Role of Gut Microbial Metabolites in the Pathogenesis of Primary Liver Cancers.

Hepatobiliary malignancies, which include hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are the sixth most common cancers and the third leading cause of cancer-related death worldwide. Hepatic carcinogenesis is highly stimulated by chronic inflammation, defined as fibrosis deposition, and an aberrant imbalance between liver necrosis and nodular regeneration. In this context, the gut-liver axis and gut microbiota have demonstrated a critical role in the pathogenesis of HCC, as dysbiosis and altered intestinal permeability promote bacterial translocation, leading to chronic liver inflammation and tumorigenesis through several pathways. A few data exist on the role of the gut microbiota or bacteria resident in the biliary tract in the pathogenesis of CCA, and some microbial metabolites, such as choline and bile acids, seem to show an association. In this review, we analyze the impact of the gut microbiota and its metabolites on HCC and CCA development and the role of gut dysbiosis as a biomarker of hepatobiliary cancer risk and of response during anti-tumor therapy. We also discuss the future application of gut microbiota in hepatobiliary cancer management.

Management of Portal Hypertension in Patients with Hepatocellular Carcinoma on Systemic Treatment: Current Evidence and Future Perspectives.

The management of CSPH in patients undergoing systemic treatment for HCC has emerged as a critical concern due to the absence of reliable diagnostic criteria and uncertainties surrounding therapeutic approaches. This review aims to underscore the primary pathophysiological aspects linking HCC and PH, while also addressing the current and emerging clinical strategies for the management of portal hypertension. A review of studies from January 2003 to June 2023 was conducted using the PubMed database and employing MeSH terms, such as "hepatocellular carcinoma", "immune checkpoint inhibitors", "systemic therapy", "portal hypertension", "variceal bleeding" and "tyrosine kinase inhibitors". Despite promising results of tyrosine kinase inhibitors in animal models for PH and fibrosis, only Sorafenib has demonstrated similar effects in human studies, whereas Lenvatinib appears to promote PH development. The impact of Atezolizumab/Bevacizumab on PH remains uncertain, with an increasing risk of bleeding related to Bevacizumab in patients with prior variceal hemorrhage. Given the absence of specific guidelines, endoscopic surveillance during treatment is advisable, and primary and secondary prophylaxis of variceal bleeding should adhere to the Baveno VII recommendations. Furthermore, in patients with advanced HCC, refinement of diagnostic criteria for CSPH and guidelines for its surveillance are warranted.

Exploring the link: Porto-sinusoidal vascular disorder and inflammatory bowel disease - A comprehensive narrative review.

Porto-sinusoidal vascular disorder (PSVD) encompasses a group of vascular disorders characterized by lesions involving the portal venules and sinusoids, independent of the presence of portal hypertension (PH), and for which liver biopsy is essential for diagnosis. PSVD has been shown to be common in patients with immune-mediated diseases, including inflammatory bowel disease (IBD). The association between PSVD and the use of thiopurines and thioguanine in patients with IBD has been well established. In addition, research suggests an association between PSVD and IBD, even in cases where patients haven't been exposed to specific medications, probably related to changes in intestinal permeability. The identification and management of patients with known IBD and PSVD is a challenge for gastroenterologists. This narrative review aims to summarize the currently available data on the association between IBD and PSVD and provide practical suggestions for the management of this group of patients.

The New Era of Systemic Treatment for Hepatocellular Carcinoma: From the First Line to the Optimal Sequence.

