NLRP3 Inflammasome in Acute and Chronic Liver Diseases.

NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is an intracellular complex that upon external stimuli or contact with specific ligands, recruits other components, forming the NLRP3 inflammasome. The NLRP3 inflammasome mainly mediates pyroptosis, a highly inflammatory mode of regulated cell death, as well as IL-18 and IL-1ß production. Acute and chronic liver diseases are characterized by a massive influx of pro-inflammatory stimuli enriched in reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs) that promote the assemblage and activation of the NLRP3 inflammasome. As the major cause of inflammatory cytokine storm, the NLRP3 inflammasome exacerbates liver diseases, even though it might exert protective effects in regards to hepatitis C and B virus infection (HCV and HBV). Here, we summarize the current knowledge concerning NLRP3 inflammasome function in both acute and chronic liver disease and in the post liver transplant setting, focusing on the molecular mechanisms involved in NLRP3 activity.

Evolution of Liver Transplantation Indications: Expanding Horizons.

Liver transplantation (LT) has significantly transformed the prognosis of patients with end-stage liver disease and hepatocellular carcinoma (HCC). The traditional epidemiology of liver diseases has undergone a remarkable shift in indications for LT, marked by a decline in viral hepatitis and an increase in metabolic dysfunction-associated steatotic liver disease (MASLD), along with expanded indications for HCC. Recent advancements in surgical techniques, organ preservation and post-transplant patients' management have opened new possibilities for LT. Conditions that were historically considered absolute contraindications have emerged as potential new indications, demonstrating promising results in terms of patient survival. While these expanding indications provide newfound hope, the ethical dilemma of organ scarcity persists. Addressing this requires careful consideration and international collaboration to ensure equitable access to LT. Multidisciplinary approaches and ongoing research efforts are crucial to navigate the evolving landscape of LT. This review aims to offer a current overview of the primary emerging indications for LT, focusing on acute-on-chronic liver failure (ACLF), acute alcoholic hepatitis (AH), intrahepatic and perihilar cholangiocarcinoma (i- and p-CCA), colorectal liver metastasis (CRLM), and neuroendocrine tumor (NET) liver metastases.

Immunosuppression for older liver transplant recipients.

Older liver transplant recipients have a lower risk of acute rejection than younger patients (9% for patients aged ≥65 years versus 23% for those aged 18-34 years) and are more vulnerable to immunosuppression-related complications. The number of liver transplant recipients ≥65 years has risen to 22% in Europe and the US, but limited information is available on the optimal immunosuppressive regimen for these patients. In this review, we discuss the appropriate management of immunosuppressive agents in older adults to minimize adverse events while avoiding acute rejection. The way the body processes drugs greatly depends on age. In the case of calcineurin inhibitor drugs, aging reduces hepatic metabolism, leading to changes in their pharmacokinetics. Corticosteroids also show decreased clearance as the patient ages. In severe cases of hypoalbuminemia, dose adjustment of mycophenolate acid derivatives may be necessary. However, the pharmacokinetic profiles of the mammalian target of rapamycin inhibitors, basiliximab, and rabbit anti-thymocyte globulin remain unaffected by age. Furthermore, age-related frailty may impact drug metabolism and require tailored interventions and closer follow-up. Although there is limited research, elderly liver transplant recipients require less immunosuppression with double or triple-agent regimens, lower exposure to calcineurin inhibitors, and a shorter course of corticosteroids. The usage of mammalian target of rapamycin inhibitors in older transplant populations has not been specifically investigated, and thus their usage should align with indications for younger patient groups.

Long-Term Impact of Direct-Acting Antivirals on Liver Fibrosis and Survival in HCV-Infected Liver Transplant Recipients.

(1) Background: Little is known about the long-term impact of sustained virological response (SVR) on fibrosis progression and patient survival in liver transplantation (LT) recipients treated with direct-acting antivirals (DAAs). We investigated liver fibrosis evolution and patient survival in hepatitis C virus (HCV)-infected patients receiving DAAs after LT. (2) Methods: All consecutive HCV-infected patients treated with DAAs after LT between May 2014 and January 2019 were considered. The clinical and virological features were registered at the baseline and during the follow-up. The liver fibrosis was assessed by liver biopsy and/or transient elastography (TE) at the baseline and at least 1 year after the end of treatment (EoT). (3) Results: A total of 136 patients were included. The SVR12 was 78% after the first treatment and 96% after retreatment. After the SVR12, biochemical tests improved at the EoT and remained stable throughout the 3-year follow-up. Liver fibrosis improved after the SVR12 (p < 0.001); nearly half of the patients with advanced liver fibrosis experienced an improvement of an F ≤ 2. The factors associated with lower survival in SVR12 patients were the baseline platelet count (p = 0.04) and creatinine level (p = 0.04). (4) Conclusions: The long-term follow-up data demonstrated that SVR12 was associated with an improvement in hepatic function, liver fibrosis, and post-LT survival, regardless of the baseline liver fibrosis. The presence of portal hypertension before the DAAs has an impact on patient survival, even after SVR12.

