of chest and abdomen and serum alpha-fetoprotein analysis and the other receiving standard posttransplant follow-up. Primary model outputs included LY and QALY gains, incremental cost-effectiveness ratio, and incremental cost-utility ratio. Willingness-to-pay for a QALY gain (cost-effectiveness threshold) was used to estimate efficiency. RESULTS: Surveillance was marginally more effective versus no surveillance, resulting in means of 0.069 LYs and 0.026 QALYs gained. Costs for surveillance were increased by an average of 988.32€, resulting in incremental cost-effectiveness ratio 14,410.15€/LY and incremental cost-utility ratio 37,547.97€/QALY. Surveillance did not seem cost-effective in our setting, considering willingness-to-pay threshold of 25,000€/QALY. Probabilistic sensitivity analysis indicated surveillance might be cost-effective in 42% of cases, but degree of uncertainty in the analysis was high. CONCLUSIONS: Performing posttransplant HCC surveillance offers marginal clinical benefits and increases costs. Although expert consensus supports surveillance, results of this decision analysis raise doubt regarding the utility of such recommendations and support ongoing need for prospective clinical trials.

Immunotolerance in liver transplantation: a primer for the clinician.

The use of immunosuppressive medications for solid organ transplantation is associated with cardiovascular, metabolic, and oncologic complications. On the other hand, the development of graft rejection is associated with increased mortality and graft dysfunction. Liver transplant recipients can withdraw from immunosuppression without developing graft injury while preserving an adequate antimicrobial response - a characteristic known as immunotolerance. Immunotolerance can be spontaneously or pharmacologically achieved. Contrary to the classic dogma, clinical studies have elucidated low rates of true spontaneous immunotolerance (no serologic or histological markers of immune injury) among liver transplant recipients. However, clinical, serologic, and tissue biomarkers can aid in selecting patients in whom immunosuppression can be safely withdrawn. For those who failed an immunosuppression withdrawal trial or are at high risk of rejection, pharmacological interventions for immunotolerance induction are under development. In this review, we provide an overview of the mechanisms of immunotolerance, the clinical studies investigating predictors and biomarkers of spontaneous immunotolerance, as well as the potential pharmacological interventions for inducing it.

The Role of Arterial Stiffness in the Estimation of Cardiovascular Risk in Liver Transplant Recipients.

BACKGROUND: Long-term cardiovascular (CV) events are a frequent cause of death and disability after liver transplant (LT). Although a more in-depth, risk-adapted control of CV risk factors may result in improved post-LT CV outcomes, an accurate stratification of the CV risk of LT recipients to better implement preventive strategies is lacking. Aortic pulse wave velocity (aPWV) is a surrogate of arterial stiffness that has been suggested as a biomarker of CV risk; it has never been evaluated in adult LT recipients. METHODS: In a single-center prospective study, we included 122 LT recipients at 12 (n = 39), 60 (n = 45), or 120 (n = 38) mo after LT. aPWV estimation by oscillometry, clinical assessment of CV risk factors, and CV risk estimation by standard clinical scores (systematic coronary risk evaluation and pooled cohort equation) were performed. The incidence of CV events during prospective follow-up was registered. RESULTS: aPWV was independently associated with age and the grade of control of blood pressure. After a median follow-up of 35 mo, 15 patients (12%) presented a CV event. Higher aPWV, diabetes, past or present smoking habit, previous CV events, lower eGFR, being in systematic coronary risk evaluation or pooled cohort equation high-risk groups, and higher levels of total cholesterol, LDL-cholesterol, creatinine, and triglycerides were associated with the incidence of CV events at univariate analysis; aPWV, past or present smoking habit, and triglycerides were independent predictors of CV events. CONCLUSIONS: According to our results, aPWV mirrors CV risk in LT recipients and thus may be a useful CV risk biomarker in this population. Considering these preliminary results, its accuracy in stratifying risk requires confirmation in further studies.

