The epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly growing worldwide. Thus, there is an urgent need for novel, non-invasive, and reliable biomarkers to replace liver biopsy for the diagnosis and prognosis of MASLD. Circulating peripheral blood mononuclear cells (PBMCs) are highly responsive to various stimuli and physiological changes. Beyond their immunomodulatory role, PBMC may act as metabolic sensors in several cardiometabolic disorders, including MASLD, with their metabolic programs shifting accordingly. Recent evidence suggests a link between impaired mitochondrial bioenergetics in PBMC and MASLD. Additionally, impaired mitochondrial respiration is intricately linked to the intracellular depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD⁺) in various cell types. Accumulating preclinical and clinical data show that NAD⁺-increasing strategies may protect against MASLD by restoring intracellular NAD⁺ pools and improving mitochondrial performance. This review will focus on [i] the relevance of mitochondrial dysfunction, including impaired bioenergetics, in PBMC as a marker for the diagnosis and prognosis of MASLD, and [ii] the potential benefits of NAD⁺ precursors in MAFLD and their relationship with improved mitochondrial respiration in blood immune cells.

Hepatitis B virus (HBV) infection is a major risk factor of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Pathogenesis of HBV-induced cirrhosis and HCC involves viral factors and virus-triggered local inflammatory and immune responses, the latter leading to progressive fibrosis, cirrhosis and carcinogenesis. Antiviral therapeutics suppress HBV replication and reduce the risks of cirrhosis and HCC. We discuss the current knowledge on the pathogenesis of HBV-induced cirrhosis and HCC, focusing on mechanisms of current and emerging antiviral therapeutics.

Microsatellite unstable (MSI) colorectal cancer (CRC) tumors have a high mutational load (particularly frame-shift mutations) that creates numerous neoantigens that are presented to major histocompatibility complex molecules and recognized by T cells. Consequently, MSI tumors have a higher presence of tumor-infiltrating lymphocytes than mismatch repair-proficient tumors. Colorectal cancer patients with MSI constitute a rare group of immune checkpoint inhibitor (ICI)-responsive patients. Nonetheless, complete radiological responders comprise between 3% and 16% of MSI advanced CRC patients, which compares poorly with the 45% to 87% rate of pathological complete response in early MSI CRC patients treated with ICIs. In this review, we address the efficacy of current ICIs and the biological differences between early and advanced MSI CRC to potentially increase the efficacy of ICIs in both settings.

Liver inflammation, injury, and hepatic cell death are caused by external agents (viruses, bacteria, drugs, alcohol, etc.) along with the genetic susceptibility of an individual. Persistent activation of the fibrogenic response in cells leads to liver fibrosis which in turn progresses to cirrhosis and cancer. The dysregulation of the immune system generates reactive oxygen species which in turn induce necrosis of hepatocytes. This process activates hepatic stellate cells and myofibroblasts to produce a huge quantity of collagens, alpha-smooth muscle actin, and extracellular matrix deposition in liver parenchyma. Due to the multifactorial nature of this disease, conventional therapies increasingly attempted combinatorial therapy or polytherapy to target multiple mechanistic sites in order to prevent entry into further complicated irreversible stages. Despite advancements in conventional therapy, several cases aggravate fibrosis (grade 3 to 4) and cirrhosis. The inconsistency in treatment outcomes and limited organ donors for liver transplantation have led to an ever-increasing and challenging demand for alternative therapies. In this review, we analyze the mechanism and causative factors of liver diseases, conventional mode, and alternative therapeutic options. The central to liver diseases are immune dysregulation, hence bioactive agents with immunomodulatory properties should be searched and exploited to meet therapeutic needs. Mesenchymal stem cells (MSCs) with their specialized anti-inflammatory and immunomodulatory properties could be utilized as an effective alternative therapeutic candidate in treating inflammatory liver diseases. MSC-derived exosome further provides an additional immunomodulatory option that could work in tandem with MSC in a synergistic form. In this series, we have reviewed preconditioned and genetically edited MSCs to augment homing, proliferation, and differentiation. Importantly, all the clinical challenges should be noted and addressed before stem cell cytotherapy should be considered safe and effective for patients with liver diseases. Published literature indicated that MSC therapy has the potential to substitute conventional options in the treatment of high-grade fibrosis and cirrhosis.