The Role of Antiviral Prophylaxis in Preventing HBV and HDV Recurrence in the Setting of Liver Transplantation.

Hepatitis B virus (HBV) is a prevalent underlying disease, leading to liver transplantation (LT) for both decompensated cirrhosis and hepatocellular carcinoma (HCC). The hepatitis delta virus (HDV) affects approximately 5-10% of HBsAg carriers, accelerating the progression of liver injury and HCC. The initial introduction of HBV immunoglobulins (HBIG), and then of nucleos(t)ide analogues (NUCs), considerably improved the survival of HBV/HDV patients post-transplantation, as they helped prevent re-infection of the graft and recurrence of liver disease. Combination therapy with HBIG and NUCs is the primary post-transplant prophylaxis strategy in patients transplanted for HBV- and HDV-related liver disease. However, monotherapy with high-barrier NUCs, such as entecavir and tenofovir, is safe and also effective in some individuals who are at low risk of HBV reactivation. To address the problems of organ shortage, last-generation NUCs have facilitated the use of anti-HBc and HBsAg-positive grafts to meet the ever-increasing demand for grafts.

Glecaprevir/Pibrentasvir is safe and effective in Italian patients with chronic hepatitis C aged 75 years or older: A multicentre study.

BACKGROUND: Glecaprevir and Pibrentasvir (G/P) determine high rates of sustained virological response (SVR) with optimal safety profile in patients with chronic hepatitis C virus (HCV) infection. The efficacy and safety of G/P in Caucasian patients aged 75 years and older have not been widely analysed. METHODS: This is a retrospective multicentre real-world study enrolling all consecutive patients 75 years and older who received G/P between October 2017 and January 2022 at five referral centres in Italy. SVR was analysed by intention-to-treat (ITT) and per-protocol analyses (PP). RESULTS: A total of 570 patients met the inclusion criteria and were analysed: mean age was 80 (75-97) years, 356 (62%) were females, 52% (298/570) had HCV-1, 44% (252/570) had HCV-2 and 137 (24%) patients had liver cirrhosis. Four hundred and sixty-three (81%) patients were taking at least one concomitant drug, with 144 (25%) taking ≥5 concomitant drugs. G/P was given for 8 weeks in 488 patients (86%). During treatment, 48 patients (8%) reported side effects, with 10 (2%) patients discontinuing treatment prematurely. Two patients developed treatment-unrelated serious adverse events. Overall, the SVR rate was 97.9% (558/570) by ITT analysis and 99.6% (558/560) by PP analysis. SVR rates remained consistently high among subgroup analysis stratified by genotype, treatment duration, fibrosis stage and concomitant medications. CONCLUSIONS: Treatment with G/P achieved 97.9% SVR rates in HCV patients older than 75 years of age. Safety was optimal with only 2% of patients discontinuing early.

Changings and Challenges in Liver Transplantation for Nonalcoholic Fatty Liver Disease/Steatohepatitis.

Liver transplantation for nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is increasing rapidly worldwide. Compared with alcohol and viral-related liver disease, NAFLD/NASH is more frequently associated with a systemic metabolic syndrome, which significantly affects other organs, requiring multidisciplinary management, in all phases of liver transplant.

Liver transplantation for non-alcoholic fatty liver disease: indications and post-transplant management.

Non-alcoholic fatty liver disease (NAFLD) is currently the fastest growing indication to liver transplantation (LT) in Western Countries, both for end stage liver disease and hepatocellular carcinoma. NAFLD/non-alcoholic steatohepatitis (NASH) is often expression of a systemic metabolic syndrome; therefore, NAFLD/NASH patients require a multidisciplinary approach for a proper pre-surgical evaluation, which is important to achieve a post-transplant outcome comparable to that of other indications to LT. NAFLD/NASH patients are also at higher risk of post-transplant cardiovascular events, diabetes, dyslipidemia, obesity, renal impairment and recurrent NASH. Lifestyle modifications, included diet and physical activity, are key to improve survival and quality of life after transplantation. A tailored immunosuppressive regimen may be proposed in selected patients. Development of new drugs for the treatment of recurrent NASH is awaited.