Modeling hepatitis C virus kinetics during liver transplantation reveals the role of the liver in virus clearance.

While the liver, specifically hepatocytes, are widely accepted as the main source of hepatitis C virus (HCV) production, the role of the liver/hepatocytes in clearance of circulating HCV remains unknown. Frequent HCV kinetic data were recorded and mathematically modeled from five liver transplant patients throughout the anhepatic (absence of liver) phase and for 4 hr post-reperfusion. During the anhepatic phase, HCV remained at pre-anhepatic levels (n = 3) or declined (n = 2) with t1/2~1 hr. Immediately post-reperfusion, virus declined in a biphasic manner in four patients consisting of a rapid decline (t1/2 = 5 min) followed by a slower decline (t1/2 = 67 min). Consistent with the majority of patients in the anhepatic phase, when we monitored HCV clearance at 37°C from culture medium in the absence/presence of chronically infected hepatoma cells that were inhibited from secreting HCV, the HCV t1/2 in cell culture was longer in the absence of chronically HCV-infected cells. The results suggest that the liver plays a major role in the clearance of circulating HCV and that hepatocytes may be involved.

Limited tumour progression beyond Milan criteria while on the waiting list does not result in unacceptable impairment of survival.

BACKGROUND & AIMS: Defining optimum management of patients progressing beyond Milan criteria on the waiting list is a controversial topic. Our aim was to determine whether the policy of allowing a limited progression beyond enlistment criteria permits acceptable post-transplant outcomes in terms of survival and recurrence. METHODS: Patients with hepatocellular carcinoma included on the waiting list for orthotopic liver transplantation (OLT) between January 1989 and December 2016 were analysed. Tumour features were assessed at inclusion on the waiting list, before OLT and at explant pathology. Patients were retained on the waiting list despite exceeding enlistment criteria if not presenting with macrovascular invasion, extrahepatic spread or cancer-related symptoms. RESULTS: A total of 495 patients constituted the target population. Comparison between the Milan-in (n = 434) and Milan-out (n = 61) groups showed statistically significant differences in: largest tumour size; BCLC stage; patients treated before OLT; alpha-fetoprotein, and time on the waiting list. Milan-out patients showed a significantly higher number of poorly differentiated nodules, satellitosis and microscopic vascular invasion. The 1-, 3-, 5- and 10-year survival rate was 89.6%, 82.5%, 75%, and 55.5%, vs. 83.6%, 70.5%, 65.5%, and 53.9% for Milan-in/Milan-out patients, respectively. Recurrence rates at 1, 3, 5 and 10 years were 1.2%, 3.3%, 5.5%, and 10.8% vs. 7.1% 14.5%, 23%, and 23% for Milan-in and Milan-out patients, respectively (p <0.01). CONCLUSION: This study shows that although limited tumour progression without reaching major adverse predictors (vascular invasion, extrahepatic spread, cancer symptoms) has an expected impact on recurrence rate, overall survival remains above the minimum proposed benchmark of 65% at 5 years. The clinically relevant increase in tumour recurrence must be considered when analysing the benefit of this approach in the face of limited organ supply. LAY SUMMARY: When considering orthotopic liver transplantation for patients with hepatocellular carcinoma, optimum results are achieved when transplanting patients within the Milan criteria. However, the most appropriate strategy for patients who progress beyond these criteria while on the waiting list is still unclear. Herein, we show that transplantation is associated with acceptable overall survival in select patients who progress beyond the Milan criteria, although recurrence rates were notably higher. Therefore, the assessment of transplantation viability in these patients must consider the availability of organs and the impact on other patient categories.

Liver and kidney transplantation in polycystic liver and kidney disease. / Trasplante hepático y renal en la enfermedad poliquística hepatorrenal.

