Liver transplantation for viral hepatitis in 2015

Liver transplantation(LT) is a life-saving treatment forpatients 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.

Therapeutic approaches for portal biliopathy: A systematic review

Portal biliopathy(PB) is defined as the presence of biliary abnormalities in patients with non-cirrhotic/nonneoplastic 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.

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 posttransplant 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 theimmunological 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.

Invasive fungal infection before and after liver transplantation

Invasive infections are a major complication before liver transplantation(LT)and in the early phase after surgery.There has been an increasing prevalence of invasive fungal disease(IFD),especially among the sickest patients with decompensated cirrhosis and acute-on-chronic liver failure,who suffer from a profound state of immune dysfunction and receive intensive care management.In such patients,who are listed for LT,development of an IFD often worsens hepatic and extra-hepatic organ dysfunction,requiring a careful evaluation before surgery.In the post-transplant setting,the burden of IFD has been reduced after the clinical advent of antifungal prophylaxis,even if several major issues still remain,such as duration,target population and drug type(s).Nevertheless,the development of IFD in the early phase after surgery significantly impairs graft and patient survival.This review outlines presentation,prophylactic and therapeutic strategies,and outcomes of IFD in LT candidates and recipients,providing specific considerations for clinical practice.

Hepatitis C virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: A single-center study

AIM To evaluate waiting list(WL) registration and liver transplantation(LT) rates in patients with hepatitis C virus(HCV)-related cirrhosis since the introduction of direct-acting antivirals(DAAs).METHODS All adult patients with cirrhosis listed for LT at Padua University Hospital between 2006-2017 were retrospectively collected using a prospectivelyupdated database; patients with HCV-related cirrhosis were divided by indication for LT [dec-HCV vs HCV/hepatocellular carcinoma(HCC)] and into two interval times(2006-2013 and 2014-2017) according to the introduction of DAAs. For each patient, indications to LT, severity of liver dysfunction and the outcome in the WL were assessed and compared between the two different time periods. For patients receiving DAA-based regimens, the achievement of viral eradication and the outcome were also evaluated. RESULTS One thousand one hundred and ninty-four [male(M)/female(F): 925/269] patients were included. Considering the whole cohort, HCV-related cirrhosis was the main etiology at the time of WL registration(490/1194 patients, 41%). HCV-related cirrhosis significantly decreased as indication to WL registration after DAA introduction(from 43.3% in 2006-2013 to 37.2% in 2014-2017, P = 0.05), especially amongst decHCV(from 24.2% in 2006-2013 to 15.9% in 2014-2017, P = 0.007). Even HCV remained the most common indication to LT over time(289/666, 43.4%), there was a trend towards a decrease after DAAs introduction(from 46.3% in 2006-2013 to 39% in 2014-2017, P = 0.06). HCV patients(M/F: 43/11, mean age: 57.7 ± 8 years) who achieved viral eradication in the WL had better transplant-free survival(log-rank test P = 0.02) and delisting rate(P = 0.002) than untreated HCV patients. CONCLUSION Introduction of DAAs significantly reduced WL registrations for HCV related cirrhosis, especially in the setting of decompensated cirrhosis.

Rethinking the role of non-selective beta blockers in patients with cirrhosis and portal hypertension

Non-selective beta blockers(NSBB) are commonly used to prevent portal hypertensive bleeding in cirrhotics.Nevertheless, in the last years, the use of NSBB in critically decompensated patients, especially in those with refractory ascites, has been questioned, mainly for an increased risk of mortality and worsening of systemic hemodynamics. Moreover, even if NSBB have been reported to correlate with a higher risk of renal failure and severe infection in patients with advanced liver disease and hypotension, their use has been associated with a reduction of risk of spontaneous bacterial peritonitis, modification of gut permeability and reduction of bacterial translocation. This manuscript systematically reviews the published evidences about harms and benefits of the use of NSBB in patients with decompensated cirrhosis.

Management of bacterial infection in the liver transplant candidate

Bacterial infection(BI) is a common cause of impairment of liver function in patients with cirrhosis, especially in the liver transplant candidates. These patients share an immunocompromised state and increased susceptibility to develop community and hospital-acquired infections. The changing epidemiology of BI, with an increase of multidrug resistant strains, especially in healthcareassociated settings, represents a critical issue both in the waiting list and in the post-operative management. This review focused on the role played by BI in patients awaiting liver transplantation, evaluating the risk of drop-out from the waiting list, the possibility to undergo liver transplantation after recovery from infection or during a controlled infection.