Hepatocellular carcinoma (HCC) represents the most common primary liver cancer and is considered a major global health problem as one of the leading causes of cancer-related death in the world. Due to the increase in life expectancy and the epidemiological growth of specific risk factors, such as metabolic dysfunction-associated steatotic liver disease (MASLD), the incidence of HCC is growing globally, and mortality rates are still high. Moreover, patients frequently present at an intermediate or advanced tumor stage, when curative treatments, such as surgical resection, liver transplantation or ablation are no longer applicable. In these cases, trans-arterial chemoembolization (TACE), trans-arterial radioembolization (TARE), and systemic therapy are the only suitable options to achieve disease control. The multi-kinase inhibitor Sorafenib has been the only systemic treatment available for unresectable advanced HCC for almost a decade, but in the last couple of years new therapeutic options have emerged. Recent advances in understanding the interactions between the tumor and its microenvironment, especially cancer immune escape, led to the advent of immunotherapy. Currently, first-line systemic treatment for HCC is represented by the combination of the immune checkpoint inhibitor (ICI) Atezolizumab plus Bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, but many other ICIs have been investigated, such as Nivolumab, Pembrolizumab, Durvalumab and Ipilimumab. However, the problem of second- and third-line therapies, and the correct sequence of treatments remains open and is not addressed in most studies. This explains the urge to find new systemic treatments that can improve the survival and quality of life in patients that can go beyond the first line of treatment. The aim of this paper is to offer a complete overview of the most recent innovations in systemic treatments for unresectable locally advanced and metastatic HCC, including emerging therapies, with a particular focus on treatment sequences. Moreover, we will provide an outlook on possible future approaches to patients who progress beyond first-line therapies.

Gut Microbiota and Neuroinflammation in Acute Liver Failure and Chronic Liver Disease.

Acute liver failure and chronic liver disease are associated with a wide spectrum of neurological changes, of which the best known is hepatic encephalopathy (HE). Historically, hyperammonemia, causing astrocyte swelling and cerebral oedema, was considered the main etiological factor in the pathogenesis of cerebral dysfunction in patients with acute and/or chronic liver disease. However, recent studies demonstrated a key role of neuroinflammation in the development of neurological complications in this setting. Neuroinflammation is characterized by activation of microglial cells and brain secretion of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6, which alter neurotransmission, leading to cognitive and motor dysfunction. Changes in the gut microbiota resulting from liver disease play a crucial role in the pathogenesis of neuroinflammation. Dysbiosis and altered intestinal permeability, resulting in bacterial translocation and endotoxemia, are responsible for systemic inflammation, which can spread to brain tissue and trigger neuroinflammation. In addition, metabolites derived from the gut microbiota can act on the central nervous system and facilitate the development of neurological complications, exacerbating clinical manifestations. Thus, strategies aimed at modulating the gut microbiota may be effective therapeutic weapons. In this review, we summarize the current knowledge on the role of the gut-liver-brain axis in the pathogenesis of neurological dysfunction associated with liver disease, with a particular focus on neuroinflammation. In addition, we highlight emerging therapeutic approaches targeting the gut microbiota and inflammation in this clinical setting.

Type 2 Diabetes Mellitus and Liver Disease: Across the Gut-Liver Axis from Fibrosis to Cancer.

Type 2 diabetes mellitus is a widespread disease worldwide, and is one of the cornerstones of metabolic syndrome. The existence of a strong relationship between diabetes and the progression of liver fibrosis has been demonstrated by several studies, using invasive and noninvasive techniques. Patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) show faster progression of fibrosis than patients without diabetes. Many confounding factors make it difficult to determine the exact mechanisms involved. What we know so far is that both liver fibrosis and T2DM are expressions of metabolic dysfunction, and we recognize similar risk factors. Interestingly, both are promoted by metabolic endotoxemia, a low-grade inflammatory condition caused by increased endotoxin levels and linked to intestinal dysbiosis and increased intestinal permeability. There is broad evidence on the role of the gut microbiota in the progression of liver disease, through both metabolic and inflammatory mechanisms. Therefore, dysbiosis that is associated with diabetes can act as a modifier of the natural evolution of NAFLD. In addition to diet, hypoglycemic drugs play an important role in this scenario, and their benefit is also the result of effects exerted in the gut. Here, we provide an overview of the mechanisms that explain why diabetic patients show a more rapid progression of liver disease up to hepatocellular carcinoma (HCC), focusing especially on those involving the gut-liver axis.

