A. Ferrarese

Risk factors for central pontine and extrapontine myelinolysis after liver transplantation: A single-center study

Background Central pontine and extrapontine myelinolysis (CPM/EPM) are severe neurologic complications after liver transplantation. Methods The present work retrospectively evaluated single-center prevalence of CPM/EPM and associated risk factors: cause of liver disease, hepatic encephalopathy, preoperative, intraoperative, and perioperative blood components use, serum levels, and variation of Na+, Cl−, and K+ and immunosuppression were compared between CPM/EPM patients and control group of transplanted patients without neurologic complications. Results Among 997 transplants, CPM/EPM were diagnosed in 11 patients (1.1%), of whom four were CPM, one was EPM, and six were associated CPM and EPM. Control group consisted of 44 transplanted patients. Central pontine and extrapontine myelinolysis patients experienced higher intraoperative and perioperative serum Na+/24 hr variations compared to controls (16.69±5.17 vs. 9.8±3.4 mEq/L, P = 0.001). Maximum peak of intraoperative or perioperative serum Na+ was significantly higher in patients compared to controls (151.5±3.3 vs. 140.8±6.2 mEq/L, P⩽0.001), but no difference in preoperative serum Na+ was detected. Three patients presented hypernatremia as isolated risk factor. Conclusion Extrapontine myelinolysis can be found isolated or associated with CPM in up to two of three liver transplanted patients with myelinolysis. A marked variation of perioperative serum Na+ remains the main risk factor even in patients without preexisting hyponatremia; however, isolated hypernatremia may be solely responsible in some cases.

Markers of acute rejection and graft acceptance in liver transplantation

The evaluation of the immunosuppression state in liver transplanted patients is crucial for a correct post-transplant management and a major step towards the personalisation of the immunosuppressive therapy. However, current immunological monitoring after liver transplantation relies mainly on clinical judgment and on immunosuppressive drug levels, without a proper assessment of the real suppression of the immunological system. Various markers have been studied in an attempt to identify a specific indicator of graft rejection and graft acceptance after liver transplantation. Considering acute rejection, the most studied markers are pro-inflammatory and immunoregulatory cytokines and other proteins related to inflammation. However there is considerable overlap with other conditions, and only few of them have been validated. Standard liver tests cannot be used as markers of graft rejection due to their low sensitivity and specificity and the weak correlation with the severity of histopathological findings. Several studies have been performed to identify biomarkers of tolerance in liver transplanted patients. Most of them are based on the analysis of peripheral blood samples and on the use of transcriptional profiling techniques. Amongst these, NK cell-related molecules seem to be the most valid marker of graft acceptance, whereas the role CD4+CD25+Foxp3+ T cells has still to be properly defined.

Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus–infected patients treated with direct‐acting antivirals

Concerns about an increased hepatocellular carcinoma (HCC) recurrence rate following direct‐acting antiviral (DAA) therapy in patients with cirrhosis with a prior complete oncological response have been raised. Data regarding the impact of HCV treatment with DAAs on wait‐list dropout rates in patients with active HCC and HCV‐related cirrhosis awaiting liver transplantation (LT) are lacking. HCV‐HCC patients listed for LT between January 2015 and May 2016 at Padua Liver Transplant Center were considered eligible for the study. After enrollment, patients were divided into 2 groups, depending on whether they underwent DAA treatment while awaiting LT or not. For each patient clinical, serological, and virological data were collected. HCC characteristics were radiologically evaluated at baseline and during follow‐up (FU). For transplanted patients, pathological assessment of the explants was performed and recurrence rates were calculated. A total of 23 patients treated with DAAs and 23 controls were enrolled. HCC characteristics at time of LT listing were comparable between the 2 groups. Median FU was 10 and 7 months, respectively, during which 2/23 (8.7%) and 1/23 (4.3%) dropout events due to HCC progression were registered (P = 0.90). No significant differences in terms of radiological progression were highlighted (P = 0.16). A total of 9 out of 23 (39%) patients and 14 out of 23 (61%) controls underwent LT, and histopathological analysis showed no differences in terms of median number and total tumor volume of HCC nodules, tumor differentiation, or microvascular invasion. During post‐LT FU, 1/8 (12.5%) DAA‐treated patient and 1/12 (8.3%) control patient experienced HCC recurrence (P = 0.60). In conclusion, viral eradication does not seem to be associated with an increased risk of dropout due to neoplastic progression in HCV‐HCC patients awaiting LT. Liver Transplantation 23 1103–1112 2017 AASLD.

