Epigenetic-sensitive challenges of cardiohepatic interactions: clinical and therapeutic implications in heart failure patients.

Heart failure and liver dysfunction can coexist owing to complex cardiohepatic interactions including the development of hypoxic hepatitis and congestive hepatopathy in patients with heart failure as well as 'cirrhotic cardiomyopathy' in advanced liver disease and following liver transplantation. The involvement of liver dysfunction in patients with heart failure reflects crucial systemic hemodynamic modifications occurring during the evolution of this syndrome. The arterial hypoperfusion and downstream hypoxia can lead to hypoxic hepatitis in acute heart failure patients whereas passive congestion is correlated with congestive hepatopathy occurring in patients with chronic heart failure. Nowadays, liquid biopsy strategies measuring liver function are well established in evaluating the prognosis of patients with heart failure. Large randomized clinical trials confirmed that gamma-glutamyltransferase, bilirubin, lactate deihydrogenase, and transaminases are useful prognostic biomarkers in patients with heart failure after transplantation. Deeper knowledge about the pathogenic mechanisms underlying cardiohepatic interactions would be useful to improve diagnosis, prognosis, and treatments of these comorbid patients. Epigenetic-sensitive modifications are heritable changes to gene expression without involving DNA sequence, comprising DNA methylation, histone modifications, and noncoding RNAs which seem to be relevant in the pathogenesis of heart failure and liver diseases when considered in a separate way. The goal of our review is to highlight the pertinence of detecting epigenetic modifications during the complex cardiohepatic interactions in clinical setting. Moreover, we propose a clinical research program which may be useful to identify epigenetic-sensitive biomarkers of cardiohepatic interactions and advance personalized therapy in these comorbid patients.

Compromised nutritional status in patients with end-stage liver disease: Role of gut microbiota.

BACKGROUND: Patients with end-stage liver disease (ESLD) have a compromised nutritional status because of the liver crucial role in regulating metabolic homeostasis and energy balance. DATA SOURCES: A systematic review of literature based on extensive relevant articles published from 2001 to 2017 in English in PubMed database was performed by searching keywords such as liver disease, non-alcoholic liver disease, alcoholic liver disease, malnutrition, epigenetics, gut microbiota, and probiotics. RESULTS: Liver transplantation would be one eligible therapy for ESLD patients, even if, the clinical outcome is negatively influenced by malnutrition and/or infections. The malnutrition is a condition of nutrient imbalance with a high incidence in ESLD patients. An accurate evaluation of nutritional status could be fundamental for reducing complications and prolonging the survival of ESLD patients including those undergoing liver transplantation. In addition, the interaction among nutrients, diet and genes via epigenetics has emerged as a potential target to reduce the morbidity and mortality in ESLD patients. The malnutrition induces changes in gut microbiota causing dysbiosis with a probable translocation of bacteria and/or pathogen-derived factors from the intestine to the liver. Gut microbiota contribute to the progression of chronic liver diseases as well as hepatocellular carcinoma. The administration of probiotics modulating gut microbiota could improve all chronic liver diseases. CONCLUSIONS: This review provides an update on malnutrition status linked to epigenetics and the potential benefit of some probiotics on the management of ESLD patients. In support of this view and to reveal the constant and growing interest in this field, some clinical trials are reported.

Liver Match, a prospective observational cohort study on liver transplantation in Italy: study design and current practice of donor-recipient matching.