Multiparametric Dynamic Ultrasound Approach for Differential Diagnosis of Primary Liver Tumors.

A correct differentiation between hepatocellular carcinoma (HCC) and intracellular cholangiocarcinoma (ICC) is essential for clinical management and prognostic prediction. However, non-invasive differential diagnosis between HCC and ICC remains highly challenging. Dynamic contrast-enhanced ultrasound (D-CEUS) with standardized software is a valuable tool in the diagnostic approach to focal liver lesions and could improve accuracy in the evaluation of tumor perfusion. Moreover, the measurement of tissue stiffness could add more information concerning tumoral environment. To explore the diagnostic performance of multiparametric ultrasound (MP-US) in differentiating ICC from HCC. Our secondary aim was to develop an US score for distinguishing ICC and HCC. Between January 2021 and September 2022 consecutive patients with histologically confirmed HCC and ICC were enrolled in this prospective monocentric study. A complete US evaluation including B mode, D-CEUS and shear wave elastography (SWE) was performed in all patients and the corresponding features were compared between the tumor entities. For better inter-individual comparability, the blood volume-related D-CEUS parameters were analyzed as a ratio between lesions and surrounding liver parenchyma. Univariate and multivariate regression analysis was performed to select the most useful independent variables for the differential diagnosis between HCC and ICC and to establish an US score for non-invasive diagnosis. Finally, the diagnostic performance of the score was evaluated by receiver operating characteristic (ROC) curve analysis. A total of 82 patients (mean age ± SD, 68 ± 11 years, 55 men) were enrolled, including 44 ICC and 38 HCC. No statistically significant differences in basal US features were found between HCC and ICC. Concerning D-CEUS, blood volume parameters (peak intensity, PE; area under the curve, AUC; and wash-in rate, WiR) showed significantly higher values in the HCC group, but PE was the only independent feature associated with HCC diagnosis at multivariate analysis (p = 0.02). The other two independent predictors of histological diagnosis were liver cirrhosis (p < 0.01) and SWE (p = 0.01). A score based on those variables was highly accurate for the differential diagnosis of primary liver tumors, with an area under the ROC curve of 0.836 and the optimal cut-off values of 0.81 and 0.20 to rule in or rule out ICC respectively. MP-US seems to be a useful tool for non-invasive discrimination between ICC and HCC and could prevent the need for liver biopsy at least in a subgroup of patients.

Molecular and Clinical Features of Hepatocellular Carcinoma in Patients with HBV-HDV Infection.

Hepatitis D virus (HDV) infection affects more than 10 million people worldwide, with an estimated prevalence of nearly 4.5% among HBsAg-positive individuals. Epidemiological studies have shown a significant increase in the prevalence of hepatocellular carcinoma (HCC) in patients with chronic HDV infection compared to those with chronic hepatitis B virus (HBV) mono-infection. Despite the clinical findings, data on molecular oncogenic mechanisms are limited and fragmentary. Moreover, the role of HDV in promoting the development of HCC has so far been controversial, because it is difficult to weigh the respective contributions of the two viruses. In this review, we focused on the direct oncogenic action of HDV, its role in modifying the tumor microenvironment, and the genetic signature of HDV-related HCC, comparing these features with HBV-related HCC.

Dynamics of liver stiffness predicts complications in patients with HCV related cirrhosis treated with direct-acting antivirals.

