Acute on Chronic Liver Failure: Role of the Bacterial Infections

Acute-on-chronic liver failure (ACLF) refers to a syndrome characterized by acute deterioration of liver function of a pre-existing chronic liver disease with increased short-term mortality at 3 months due to multiorgan failure. Definition of ACLF has been refined, but differences between western and eastern areas still exist. Diagnosis of ACLF as recommended by the EASL-CLIF consortium is based on the assessment of organ dysfunction. The pathogenesis of this syndrome is attributable to an exaggerated host response to inflammation, responsible for the severe haemodynamic derangement leading to multiorgan failure. ACLF is triggered by precipitating events like acute hepatitis either viral, drug-induced, toxic, or alcoholic, variceal bleeding and sepsis. Bacterial infection is currently considered the most frequent trigger of ACLF in Western countries. Cirrhotic patients, particularly if decompensated are prone to develop bacterial infection because loss of integrity of the intestinal mucosal barrier and translocation of pathogen-associated molecular patterns (PAMPs). Bacterial translocation may develop into overt infection at different sites, along with sepsis and septic shock that may lead to ACLF. Epidemiology of bacterial infection in cirrhosis has been changing and this accounts for new antibiotic regimens as empirical therapy in critically ill cirrhotic patients with bacterial infection. In this chapter, we will discuss on definition, pathogenesis, clinical aspects and therapy of bacterial infection-related ACLF

Liver carcinogenesis: diagnostic and clinical aspects of preneoplastic nodules

In multistep hepatocarcinogenesis, sizable lesions can precede the development of hepatocellular carcinoma (HCC). These lesions are currently classified as low grade (LG)- and high grade (HG)-dysplastic nodules. Following international guidelines recommending the surveillance of cirrhotic patients, a growing number of 1-2 cm hepatocellular nodules are recognized including early hepatocellular carcinoma (eHCC) and DN the latter accounting for as many as 70% of nodules < 1 cm. HG-DN are currently considered the most advanced HCC precursors. The histological diagnosis of low-grade dysplastic nodule (LG-DN), high- grade dysplastic nodule (HG-DN) and eHCC in small liver biopsies requires a comprehensive stepwise morphological and immunocytochemical approach. By imaging the differential diagnosis among these lesions is a challenge. According to vascular enhancement at dynamic computed tomography (CT) or magnetic resonance imaging (MRI) these precursors are classified as hypo-vascular/indeterminate nodules even though distinction between LG-DN and HG-DN is almost impossible. The introduction of gadoexetic acid-enhanced MRI has represented an extremely important advance in this field allowing a better differentiation of dysplastic lesions from eHCC and progressed HCC. Additional MRI features as diffusion-weighted imaging further improved diagnostic accuracy of imaging. According to Liver Imaging Reporting and Data System (LI-RADS), either CT/MRI or Contrast-Enhanced Ultrasound LI-RADS, the dysplastic lesions should be categorized as LR-3 or LR-4. Natural history of these lesions confirmed that HCC can develop from HG-DN but which nodule and when it will undergo malignant transformation is not predictable. The search and validation of radiological and tissue markers able to select lesions more prone to HCC development, is currently underway. Whether and how HG-DN should be ablated or closely followed up is currently debated

Overview of Immune Checkpoint Inhibitors Therapy for Hepatocellular Carcinoma, and The ITA.LI.CA Cohort Derived Estimate of Amenability Rate to Immune Checkpoint Inhibitors in Clinical Practice

Despite progress in our understanding of the biology of hepatocellular carcinoma (HCC), this tumour remains difficult-to-cure for several reasons, starting from the particular disease environment where it arises-advanced chronic liver disease-to its heterogeneous clinical and biological behaviour. The advent, and good results, of immunotherapy for cancer called for the evaluation of its potential application also in HCC, where there is evidence of intra-hepatic immune response activation. Several studies advanced our knowledge of immune checkpoints expression in HCC, thus suggesting that immune checkpoint blockade may have a strong rationale even in the treatment of HCC. According to this background, initial studies with tremelimumab, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, and nivolumab, a programmed cell death protein 1 (PD-1) antibody, showed promising results, and further studies exploring the effects of other immune checkpoint inhibitors, alone or with other drugs, are currently underway. However, we are still far from the identification of the correct setting, and sequence, where these drugs might be used in clinical practice, and their actual applicability in real-life is unknown. This review focuses on HCC immunobiology and on the potential of immune checkpoint blockade therapy for this tumour, with a critical evaluation of the available trials on immune checkpoint blocking antibodies treatment for HCC. Moreover, it assesses the potential applicability of immune checkpoint inhibitors in the real-life setting, by analysing a large, multicentre cohort of Italian patients with HCC