OBJECTIVE: To evaluate the results of isolated liver and combined liver and kidney transplantation in a retrospective series of 32 patients with hepatorenal liver and kidney disease. MATERIALS AND METHODS: A retrospective observational study that enrolled patients with polycystic liver disease (PLD) and polycystic liver and kidney disease (PLKD) who were evaluated for transplantation between January 1999 and December 2019 at Hospital Clínic de Barcelona [Clinical Hospital of Barcelona]. RESULTS: We included a total of 53 patients enrolled, 32 (60.3%) had indication for transplantation, of which 12 received a single liver transplant and 20 received a double liver and kidney transplant. The mean age was 52 years and 83.9% of the recipients were women. The main indication for liver transplantation was disabling symptomatic hepatomegaly (93.5%). Among the postoperative complications, in the combined liver and kidney transplant group, hepatic artery thrombosis in one case and renal artery thrombosis in other were detected. In both groups there was one case of inferior vena cava lesion. Three patients presented acute cellular rejection responding to corticosteroids and one presented humoral rejection which was treated with plasmapheresis. During the follow-up period of 80 (27-121) months, the liver transplant survival rate was 100% and the kidney transplant survival rate was 90%. Two patients in the combined liver and kidney transplant group died (one due to cardiovascular causes and the other due to intestinal adenocarcinoma). CONCLUSIONS: Isolated liver transplantation or combined liver and kidney transplantation in selected patients with polycystic disease yields excellent results, with few complications, very good transplant survival and excellent patient survival (93.8%).

Active Smoking Before Liver Transplantation in Patients with Alcohol Use Disorder: Risk Factors and Outcomes.

Tobacco use is more prevalent among alcohol liver disease (ALD) transplant patients and exerts harmful effects to the patient and to the graft. The aims of this study were to examine the impact of smoking status (nonsmoker, ex-smoker, active smoker) on patient survival and clinical outcomes, and to assess risk factors for active smoking before and after liver transplant (LT). An observational retrospective cohort study with 314 ALD patients undergoing LT from January 2004 to April 2016. Recipients were followed until April 2017 or death. Kaplan-Meier and Cox proportional hazards regression analyses were used to assess risk of mortality according to smoking status before LT. Smokers had a 79% higher risk of dying than those who had never smoked or quit smoking before LT. Ex-smokers had a greater survival probability (96.2%, 93.8%, 86.9%, and 83.1% at 1, 3, 5, and 10 years after LT) than active smokers until LT (96.0%, 85.6%, 80.0%, and 70.4%). Active smokers before LT with poor toxicity awareness had more than a twofold higher risk of mortality (Cox HR = 2.20, 95% CI: 1.05-4.58, p = 0.04) than ex-smokers. Younger age (OR = 94), higher Model for End-Stage Liver Disease (MELD) (OR = 1.06), and comorbid substance use disorder (OR = 2.35) were predictors of smoking until LT. Six months or less of alcohol abstinence (OR = 3.23), and comorbid substance use disorder (OR = 4.87) were predictors of active smoking after LT. Quitting smoking before transplantation improved survival. Evidence based smoking cessation interventions should be offered before and after LT.

MicroRNAs 155-5p, 122-5p, and 181a-5p Identify Patients With Graft Dysfunction Due to T Cell-Mediated Rejection After Liver Transplantation.