BACKGROUND: Direct acting antivirals(DAAs) are effective in reducing inflammatory ant fibrotic markers in patients with chronic hepatitis C virus(HCV) infection and to prevent liver-related complications. Two-dimensional shear wave elastography(2D-SWE) is an effective technique for the assessment of liver fibrosis. AIM: To evaluate changes in liver stiffness(LS) in HCV cirrhotic patients undergoing DAA therapy and to identify non-invasive parameters that predict the occurrence of liver-related events. METHODS: We enrolled 229 patients who received DAAs between January 2015 and October 2018. Ultrasound parameters and laboratory data were assessed before treatment and 24(T1) and 48(T2) weeks after end of treatment. Patients were followed up every 6 months to evaluate the development of HCC and other liver related complications. Multiple Cox regression analysis was used to determine parameters associated with the development of complications. RESULTS: Model for End-stage Liver Disease(MELD) score(HR 1.16; CI 95% 1.01-1.33; p = 0.026) and a change in LS at T2(1-year Delta LS) < 20%(HR 2.98; CI 95% 1.01-8.1; p = 0.03) were independently associated with HCC risk. One-year Delta-LS <20% was independently associated with the development of ascites(HR 5.08; CI 95% 1.03 - 25.14; p = 0.04). CONCLUSIONS: Dynamic changes of 2D-SWE-measured LS after DAA therapy may be a useful tool to identify patients who are at higher risk of liver related complications.

Role of Akkermansia in Human Diseases: From Causation to Therapeutic Properties.

The gut microbiota plays a critical role in the modulation of host metabolism and immune response, and its impairment has been implicated in many gastrointestinal and extraintestinal diseases. Current evidence shows the well-documented role of A. muciniphila in maintaining the integrity of the intestinal barrier, modulating the host immune response, and improving several metabolic pathways, making it a key element in the pathogenesis of several human diseases. In this scenario, A. muciniphila is the most promising next-generation probiotic and one of the first microbial species suitable for specific clinical use when compared with traditional probiotics. Further studies are needed to provide more accurate insight into its mechanisms of action and to better elucidate its properties in several major areas, paving the way for a more integrated and personalized therapeutic approach that finally makes the most of our knowledge of the gut microbiota.

Gut microbiota modulation in patients with non-alcoholic fatty liver disease: Effects of current treatments and future strategies.

Non-alcoholic fatty liver disease (NAFLD) is frequently associated with metabolic disorders, being highly prevalent in obese and diabetic patients. Many concomitant factors that promote systemic and liver inflammation are involved in NAFLD pathogenesis, with a growing body of evidence highlighting the key role of the gut microbiota. Indeed, the gut-liver axis has a strong impact in the promotion of NAFLD and in the progression of the wide spectrum of its manifestations, claiming efforts to find effective strategies for gut microbiota modulation. Diet is among the most powerful tools; Western diet negatively affects intestinal permeability and the gut microbiota composition and function, selecting pathobionts, whereas Mediterranean diet fosters health-promoting bacteria, with a favorable impact on lipid and glucose metabolism and liver inflammation. Antibiotics and probiotics have been used to improve NAFLD features, with mixed results. More interestingly, medications used to treat NAFLD-associated comorbidities may also modulate the gut microbiota. Drugs for the treatment of type 2 diabetes mellitus (T2DM), such as metformin, glucagon-like peptide-1 (GLP-1) agonists, and sodium-glucose cotransporter (SGLT) inhibitors, are not only effective in the regulation of glucose homeostasis, but also in the reduction of liver fat content and inflammation, and they are associated with a shift in the gut microbiota composition towards a healthy phenotype. Even bariatric surgery significantly changes the gut microbiota, mostly due to the modification of the gastrointestinal anatomy, with a parallel improvement in histological features of NAFLD. Other options with promising effects in reprogramming the gut-liver axis, such as fecal microbial transplantation (FMT) and next-generation probiotics deserve further investigation for future inclusion in the therapeutic armamentarium of NAFLD.

Endotoxemia and Gastrointestinal Cancers: Insight into the Mechanisms Underlying a Dangerous Relationship.

