Mortality from chronic liver disease:Recent trends and impact of the COVID-19 pandemic

Prepandemic time trends in mortality from chronic liver disease(CLD)differed according to specific cause of death(decreasing for liver cirrhosis,stable or increasing for liver cancer),etiology(increasing for nonalcoholic fatty liver disease,generally decreasing for other etiologies),and world region(decreasing in areas with the highest burden of hepatitis B virus,increasing in Eastern Europe and other countries).The coronavirus disease 2019(COVID-19)pandemic affected mortality of patients with CLD both directly,with a higher risk for severe illness and death depending on age,stage and etiology of the disease,and indirectly,through social isolation and loss of support,harmful drinking,and difficulties in access to care.Nevertheless,only sparse data are available on variations in CLD as a cause of death during the pandemic.In the USA,in 2020-2021 a growth in mortality was registered for all liver diseases,more marked for alcoholic liver disease,especially among young people aged 25-44 years and in selected ethnic groups.COVID-19 related deaths accounted only for a minor part of the excess.Further data from mortality registers of other countries are warranted,preferably adopting the so-called multiple cause-of-death approach,and extended to deaths attributed to viral hepatitis and liver cancer.

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.

Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease

Hepatitis B virus(HBV) infection is a dynamic state ofinteractions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B(CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma(HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation.

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.

Long term follow-up and outcome of liver transplantation from hepatitis B surface antigen positive donors

Liver transplant for hepatitis B virus(HBV) currently yields excellent outcomes: it allows to rescue patients with an HBV-related advanced liver disease, resulting in a demographical modification of the waiting list for liver transplant. In an age of patient-tailored treatments, in liver transplantation as well the aim is to offer the best suitable graft to the patient who can benefit from it, also expanding the criteria for organ acceptance and allocation. With the intent of developing strategies to increase the donor pool, we set-up a multicenter study involving 3 Liver Transplant Centers in Italy: patients undergoing liver transplantation between March 03, 2004, and May 21, 2010, were retrospectively evaluated. 1408 patients underwent liver transplantation during the study period, 28(2%) received the graft from hepatitis B surface antigen positive(HBs Ag)-positive deceased donors. The average follow-up after liver transplantation was 63.7 mo [range: 0.1-119.4; SD ± 35.8]. None Primary nonfunction, re-liver transplantation, early or late hepatic artery thrombosis occurred. The 1-, 3-and 5-year graft and patient survival resulted of 85.7%, 82.1%, 78.4%. Our results suggest that the use of HBs Agpositive donors liver grafts is feasible, since HBV can be controlled without affecting graft stability. However, the selection of grafts and the postoperative antiviral therapy should be managed appropriately.

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.

Prevalence of celiac disease in adult patients with refractory functional dyspepsia:Value of routine duodenal biopsy

AIM: To investigate the prevalence of celiac disease (CD) in adult patients referred to an open access gas-troenterology clinic in the south of Italy and submitted to esophago-gastro-duodenoscopy (EGD) for evaluation of refractory functional dyspepsia.METHODS: Seven hundred and twenty six consecutive dyspeptic patients (282 male, 444 female; mean age 39.6 years, range 18-75 years) with unexplained prolonged dyspepsia were prospectively enrolled. Duo-denal biopsies were taken and processed by standard staining. Histological evaluation was carried out according to the Marsh-Oberhuber criteria.RESULTS: The endoscopic findings were: normal in 61.2%, peptic lesions in 20.5%, malignancies in 0.5%, miscellaneous in 16.7%. CD was endoscopically diagnosed in 8 patients (1.1%), histologically in 15 patients (2%). The endoscopic features alone showed a sensitivity of 34.8% and specificity of 100%, with a positive predictive value (PPV) of 100% and a negative predictive value (NPP) of 97.9%.CONCLUSION: This prospective study showed that CD has a high prevalence (1:48) in adult dyspeptic patients and suggests the routine use of duodenal biopsy in this type of patient undergoing EGD.

Therapeutic application of stem cells in gastroenterology:An up-date

Adult stem cells represent the self-renewing progenitors of numerous body tissues, and they are currently classified according to their origin and differentiation ability. In recent years, the research on stem cells has expanded enormously and holds therapeutic promises for many patients suffering from currently disabling diseases. This paper focuses on the possible use of stem cells in the two main clinical settings in gastro-enterology, i.e., hepatic and intestinal diseases, which have a strong impact on public health worldwide. Despite encouraging results obtained in both regenerative medicine and immunemediated conditions,further studies are needed to fully understand the biology of stem cellsand carefully assess their put ativeonco- genicproperties.Moreover,there searchonstemcellsarousesferventethical,socialandpoliticaldebate.TheItalianSocietyofGastroenterologysponsoredaworkshoponstemcellsheldinVeronaduringtheⅩⅥCongressoftheFederationofItalianSocietiesofDigestiveDiseases(March 6-9,2010).Here,we report on the issues discussed,including liver and intestinal diseases that may benefit from stemcell therapy,the biology of hepatic and intestinal tissue repair,and stem cell usage inclinical trials.

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.

HCV clearance by direct antiviral therapy and occurrence/recurrence of hepatocellular carcinoma:still an issue?

New regimens with direct-acting antivirals (DAAs) agents have changed both efficacy and safety of hepatitis C virus (HCV)-treatment, as almost all patients can be treated and cured at any stage of liver disease. The rates of sustained virological response to currently available combinations exceed 95% in real-life practice. However, conflicting results have been produced on the occurrence/recurrence of hepatocellular carcinoma (HCC) in patients with HCV-associated cirrhosis treated with DAAs. In this review we analyse the data available in the literature in order to elucidate the impact of DAAs on the risk of HCC occurrence in patients without previous history of tumor, and of recurrence after successful treatment of the tumor. Data on 'de novo' HCC incidence were quite homogeneous, suggesting that the treatment with DAAs does not modify the risk of HCC developing during the first 6-12 months after HCV eradication. On the contrary, HCC recurrence rates after DAAs were extremely variable across different studies, reflecting a large heterogeneity in this clinical setting. The possibility that treatment with DAAs may favour tumour growth and spread in individual patients with active HCC foci is supported by some observations but remains unproven.

Role of antiviral therapy in patients with chronic hepatitis B or C virus in preventing the development of hepatocellular carcinoma

Patients with chronic hepatitis B virus(HBV)and hepatitis C virus(HCV)infection are at significant risk for hepatocellular carcinoma(HCC).The most important risk factor associated with HCC is liver cirrhosis,which is again predominantly caused by chronic HBV or HCV infection.The most effective approach to avoid HCC development is to prevent HBV and HCV infection through vaccination.Indeed,HBV vaccine is the first vaccine demonstrated to prevent cancers.However,a vaccine for HCV is not available.Thus,the prevention of HCV-related HCC and to a large extent HBV-related HCC(among persons who are already chronically infected)will rely on antiviral therapy to prevent progressive liver disease.The evidence that these patients can effectively be protected against HCC risk by the treatment with antiviral therapy is rather controversial,due to the lack of randomized controlled trials(RCTs)that are ideally needed to establish the effi cacy,but are logistically and ethically challenging.Although the strongest evidence to support that antiviral therapy can prevent HCC should be derived from RCTs with HCC as an endpoint,it should be emphasized that clinical trials showing the efficacy of antiviral therapy on virus suppression or eradication,and/or improvement in liver histology can be considered indirect evidence that antiviral therapy can prevent HCC because high virus levels(in the case of HBV infection)and cirrhosis(in both HBV and HCV infection)are the most important risk factors for HCC.