MicroRNAs (miRNAs) are small noncoding RNAs that can be detected in plasma and whose expression is associated with pathological processes. The role of miRNAs in the noninvasive diagnosis of T cell-mediated rejection (TCMR) after liver transplantation (LT) is unclear. Thus, we aimed to assess the effectiveness of a panel of 4 miRNAs (155-5p, 122-5p, 181a-5p, and 148-3p) in diagnosing TCMR in LT recipients with graft dysfunction (GD), and we compared its accuracy with previously published tests for diagnosing TCMR based on routine laboratory parameters. From a prospective cohort of 145 patients followed during the first year after transplant, 49 developed GD and underwent a liver biopsy and plasma collection for miRNA analysis using quantitative real-time polymerase chain reaction. Patients with GD due to TCMR (n = 21) exhibited significantly higher (P < 0.001) expression of miRNA 155-5p (2.05 versus 0.07), 122-5p (19.36 versus 1.66), and 181a-5p (1.33 versus 0.37) compared with those with GD from other causes (n = 28). The area under the receiver operating characteristic curve of miRNAs 155-5p, 122-5p, and 181a-5p for the diagnosis of TCMR was 0.87, 0.91, and 0.89, respectively, significantly higher than those of the other noninvasive tests (P < 0.001). Furthermore, miRNA 155-5p identified all patients who presented TCMR during the first 2 weeks after transplant. miRNA plasmatic expression differentiates TCMR from other causes of GD in patients who have undergone LT and may be a useful tool in clinical practice.

Original and generic preservation solutions in organ transplantation. A new paradigm?

Solid organ transplantation is a very complex process, in which the storage of the graft in a preservation solution is mandatory in order to extend ischemic times and contain further damage. The condition in which the organ is transplanted is critical for the outcome of the organ recipient. The recent emergence of generic versions of organ preservation solutions (solutions with the same composition and under the same legislation as the original versions, but with different brands) compelled us to study whether the standards are maintained when comparing the original and its generic counterpart. Along these lines, we discuss and comment on some aspects concerning this issue of general interest in the organ transplantation field.

Bespoken Nanoceria: An Effective Treatment in Experimental Hepatocellular Carcinoma.

BACKGROUND AND AIMS: Despite the availability of new-generation drugs, hepatocellular carcinoma (HCC) is still the third most frequent cause of cancer-related deaths worldwide. Cerium oxide nanoparticles (CeO2 NPs) have emerged as an antioxidant agent in experimental liver disease because of their antioxidant, anti-inflammatory, and antisteatotic properties. In the present study, we aimed to elucidate the potential of CeO2 NPs as therapeutic agents in HCC. APPROACH AND RESULTS: HCC was induced in 110 Wistar rats by intraperitoneal administration of diethylnitrosamine for 16 weeks. Animals were treated with vehicle or CeO2 NPs at weeks 16 and 17. At the eighteenth week, nanoceria biodistribution was assessed by mass spectrometry (MS). The effect of CeO2 NPs on tumor progression and animal survival was investigated. Hepatic tissue MS-based phosphoproteomics as well as analysis of principal lipid components were performed. The intracellular uptake of CeO2 NPs by human ex vivo perfused livers and human hepatocytes was analyzed. Nanoceria was mainly accumulated in the liver, where it reduced macrophage infiltration and inflammatory gene expression. Nanoceria treatment increased liver apoptotic activity, while proliferation was attenuated. Phosphoproteomic analysis revealed that CeO2 NPs affected the phosphorylation of proteins mainly related to cell adhesion and RNA splicing. CeO2 NPs decreased phosphatidylcholine-derived arachidonic acid and reverted the HCC-induced increase of linoleic acid in several lipid components. Furthermore, CeO2 NPs reduced serum alpha-protein levels and improved the survival of HCC rats. Nanoceria uptake by ex vivo perfused human livers and in vitro human hepatocytes was also demonstrated. CONCLUSIONS: These data indicate that CeO2 NPs partially revert the cellular mechanisms involved in tumor progression and significantly increase survival in HCC rats, suggesting that they could be effective in patients with HCC.

Original and generic preservation solutions in organ transplantation. A new paradigm?

Abstract Solid organ transplantation is a very complex process, in which the storage of the graft in a preservation solution is mandatory in order to extend ischemic times and contain further damage. The condition in which the organ is transplanted is critical for the outcome of the organ recipient. The recent emergence of generic versions of organ preservation solutions (solutions with the same composition and under the same legislation as the original versions, but with different brands) compelled us to study whether the standards are maintained when comparing the original and its generic counterpart. Along these lines, we discuss and comment on some aspects concerning this issue of general interest in the organ transplantation field.