BACKGROUND: The Liver Match is an observational cohort study that prospectively enrolled liver transplantations performed at 20 out of 21 Italian Transplant Centres between June 2007 and May 2009. Aim of the study is to investigate the impact of donor/recipient matching on outcomes. In this report we describe the study methodology and provide a cross-sectional description of donor and recipient characteristics and of graft allocation. METHODS: Adult primary transplants performed with deceased heart-beating donors were included. Relevant information on donors and recipients, organ procurement and allocation were prospectively entered in an ad hoc database within the National Transplant Centre web-based Network. Data were blindly analysed by an independent Biostatistical Board. RESULTS: The study enrolled 1530 donor/recipient matches. Median donor age was 56 years. Female donors (n = 681, median 58, range 12-92 years) were older than males (n = 849, median 53, range 2-97 years, p < 0.0001). Donors older than 60 years were 42.2%, including 4.2% octogenarians. Brain death was due to non-traumatic causes in 1126 (73.6%) cases. Half of the donor population was overweight, 10.1% was obese and 7.6% diabetic. Hepatitis B core antibody (HBcAb) was present in 245 (16.0%) donors. The median Donor Risk Index (DRI) was 1.57 (>1.7 in 35.8%). The median cold ischaemia time was 7.3h (≥ 10 in 10.6%). Median age of recipients was 54 years, and 77.7% were males. Hepatocellular carcinoma (HCC) was the most frequent indication overall (44.4%), being a coindication in roughly 1/3 of cases, followed by viral cirrhosis without HCC (28.2%) and alcoholic cirrhosis without HCC (10.2%). Hepatitis C virus infection (with or without HCC) was the most frequent etiologic factor (45.9% of the whole population and 71.4% of viral-related cirrhosis), yet hepatitis B virus infection accounted for 28.6% of viral-related cirrhosis, and HBcAb positivity was found in 49.7% of recipients. The median Model for End Stage Liver Disease (MELD) at transplant was 12 in patients with HCC and 18 in those without. Multivariate analysis showed a slight but significant inverse association between DRI and MELD at transplant. CONCLUSIONS: The deceased donor population in Italy has a high-risk profile compared to other countries, mainly due to older donor age. Almost half of the grafts are transplanted in recipients with HCC. Higher risk donors tend to be preferentially allocated to recipients with HCC, who are usually less ill and older. No other relevant allocation strategy is currently adopted at national level.

Feasibility and limits of split liver transplantation from pediatric donors: an italian multicenter experience.

OBJECTIVE: To report the results of a multicenter experience of split liver transplantation (SLT) with pediatric donors. SUMMARY BACKGROUND DATA: There are no reports in the literature regarding pediatric liver splitting; further; the use of donors weighing <40 kg for SLT is currently not recommended. METHODS: From 1997 to 2004, 43 conventional split liver procedures from donors aged <15 years were performed. Nineteen donors weighing < or =40 kg and 24 weighing >40 kg were used. Dimensional matching was based on donor-to-recipient weight ratio (DRWR) for left lateral segment (LLS) and on estimated graft-to-recipient weight ratio (eGRWR) for extended right grafts (ERG). In 3 cases, no recipient was found for an ERG. The celiac trunk was retained with the LLS in all but 1 case. Forty LLSs were transplanted into 39 children, while 39 ERGs were transplanted into 11 children and 28 adults. RESULTS: Two-year patient and graft survival rates were not significantly different between recipients of donors < or =40 kg and >40 kg, between pediatric and adult recipients, and between recipients of LLSs and ERGs. Vascular complication rates were 12% in the < or =40 kg donor group and 6% in the >40 kg donor group (P = not significant). There were no differences in the incidence of other complications. Donor ICU stay >3 days and the use of an interposition arterial graft were associated with an increased risk of graft loss and arterial complications, respectively. CONCLUSIONS: Splitting of pediatric liver grafts is an effective strategy to increase organ availability, but a cautious evaluation of the use of donors < or =40 kg is necessary. Prolonged donor ICU stay is associated with poorer outcomes. The maintenance of the celiac trunk with LLS does not seem detrimental for right-sided grafts, whereas the use of interposition grafts for arterial reconstruction should be avoided.

Characteristics at presentation and outcome of hepatocellular carcinoma (HCC) in the elderly. A study of the Cancer of the Liver Italian Program (CLIP).

PURPOSE: To describe the characteristics at presentation and the outcome of elderly patients (> or =70 years old) with HCC, a retrospective analysis using a CLIP database was performed. PATIENTS AND METHODS: The database included 650 patients. Chi2-test, logistic and Cox model were applied. RESULTS: Baseline characteristics and stage were similarly among elderly (n=158) and non-elderly (n=492) patients. More elderly patients did not receive any local treatment (56% versus 38%, p<0.0001). Age and CLIP score were independently predictive of the odds of locoregional treatment. Prognosis was worse for elderly patients with a hazard ratio of death of 1.49 (95% CI 1.20-1.86) at multivariable analysis. The survival difference disappeared when patients were compared within each treatment group, suggesting a close link between undertreatment and shorter survival. CONCLUSION: Elderly patients with HCC have a worse prognosis compared to non-elderly ones. Such difference seems the consequence of undertreatment.