Liver transplantation for viral hepatitis in 2015

Liver transplantation (LT) is a life-saving treatment for patients with end-stage liver disease and for patients with liver cell cancer related to liver disease. Acute and chronic liver diseases related to hepatitis viruses are between the main indications for liver transplantation. The risk of viral reinfection after transplantation is the main limiting factor in these indications. Before the availability of antiviral prophylaxis, hepatitis B virus (HBV) recurrence was universal in patients who were HBV DNA-positive before transplantation. The natural history of recurrent HBV was accelerated by immunosuppression, and it progressed rapidly to graft failure and death. Introduction of post-transplant prophylaxis with immunoglobulin alone first, and associated to antiviral drugs later, drastically reduced HBV recurrence, resulting in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Overall, patient and graft survival after LT for hepatitis C virus (HCV)-associated cirrhosis is inferior compared with other indications. However, successful pretransplant or post transplant antiviral therapy has been associated with increased graft and overall survival. Until recently, the combination of pegylated interferon and ribavirin was the standard of care for the treatment of patients with chronic hepatitis C. Highly active antiviral compounds have been developed over the past decade, thanks to new in vitro systems to study HCV entry, replication, assembly, and release.

Obliterative portal venopathy without portal hypertension: an underestimated condition.

Obliterative portal venopathy without portal hypertension has been described by a single study in a limited number of patients, thus very little is known about this clinical condition. This study aimed to investigate the prevalence of obliterative portal venopathy and its clinical‐pathological correlations in patients with cryptogenic chronic liver test abnormalities without clinical signs of portal hypertension.

Current challenges and future directions for liver transplantation.

Liver transplantation is an effective and widely used therapy for several patients with acute and chronic liver diseases. The discrepancy between the number of patients on the waiting list and available donors remains the key issue and is responsible for the high rate of waiting list mortality. The recent news is that the majority of patients with hepatitis C virus related liver disease will be cured by new antivirals therefore we should expect soon a reduction in the need of liver transplantation for these recipients. This review aims to highlight, in two different sections, the main open issues of liver transplantation concerning the current and future strategies to the best use of limited number of organs. The first section cover the strategies to increase the donor pool, discussing the use of older donors, split grafts, living donation and donation after cardiac death and mechanical perfusion systems to improve the preservation of organs before liver transplantation. Challenges in immunosuppressive therapy and operational tolerance induction will be evaluated as potential tools to increase the survival in liver transplant recipients and to reducing the need of re‐transplantation. The second section is devoted to the evaluation of possible new indications to liver transplantation, where the availability of organs by implementing the strategies mentioned in the first section and the reduction in the number of waiting transplants for HCV disease is realized. Among these new potential indications for transplantation, the expansion of the Milan criteria for hepatocellular cancer is certainly the most open to question.

Beta-blockers in cirrhosis: Therapeutic window or an aspirin for all?

To the Editor: We have read with interest the review article by Ge and Runyon on the changing role of non-selective b-blockers (NSBBs) in cirrhosis [1]. Their role in reduction of portal hypertension is accomplished by lowering portal inflow (b1 blockade) and inducing splanchnic vasoconstriction (b2 blockade). Risk of variceal bleeding correlates also with other factors, i.e., infections and severity of liver dysfunction, suggesting absence of a pure mechanical model. For this reason, patients with more severe disease (Child-Pugh Class C) should undergo primary prophylaxis even in the presence of small varices [2]. In this paper, the authors suggested a ‘‘window hypothesis’’, also supported by Krag and co-authors [3], according to which NSBBs are beneficial only in decompensated patients with medium-large varices but not in patients with early or end-stage cirrhosis with refractory ascites. Their recommendation on patients with refractory ascites is mainly based on data from a study performed by Serstè and collaborators, which showed that mortality in patients with refractory ascites was increased in those taking NSBBs. The same group hypothesized that b-blockade could induce counter-regulatory over-activation of the Renin-AngiotensinAldosterone axis, increasing incidence of paracentesis-induced circulatory dysfunction, which could be associated with impaired renal function and reduced survival [4,5]. These data were not confirmed by another study on patients with ascites taking propranolol [6]; moreover, by analyzing all published randomized controlled trials on prophylaxis for variceal hemorrhage, bleeding unrelated mortality was similar between patients on NSBBs and those treated with other therapies in primary (277/955 vs. 287/1175; OR 0.91 95% CI 0.73 to 1.15) and secondary prophylaxis (188/1143 vs. 225/1208; OR 0.87 95% CI 0.68 to 1.12) without heterogeneity amongst studies, while causes of death were not different between patients on and off NSBBs therapy. These results were confirmed in the subgroup analysis of studies with higher prevalence of ascites (>50%) [7]. Moreover the dose of propranolol should be further investigated as a potential factor associated with increased mortality; for instance, in the French study, high propranolol doses (mean 132 mg/day) could have contributed to altered haemodynamics [8]. Furthermore, chronotropic and inotropic negative effect by NSBBs may reduce cardiac function in patients with more severe cirrhotic cardiomyopathy or new onset of sepsis. For instance, we admitted a patient with alcoholic cirrhosis on the waiting list for liver transplantation who developed spontaneous bacterial peritonitis and sepsis and required large volume paracentesis (LVP); systemic vascular resistances were severely reduced at baseline in respect of previous procedures, and at the end of LVP there was a further reduction of 31.2%; notwithstanding, a counterbalancing increase of cardiac output to 12.9 L/m (+30.9%) prevented development of hepatorenal syndrome after LVP.