Torque Teno Virus Is Associated With the State of Immune Suppression Early After Liver Transplantation.

The development of noninvasive biomarkers that reflect the state of immunosuppression (IS) remains an unmet need in liver transplantation (LT). Torque Teno virus (TTV) is a highly prevalent, nonpathogenic DNA virus whose plasma levels may be associated with the immune status of the host. The aim of this study was to assess the role of TTV as a biomarker of IS in LT recipients. TTV DNA in plasma was quantified by real-time polymerase chain reaction at different time points during the first year after transplant in a prospectively followed cohort of 63 de novo LT recipients, and any correlation between TTV DNA and biopsy-proven acute cellular rejection (ACR) and opportunistic infections was then evaluated. In addition, TTV DNA was studied in 10 longterm LT recipients in monotherapy with tacrolimus, 10 tolerant recipients, and 10 healthy controls. TTV was detected in the plasma of all patients. Among the 63 LT recipients, 20 episodes of ACR were diagnosed, and there were 28 opportunistic infections, 26 of them being cytomegalovirus (CMV) infections. TTV viremia was significantly lower during ACR (4.41 versus 5.95 log10 copies/mL; P = 0.002) and significantly higher during CMV infections (5.79 versus 6.59 log10 copies/mL; P = 0.009). The area under the receiver operating characteristic curve of TTV viral load for the diagnosis of moderate ACR was 0.869, with a sensitivity and negative predictive value of 100%, respectively, for a cutoff point of 4.75 log10 copies/mL. There were no statistically significant differences in TTV DNA in either longterm or tolerant patients and healthy controls. In conclusion, plasma TTV DNA levels are associated with immune-related events after LT and could constitute a potential biomarker of the state of IS during the first months after transplant.

Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients.

BACKGROUND & AIMS: Subclinical inflammatory changes are commonly described in long-term transplant recipients undergoing protocol liver biopsies. The pathogenesis of these lesions remains unclear. The aim of this study was to identify the key molecular pathways driving progressive subclinical inflammatory liver allograft damage. METHODS: All liver recipients followed at Hospital Clínic Barcelona who were >10 years post-transplant were screened for participation in the study. Patients with recurrence of underlying liver disease, biliary or vascular complications, chronic rejection, and abnormal liver function tests were excluded. Sixty-seven patients agreed to participate and underwent blood and serological tests, transient elastography and a liver biopsy. Transcriptome profiling was performed on RNA extracted from 49 out of the 67 biopsies employing a whole genome next generation sequencing platform. Patients were followed for a median of 6.8 years following the index liver biopsy. RESULTS: Median time since transplantation to liver biopsy was 13 years (10-22). The most frequently observed histological abnormality was portal inflammation with different degrees of fibrosis, present in 45 biopsies (67%). Two modules of 102 and 425 co-expressed genes were significantly correlated with portal inflammation, interface hepatitis and portal fibrosis. These modules were enriched in molecular pathways known to be associated with T cell mediated rejection. Liver allografts showing the highest expression levels for the two modules recapitulated the transcriptional profile of biopsies with clinically apparent rejection and developed progressive damage over time, as assessed by non-invasive markers of fibrosis. CONCLUSIONS: A large proportion of adult liver transplant recipients who survive long-term exhibit subclinical histological abnormalities. The transcriptomic profile of these patients' liver tissue closely resembles that of T cell mediated rejection and may result in progressive allograft damage. LAY SUMMARY: A large proportion of adult liver transplant recipients who survive for a long time exhibit subclinical histological abnormalities. The expression profile (a measurement of the activity of genes) of liver tissue from a large fraction of these patients closely resembles the profile of T cell mediated rejection. Liver allografts showing the highest expression levels of rejection-related genes developed progressive damage over time.

Endoscopic management of bile leaks after liver transplantation: An analysis of two high-volume transplant centers.