Spontaneous bleeding or thrombosis in cirrhosis: What should be feared the most?

The more modern and accurate concept of a rebalanced hemostatic status in cirrhosis is slowly replacing the traditional belief of patients with cirrhosis being "auto-anticoagulated", prone only to bleeding complications, and protected from thrombotic events. With greater attention to clinical thrombotic events, their impact on the natural history of cirrhosis, and with the emergence and increased use of point-of-care and global assays, it is now understood that cirrhosis results in profound hemostatic alterations that can lead to thrombosis as well as to bleeding complications. Although many clinical decisions are still based on traditional coagulation parameters such as prothrombin(PT), PT, and international normalized ratio, it is increasingly recognized that these tests do not adequately predict the risk of bleeding, nor they should guide pre-emptive interventions. Moreover, altered coagulation tests should not be considered as a contraindication to the use of anticoagulation, although this therapeutic or prophylactic approach is not at present routinely undertaken. Gastroesophageal variceal bleeding continues to be one of the most feared and deadly complications of cirrhosis and portal hypertension, but great progresses have been made in prevention and treatment strategies. Other bleeding sites that are frequently part of end-stage liver disease are similar to clinical manifestations of thrombocytopenia, with gum bleeding and epistaxis being very common but fortunately only rarely a cause of life-threatening bleeding. On the contrary, manifestations of coagulation factor deficiencies like soft tissue bleeding and hemartrosis are rare in patients with cirrhosis. As far as thrombotic complications are concerned, portal vein thrombosis is the most common event in patients with cirrhosis, but venous thromboembolism is not infrequent, and results in important morbidity and mortality in patients with cirrhosis, especially those with decompensated disease. Future studies and the more widespread use of point-ofcare tests in evaluating hemostasis will aid the clinician in decision making when facing the patient with bleeding or with thrombotic complications, with both ends of a continuum being potentially fatal.

Antibiotic prophylaxis in patients with cirrhosis: Current evidence for clinical practice

Patients with cirrhosis show an increased susceptibility to infection due to disease-related immune-dysfunction.Bacterial infection therefore represents a common,often detrimental event in patients with advanced liver disease,since it can worsen portal hypertension and impair the function of hepatic and extrahepatic organs.Among pharmacological strategies to prevent infection,antibiotic prophylaxis remains the first-choice,especially in high-risk groups,such as patients with acute variceal bleeding,low ascitic fluid proteins,and prior episodes of spontaneous bacterial peritonitis.Nevertheless,antibiotic prophylaxis has to deal with the changing bacterial epidemiology in cirrhosis,with increased rates of gram-positive bacteria and multidrug resistant rods,warnings about quinolonesrelated side effects,and low prescription adherence.Short-term antibiotic prophylaxis is applied in many other settings during hospitalization,such as before interventional or surgical procedures,but often without knowledge of local bacterial epidemiology and without strict adherence to antimicrobial stewardship.This paper offers a detailed overview on the application of antibiotic prophylaxis in cirrhosis,according to the current evidence.

Direct-acting antivirals and hepatocellular carcinoma occurrence and recurrence in hepatitis C virus-related liver cirrhosis: fact or fiction

Since the widespread adoption of new direct-acting antiviral agents (DAAs), the approach to hepatitis C virus (HCV) infection has changed profoundly as almost all patients can be cured regardless of the stage of their liver disease. On the other hand, there are a few conflicting reports on the risk of hepatocellular carcinoma (HCC) occurring and recurring in patients given DAA-based therapy. The present review focuses on the latest and most relevant literature providing evidence on the occurrence and recurrence of HCC after HCV antiviral treatment with the new DAAs. Retaining the distinction between HCC occurrence and recurrence, we also discuss its patterns of presentation and speculate on the possible pathogenic mechanisms. We offer our personal viewpoints on this important issue, which has kept clinicians second-guessing in real-world clinical practice, when dealing with HCV eradication in the setting of advanced liver disease in this interferon-free era.