Hepatitis C virus infection in end-stage renal disease and kidney transplantation.

Liver disease secondary to chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in patients with end‐stage renal disease (ESRD) on renal replacement therapy and after kidney transplantation (KT). Hemodialytic treatment (HD) for ESRD constitutes a risk factor for bloodborne infections because of prolonged vascular access and the potential for exposure to infected patients and contaminated equipment. Evaluation of HCV‐positive/ESRD and HCV‐positive/KT patients is warranted to determine the stage of disease and the appropriateness of antiviral therapy, despite such treatment is challenging especially due to tolerability issues. Antiviral treatment with interferon (IFN) is contraindicated after transplantation due to the risk of rejection, and therefore, treatment is recommended before KT. Newer treatment strategies of direct‐acting antiviral agents in combination are revolutionizing HCV therapy, as a result of encouraging outcomes streaming from recent studies which report increased sustained viral response, low or no resistance, and good safety profiles, including preservation of renal function. KT has been demonstrated to yield better outcomes with respect to remaining on HD although survival after KT is penalized by the presence of HCV infection with respect to HCV‐negative transplant recipients. Therefore, an appropriate, comprehensive, easily applicable set of clinical practice management guidelines is necessary in both ESRD and KT patients with HCV infection and HCV‐related liver disease.

Thromboelastometry hypercoagulable profiles and portal vein thrombosis in cirrhotic patients with hepatocellular carcinoma

BACKGROUND Cirrhotic patients with hepatocellular carcinoma (HCC) exhibit hypercoagulability. AIM We investigated whether thromboelastometry can detect hypercoagulability in these patients and the association with portal vein thrombosis (PVT). METHODS At baseline, cirrhotic patients with and without HCC underwent thromboelastometry. PVT onset was recorded over a 12-month follow-up period. RESULTS Seventy-six patients (41 with and 35 without HCC) were included. Vital tumor volume (VTV) was  >5cm3 in 18 patients. Fibrinogen was higher in HCC patients with VTV>5cm3 as compared to those with VTV≤5cm3 and those without HCC. Mean platelet count was significantly increased in HCC patients compared with non-HCC. At baseline thromboelastometry, HCC patients showed shorter CTF and higher MCF than non-HCC. PVT incidence was 24,4% and 11.4% in patients with (10/41) and without (4/35) HCC, respectively. Among HCC, 50% of PVT occurred in Child A patients. In HCC, FIBTEM MCF>25mm was associated with a 5-fold increased PVT risk [RR: 4.8 (2-11.3); p=0.0001]. Cox multivariate analysis confirmed HCC and increased MCF (FIBTEM) to be independently associated with increased PVT risk. CONCLUSIONS Hypercoagulability in HCC which can be detected by thromboelastometry is associated with increased risk of PVT even in Child A patients. The clinical implication of these findings deserves further investigation.

Therapeutic approaches for portal biliopathy: A systematic review

Portal biliopathy (PB) is defined as the presence of biliary abnormalities in patients with non-cirrhotic/non-neoplastic extrahepatic portal vein obstruction (EHPVO) and portal cavernoma (PC). The pathogenesis of PB is due to ab extrinseco compression of bile ducts by PC and/or to ischemic damage secondary to an altered biliary vascularization in EHPVO and PC. Although asymptomatic biliary abnormalities can be frequently seen by magnetic resonance cholangiopancreatography in patients with PC (77%-100%), only a part of these (5%-38%) are symptomatic. Clinical presentation includes jaundice, cholangitis, cholecystitis, abdominal pain, and cholelithiasis. In this subset of patients is required a specific treatment. Different therapeutic approaches aimed to diminish portal hypertension and treat biliary strictures are available. In order to decompress PC, surgical porto-systemic shunt or transjugular intrahepatic porto-systemic shunt can be performed, and treatment on the biliary stenosis includes endoscopic (Endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy, balloon dilation, stone extraction, stent placement) and surgical (bilioenteric anastomosis, cholecystectomy) approaches. Definitive treatment of PB often requires multiple and combined interventions both on vascular and biliary system. Liver transplantation can be considered in patients with secondary biliary cirrhosis, recurrent cholangitis or unsuccessful control of portal hypertension.