Lipopolysaccharide (LPS), also known as endotoxin, is a component of the membrane of gram-negative bacteria and a well-recognized marker of sepsis. In case of disruption of the intestinal barrier, as occurs with unhealthy diets, alcohol consumption, or during chronic diseases, the microbiota residing in the gastrointestinal tract becomes a crucial factor in amplifying the systemic inflammatory response. Indeed, the translocation of LPS into the bloodstream and its interaction with toll-like receptors (TLRs) triggers molecular pathways involved in cytokine release and immune dysregulation. This is a critical step in the exacerbation of many diseases, including metabolic disorders and cancer. Indeed, the role of LPS in cancer development is widely recognized, and examples include gastric tumor related to Helicobacter pylori infection and hepatocellular carcinoma, both of which are preceded by a prolonged inflammatory injury; in addition, the risk of recurrence and development of metastasis appears to be associated with endotoxemia. Here, we review the mechanisms that link the promotion and progression of tumorigenesis with endotoxemia, and the possible therapeutic interventions that can be deployed to counteract these events.

The Gut-Vascular Barrier as a New Protagonist in Intestinal and Extraintestinal Diseases.

The intestinal barrier, with its multiple layers, is the first line of defense between the outside world and the intestine. Its disruption, resulting in increased intestinal permeability, is a recognized pathogenic factor of intestinal and extra-intestinal diseases. The identification of a gut-vascular barrier (GVB), consisting of a structured endothelium below the epithelial layer, has led to new evidence on the etiology and management of diseases of the gut-liver axis and the gut-brain axis, with recent implications in oncology as well. The gut-brain axis is involved in several neuroinflammatory processes. In particular, the recent description of a choroid plexus vascular barrier regulating brain permeability under conditions of gut inflammation identifies the endothelium as a key regulator in maintaining tissue homeostasis and health.

Cellular therapies in liver and pancreatic diseases.

Over the past two decades, developments in regenerative medicine in gastroenterology have been greatly enhanced by the application of stem cells, which can self-replicate and differentiate into any somatic cell. The discovery of induced pluripotent stem cells has opened remarkable perspectives on tissue regeneration, including their use as a bridge to transplantation or as supportive therapy in patients with organ failure. The improvements in DNA manipulation and gene editing strategies have also allowed to clarify the physiopathology and to correct the phenotype of several monogenic diseases, both in vivo and in vitro. Further progress has been made with the development of three-dimensional cultures, known as organoids, which have demonstrated morphological and functional complexity comparable to that of a miniature organ. Hence, owing to its protean applications and potential benefits, cell and organoid transplantation has become a hot topic for the management of gastrointestinal diseases. In this review, we describe current knowledge on cell therapies in hepatology and pancreatology, providing insight into their future applications in regenerative medicine.

Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: Lights and shadows.

About one-fourth of adults globally suffer from nonalcoholic fatty liver disease (NAFLD), which is becoming a leading cause of chronic liver disease worldwide. Its prevalence has rapidly increased in recent years, and is projected to increase even more. NAFLD is a leading cause of hepatocellular carcinoma (HCC), the sixth-most prevalent cancer worldwide and the fourth most common cause of cancer-related death. Although the molecular basis of HCC onset in NAFLD is not completely known, inflammation is a key player. The tumor microenvironment (TME) is heterogeneous in patients with HCC, and is characterized by complex interactions between immune system cells, tumor cells and other stromal and resident liver cells. The etiology of liver disease plays a role in controlling the TME and modulating the immune response. Markers of immune suppression in the TME are associated with a poor prognosis in several solid tumors. Immunotherapy with immune checkpoint inhibitors (ICIs) has become the main option for treating cancers, including HCC. However, meta-analyses have shown that patients with NAFLD-related HCC are less likely to benefit from therapy based on ICIs alone. Conversely, the addition of an angiogenesis inhibitor showed better results regarding the objective response rate and progression-free survival. Adjunctive diagnostic and therapeutic strategies, such as the application of novel biomarkers and the modulation of gut microbiota, should be considered in the future to guide personalized medicine and improve the response to ICIs in patients with NAFLD-related HCC.

Non-Invasive Biomarkers for Immunotherapy in Patients with Hepatocellular Carcinoma: Current Knowledge and Future Perspectives.