Nash Up, Virus Down: How the Waiting List Is Changing for Liver Transplantation: A Single Center Experience from Italy.

Background and Objectives: Non-alcoholic steatohepatitis (NASH) has become the leading indication for liver transplantation in many countries, with a growing rate in the Western world. NASH patients are older and share a higher risk of comorbidities and cancer than patients with viral and/or alcoholic etiologies. The aims of this study were to evaluate waiting list (WL) registration and liver transplantation rates in patients with NASH-related cirrhosis at Padua University Hospital in the last fifteen years (1.2006-6.2020) and to compare clinical characteristics and indications for liver transplantation between patients with and without NASH, as well as the WL survival and post-transplant outcome. Materials and Methods: All adult patients with cirrhosis listed for liver transplantation at Padua University Hospital between 1.2006 and 6.2020 were retrospectively collected using a prospectively updated database; patients with NASH-related cirrhosis were divided by indication for liver transplantation (Dec-NASH vs. hepatocellular carcinoma (HCC)-NASH) and compared with patients with other etiologies of liver disease. The outcomes in terms of waiting list survival and post-transplant outcome were assessed. Results: One thousand four hundred and ninety-one adult cirrhotic patients were waitlisted during the study period. NASH patients accounted for 12% of all WL registrations, showing an increasing trend over time (from 2.5% in 2006 to 23% in 2020). In the last five years, NASH was the third, but most rapidly growing, indication for liver transplantation at our center. This trend was confirmed both for patients with decompensated cirrhosis (from 1.8% to 18%) and HCC as leading indication for transplantation (from 4% to 30%). NASH patients were older than non-NASH ones (mean ± SD age 59 ± 9 vs. 56 ± 9 years; p < 0.01), whereas no difference was found in gender or Child-Pugh of the model for end-stage liver disease score at WL registration. A majority (60.9%) of NASH patients underwent liver transplantation, showing 1-, 5- and 10-y post-transplant survivals of 86%, 73% and 60%, respectively. Conclusion: NASH cirrhosis has become a rapidly growing indication for liver transplantation at our center, both for HCC and decompensated disease, with good post-transplant survival.

Hepatocellular Carcinoma in Chronic Viral Hepatitis: Where Do We Stand?

Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in "high-risk" patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient's risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.

Malnourished cirrhotic patient: what should we do?

Malnutrition and sarcopenia have a high prevalence in cirrhotic patients. Frailty generally overlaps with malnutrition and sarcopenia in cirrhosis, leading to increased morbidity and mortality. Rapid nutritional screening assessment should be performed in all patients with cirrhosis, and more specific tests for sarcopenia should be performed in those at high risk. The pathogenesis of malnutrition in cirrhosis is complex and multifactorial and it is not just due to reduction in protein and calorie intake. Nutritional management in malnourished patients with cirrhosis should be undertaken by a multidisciplinary team to achieve adequate protein/calorie intake. While the role of branched-chained amino acids remains somewhat contentious in achieving a global benefit of decreasing mortality- and liver-related events, these latter and vitamin supplements, are recommended for those with advanced liver disease. Novel strategies to reverse sarcopenia such as hormone supplementation, long-term ammonia-lowering agents and myostatin antagonists, are currently under investigation. Malnutrition, sarcopenia and frailty are unique, inter-related and multidimensional problems in cirrhosis which require special attention, prompt assessment and appropriate management as they significantly impact morbidity and mortality.