BACKGROUND: Bile leak after liver transplantation (LT) is commonly treated with endoscopic retrograde cholangiopancreatography (ERCP); however, there are limited data regarding the optimal treatment strategy. OBJECTIVE: We aimed to examine the role of ERCP in LT recipients with bile leaks at two large institutions. METHODS: We reviewed all ERCPs performed in LT recipients with bile leak and duct-to-duct biliary anastomosis at two high-volume transplant centers. RESULTS: Eighty patients were included. Forty-seven (59%) patients underwent ERCP with plastic stent placement (with or without sphincterotomy) and 33 patients (41%) underwent sphincterotomy alone. Complete resolution was obtained in 94% of the stent group vs. 58% of the sphincterotomy group (p < 0.01). There was no difference in three-month survival among both groups. Percutaneous transhepatic therapy and surgery were required in 4% and 6% in the stent group vs. 12% and 42% in the sphincterotomy group, respectively (p = 0.22 and p < 0.001). The only predictive factor of bile leak resolution was stent placement. CONCLUSION: ERCP with plastic stent placement is highly successful and more effective than sphincterotomy alone for post-LT bile leak treatment. These results indicate that ERCP and plastic stent placement should be considered the standard of care for the treatment of bile leaks in LT.

Portal pressure and liver stiffness measurements in the prediction of fibrosis regression after sustained virological response in recurrent hepatitis C.

Sustained virological response (SVR) improves survival in post-liver transplant (LT) recurrent hepatitis C. However, the impact of SVR on fibrosis regression is not well defined. In addition, the performance of noninvasive methods to evaluate the presence of fibrosis and portal hypertension (PH) post-SVR has been scarcely evaluated. We aimed to investigate the degree of fibrosis regression (decrease ≥1 METAVIR stage) after-SVR and its associated factors in recurrent hepatitis C, as well as the diagnostic capacity of noninvasive methods in the assessment of liver fibrosis and PH after viral clearance. We evaluated 112 hepatitis C virus-infected LT recipients who achieved SVR between 2001 and 2015. A liver biopsy was performed before treatment and 12 months post-SVR. Hepatic venous pressure gradient (HVPG), liver stiffness measurement (LSM), and Enhanced Liver Fibrosis (ELF) score were also determined at the same time points. Sixty-seven percent of the cohort presented fibrosis regression: 43% in recipients with cirrhosis and 72%-85% in the remaining stages (P = 0.002). HVPG, LSM, and ELF significantly decreased post-SVR. Liver function significantly improved, and survival was significantly better in patients achieving fibrosis regression. Baseline HVPG and LSM as well as decompensations before therapy were independent predictors of fibrosis regression. One year post-SVR, LSM had a high diagnostic accuracy to discard the presence of advanced fibrosis (AF) and clinically significant PH (AUROC, 0.902 and 0.888). CONCLUSION: In conclusion, SVR post-LT induces fibrosis regression in most patients, leading to significant clinical benefits. Pretreatment HVPG and LSM are significant determinants of the likelihood of fibrosis regression. Finally, LSM accurately predicts the presence of AF and PH 1 year after SVR and thus can be used to determine monitoring strategies. (Hepatology 2018;67:1683-1694).

A Metabolomics Signature Linked To Liver Fibrosis In The Serum Of Transplanted Hepatitis C Patients.