The treatment perspectives of advanced hepatocellular carcinoma (HCC) have deeply changed after the introduction of immunotherapy. The results in responders show improved survival compared with Sorafenib, but only one-third of patients achieve a significant benefit from treatment. As the tumor microenvironment exerts a central role in shaping the response to immunotherapy, the future goal of HCC treatment should be to identify a proxy of the hepatic tissue condition that is easy to use in clinical practice. Therefore, the search for biomarkers that are accurate in predicting prognosis will be the hot topic in the therapeutic management of HCC in the near future. Understanding the mechanisms of resistance to immunotherapy may expand the patient population that will benefit from it, and help researchers to find new combination regimens to improve patients' outcomes. In this review, we describe the current knowledge on the prognostic non-invasive biomarkers related to treatment with immune checkpoint inhibitors, focusing on serological markers and gut microbiota.

Benign liver lesions 2022: Guideline for clinical practice of Associazione Italiana Studio del Fegato (AISF), Società Italiana di Radiologia Medica e Interventistica (SIRM), Società Italiana di Chirurgia (SIC), Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB), Associazione Italiana di Chirurgia Epatobilio-Pancreatica (AICEP), Società Italiana Trapianti d'Organo (SITO), Società Italiana di Anatomia Patologica e Citologia Diagnostica (SIAPEC-IAP) - Part II - Solid lesions.

Benign liver lesions are increasingly diagnosed in daily clinical practice due to the growing use of imaging techniques for the study of the abdomen in patients who have non-specific symptoms and do not have an increased risk of hepatic malignancy. They include simple or parasitic hepatic cysts and solid benign tumors which differ widely in terms of prevalence, clinical relevance, symptoms and natural history and often lead to significant clinical problems relating to diagnosis and clinical management. Following the need to have updated guidelines on the management of benign focal liver lesions, the Scientific Societies mainly involved in their management have promoted the drafting of a new dedicated document. This document was drawn up according to the present Italian rules and methodologies necessary to produce clinical, diagnostic, and therapeutic guidelines based on evidence. Here we present the second part of the guideline, concerning the diagnosis and clinical management of hemangioma, focal nodular hyperplasia, and hepatocellular adenoma.

Benign liver lesions 2022: Guideline for clinical practice of Associazione Italiana Studio del Fegato (AISF), Società Italiana di Radiologia Medica e Interventistica (SIRM), Società Italiana di Chirurgia (SIC), Società Italiana di Ultrasonologia in Medicina e Biologia (SIUMB), Associazione Italiana di Chirurgia Epatobilio-Pancreatica (AICEP), Società Italiana Trapianti d'Organo (SITO), Società Italiana di Anatomia Patologica e Citologia Diagnostica (SIAPEC-IAP) - Part I - Cystic lesions.

Benign liver lesions are increasingly diagnosed in daily clinical practice due to the growing use of imaging techniques for the study of the abdomen in patients who have non-specific symptoms and do not have an increased risk of hepatic malignancy. They include simple or parasitic cysts and solid benign tumors which differ widely in terms of prevalence, clinical relevance, symptoms and natural history and often lead to significant clinical problems relating to diagnosis and clinical management. Following the need to have updated guidelines on the management of benign focal liver lesions, the Scientific Societies mainly involved in their management have promoted the drafting of a new dedicated document. This document was drawn up according to the present Italian rules and methodologies necessary to produce clinical, diagnostic, and therapeutic guidelines based on evidence. Here we present the first part of the guideline, concerning the characterization of focal hepatic lesions detected by ultrasound, and the diagnosis and clinical management of simple and parasitic hepatic cysts, and of polycystic liver disease.

SIRT in 2025.

Selective internal radiation therapy represents an endovascular treatment option for patients with primary liver malignancies, in different clinical stages. Potential applications of this treatment are in early-stage hepatocellular carcinoma, as a curative option, or in combination with systemic treatments in intermediate and advanced-stages. This review, based on existing literature and ongoing trials, will focus on the future of this treatment in patients with hepatocellular carcinoma, in combination with systemic treatments, or with the use of new devices and technological developments; it will also describe new potential future indications and structural and organizational perspectives.