Current and future perspective on targeted agents and immunotherapies in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide. HCC occurs predominantly in patients with underlying chronic liver disease and cirrhosis, and it presents a poor prognosis in advanced stage. Since its approval, for the following 10 years, sorafenib remained the only systemic agent with proven clinical efficacy for patients with advanced HCC. Recently, more drugs have been studied and several advances in first­line and second­line treatment options should yield significant improvements in survival. Lenvatinib, another tyrosine­kinase inhibitor, was found to be non-inferior to sorafenib in terms of overall survival (OS), with significantly better progression-free survival and objective response rate (ORR). The tyrosinekinase inhibitors, regorafenib and cabozantinib, were shown to significantly improve survival in the second­line setting after sorafenib failure. Ramucirumab, a VEGF inhibitor, can also improve survival in the second­line setting among patients with AFP≥400 ng/dL. Moreover, good efficacy was seen in phase I/II trials of immune checkpoint inhibitors as monotherapy. Ongoing trials are evaluating combination immune checkpoint inhibitor and tyrosine­kinase inhibitors or VEGF inhibitors for increasing overall survival in this patient population with advanced HCC.

Hepatocellular carcinoma risk in patients with HBV-related liver disease receiving antiviral therapy.

Hepatitis B virus (HBV) is a major health problem worldwide, with approximatively 240 million people living with a chronic HBV infection. HBV chronic infection remains the major cause of hepatocellular carcinoma worldwide, with more than half of HCC patients being chronic HBV carriers, even if underlying mechanisms of tumorigenesis are not totally understood. HBV-related HCC can be prevented by reducing the exposure to HBV by vaccination or by treatment of CHB infection. Current treatment of CHB are Peg-IFN alpha and oral NUCs. Treating HBV infection, either with IFN or NUCs, substantially reduces the risk of HCC development, even if antiviral therapy fails to completely eliminate HCC risk. Among treated patients, cirrhosis, HBeAg negative at baseline and failure to remain in virological remission were associated with an increased risk of HCC. The reduction of the risk of developing HCC during antiviral therapy is largely dependent upon the maintenance of virological remission, since viral load is found to be the most important factor leading to cirrhosis and its complications, including liver cancer development. The question whether Peg-IFN-alpha is superior to NUCs and whether there is a superior agent among NUCs is still controversial. Several studies demonstrated that antiviral therapy with NUCs could reduce the risk of HCC recurrence after curative treatment of HBV-related HCC.

Drug induced liver injury: from pathogenesis to liver transplantation.

Drug induced liver injury (DILI) is a necro-inflammatory liver disease caused by several drugs commonly used in clinical practice, herbs and dietary supplements prescribed for medical purposes. Despite its rarity, it represents the major cause of acute liver failure (ALF) requiring liver transplantation in USA and its frequency is increasing in Europe too. Two types of drug induced liver injury have been recognized: intrinsic and idiosyncratic. Predisposing factors may be classified in environmental, drugs- and individual- related risk factors, with the latter further distinguished in genetics and non-genetics. The liver injury can present with a hepatocellular, cholestatic or mixed pattern of disease. A definitive diagnosis of DILI is, nowadays, one of the main challenging issue in the management of these patients. Diagnosis often is based on suspicion derived from clinical history, biochemical exams and eventually on histological examination from liver biopsy. Score system may be helpful in these setting and new markers are gaining more prominence. Evaluation for liver transplantation is indicated when spontaneous resolution does not occur or in cases of ALF. Overall, the 1-year survival rate following liver transplantation is lower than that seen in patients who have been transplanted for chronic liver failure; however long-term survival is higher compared to other indications.

Management of portal hypertension severe complications.

Portal hypertension is a clinical syndrome characterized by an increase in the portal pressure gradient, defined as the gradient between the portal vein at the site downstream of the site of obstruction and the inferior vena cava. The most frequent cause of portal hypertension is cirrhosis. In patients with cirrhosis, portal hypertension is the main driver of cirrhosis progression and development of hepatic decompensation (ascites, variceal hemorrhage and hepatic encephalopathy), which defines the transition from compensated to decompensated stage. In decompensated patients, treatments aim at lowering the risk of death by preventing further decompensation and/or development of acute-on-chronic liver failure. Decompensated patients often pose a complex challenge which typically requires a multidisciplinary approach. The aims of the present review were to discuss the current knowledge regarding interventional treatments for patients with portal hypertension complications as well as to highlight useful information to aid hepatologists in their clinical practice. Specifically, we discussed the indications and contraindications of transjugular intra-hepatic portosystemic shunt and for the treatment of gastro-esophageal variceal hemorrhage in patients with decompensated cirrhosis (first section); we reviewed the use of interventional treatments in patients with hepatic vein obstruction (Budd-Chiari Syndrome) and in those with portal vein thrombosis (second section); and we briefly comment on the most frequent applications of selective splenic embolization in patients with and without underlying cirrhosis (third section).