Liver fibrosis must be evaluated in patients with hepatitis C virus (HCV) after liver transplantation because its severity affects their prognosis and the recurrence of HCV. Since invasive biopsy is still the gold standard to identify patients at risk of graft loss from rapid fibrosis progression, it becomes crucial the development of new accurate, non-invasive methods that allow repetitive examination of the patients. Therefore, we have developed a non-invasive, accurate model to distinguish those patients with different liver fibrosis stages. Two hundred and three patients with HCV were histologically classified (METAVIR) into five categories of fibrosis one year after liver transplantation. In this cross-sectional study, patients at fibrosis stages F0-F1 (n = 134) were categorised as "slow fibrosers" and F2-F4 (n = 69) as "rapid fibrosers". Chloroform/methanol serum extracts were analysed by reverse ultra-high performance liquid chromatography coupled to mass spectrometry. A diagnostic model was built through linear discriminant analyses. An algorithm consisting of two sphingomyelins and two phosphatidylcholines accurately classifies rapid and slow fibrosers after transplantation. The proposed model yielded an AUROC of 0.92, 71% sensitivity, 85% specificity, and 84% accuracy. Moreover, specific bile acids and sphingomyelins increased notably along with liver fibrosis severity, differentiating between rapid and slow fibrosers.

Cost-effectiveness of enhanced liver fibrosis test to assess liver fibrosis in chronic hepatitis C virus and alcoholic liver disease patients.

AIM: To assess liver fibrosis (LF) in hepatitis C virus (HCV) and alcoholic liver disease (ALD), estimate health outcomes and costs of new noninvasive testing strategies. METHODS: A Markov model was developed to simulate LF progression in HCV and ALD for a cohort of 40-year-old men with abnormal levels of transaminases. Three different testing alternatives were studied: a single liver biopsy; annual Enhanced liver fibrosis (ELF™) followed by liver stiffness measurement (LSM) imaging as a confirmation test if the ELF test is positive; and annual ELF test without LSM. The analysis was performed from the perspective of a university hospital in Spain. Clinical data were obtained from published literature. Costs were sourced from administrative databases of the hospital. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: In HCV patients, annual sequential ELF test/LSM and annual ELF test alone prevented respectively 12.9 and 13.3 liver fibrosis-related deaths per 100 persons tested, compared to biopsy. The incremental cost-effectiveness ratios (ICERs) were respectively €13400 and €11500 per quality-adjusted life year (QALY). In ALD, fibrosis-related deaths decreased by 11.7 and 22.1 per 100 persons tested respectively with sequential ELF test/LSM and annual ELF test alone. ICERs were €280 and €190 per QALY, respectively. CONCLUSION: The use of the ELF test with or without a confirmation LSM are cost-effective options compared to a single liver biopsy for testing liver fibrosis in HCV and ALD patients in Spain.

Liver transplantation in Spain.

Liver transplantation (LT) activity started in Spain in 1984 and has exceeded 23,700 interventions, with more than 1000 transplants performed yearly. Every hospital needs official authorization to perform a LT, which implies the obligation to register all patients on the national waiting list. The Spanish National Transplant Organization (ONT) provides essential support for organ procurement, allocation, and management of the waiting list at a national level. Liver allocation is center-oriented as all available organs are referred to the ONT for the whole country. The allocation rules for LT are made according to disease severity after consensus among professionals from every transplant center and ratified by representatives of the regional health authorities. Authorization and location/distribution of transplant centers are regulated by the country (Spain) and by the different regions according to the Real Decreto 1723/2012. For a total population of 47,850,795 inhabitants, there are 24 centers for LT for adults (1 team/2 million people) and 5 for LT for children (1 team/9.5 million people). Nonbiliary cirrhosis, particularly alcohol- and hepatitis C virus-related cirrhosis (60%), and tumors, mainly hepatocellular carcinoma (19%), are the most common indications for LT in Spain. Unusual causes of LT include metabolic diseases like Wilson's disease, familial amyloid polyneuropathy and hyperoxaluria type I, polycystic kidney and liver disease, and some tumors (epithelioid hemangioendothelioma and neuroendocrine tumors). Important efforts are now being undertaken to improve the quality and transplantability of extended criteria livers, in particular those arising from DCD, which represent the greatest opportunity to expand the donor pool. These efforts have to be addressed to adapt the organ preservation procedures, be it through the application of regional perfusion in situ or the use of machine perfusion preservation ex situ. Liver Transplantation 22 1259-1264 2016 AASLD.