Mitochondria are essential organelles responsible for intracellular energy production and play crucial roles in cellular metabolism, inflammation, and apoptosis. Reactive oxygen species (ROS) are primarily produced in the mitochondria and endoplasmic reticulum of hepatocytes due to the activity of cytochrome P450 enzymes. Under ideal conditions, cells have specific molecular mechanisms that manage oxidative stress levels, thus ensuring a balance between oxidants and antioxidants. The interplay between ROS-induced mitochondrial dysfunction and the activation of the NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome in the context of liver diseases has been extensively studied. However, the exact mechanisms by which mitochondria promote the activation of the NLRP3 inflammasome and contribute to the onset of liver disease remain unclear. This review aims to elucidate the recently discovered mitochondrial regulation of the NLRP3 inflammasome in liver disorders, including alcohol-related liver disease (ALD), metabolic-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). Finally, it summarizes various natural and pharmaceutical agents that can mitigate liver damage by modulating the activation of the NLRP3 inflammasome through mitochondrial pathways. This work serves as an important resource for identifying new therapeutic approaches and provides further support for advancing the understanding of liver diseases.

Steatotic liver disease (SLD) has been known for a long time, but our understanding of this disease has remained poor until the past decade. Despite extensive research, our ability to comprehend the etiopathogenesis and natural course of SLD is far from the desired level of comprehension. This is required to develop a universally effective novel therapeutic agent. This review aims to concisely elaborate the conceptual approach and advancement in the understanding of global disease burden and etiopathogenic process, identifying the gaps and the pathophysiologic mechanism behind developing novel therapeutic agents. We searched two major databases, PubMed and Google Scholar, to identify publications related to the abovementioned topics. All publications, including original papers, reviews, and commentaries, were reviewed. Findings: Metabolic dysfunction-associated steatotic liver disease (MASLD) is not limited to obese individuals, rather, it may develop in any individual independent of weight. Visceral adiposity is strongly associated with MASLD and subsequent risks of cirrhosis, hepatocellular carcinoma, and cardiovascular disease. MASLD is associated with diabetes mellitus independent of underlying pathogenic mechanisms, and there is a bidirectional connection between MASLD and diabetes mellitus, making the situation quite challenging. Not all patients with MASLD exhibit atherogenic dyslipidemia and thus do not have a higher risk of cardiovascular disease. The overlap of these metabolic risk factors is not straightforward. There is a differential contribution of these risk factors based on age, gender, race, ethnicity, alcohol consumption, and microbiota composition. Poor dietary habits and lifestyle directly affect the microbiota, modulators, and mediators, thereby affecting the final biochemical processes leading to steatosis, steatohepatitis, fibrosis, and oncogenesis. In conclusion, MASLD is a complex and pathogenically heterogeneous disease with significant interpatient variation in the natural course and outcome. Understanding the precise mechanism of variability is the key gap and a limiting factor in the development of a novel therapeutic agent.

Hepatitis B virus (HBV) infection affects 262 million people worldwide, leading to over 820,000 deaths annually. The reason HBV has been a persistent issue for decades is that it is a non-cytopathic, liver-specific virus with the ability for persistent infection, which cannot be completely eliminated by drugs, eventually progressing to cirrhosis and hepatocellular carcinoma (HCC). Although HBV seems to induce little innate immune activation, adaptive immune responses can mediate viral clearance and liver disease. Here, we review the epidemiology, natural history, lifecycle, and modes of transmission of HBV. We also pay particular attention to the adaptive and innate immune responses to HBV and the research progress on therapeutic vaccines, which may provide new insights for targeted HBV treatment.

Metabolic-associated steatotic liver disease (MASLD) and its pathological version, metabolic dysfunction-associated steatohepatitis (MASH), are becoming the main leading causes of chronic liver disease almost worldwide and are the fastest growing aetiology of hepatocellular carcinoma (HCC), especially in the Western countries. The combination of high incidence and morbidity with limited treatment options for both MASH and HCC highlights an urgent need for the discovery of novel therapeutic candidates to inform drug development. The importance of lysosomes and cathepsins, their most abundant hydrolases, has been overlooked for decades. They were considered organelles only involved in the recycling of macromolecules, with cathepsins simply being their effectors. Contrary to this traditional view, recent findings have shed new light on the lysosome and its enzymes as drivers of essential cellular processes, such as apoptosis and autophagy. Bringing lysosomal activity and the regulation of cathepsins into the spotlight of MASH and HCC research can open new avenues for the development of novel drugs based on targeting cathepsin-driven lysosomal activity and its associated pathological processes. This review comprehensively summarises the current knowledge on the role and contribution of lysosomal cathepsins to MASLD/MASH and HCC progression.

The formation of metabolic changes is based on many factors. In particular, the infectious theory of the development of metabolic “breakdowns” has not lost its relevance. In this regard, many scientists are investigating the role of various microorganisms in the pathogenesis of metabolic syndrome. The review provides the results of current research on the role of Helicobacter pylori (as one of the most well-known and widespread bacterial pathogens) in the pathogenesis of metabolic syndrome. However, the results of scientific work are sometimes contradictory, which dictates the need for novel further research to clarify the characteristics of the influence Helicobacter pylori on the formation of various components of the metabolic syndrome.

Lipids are intricate biomolecules responsible for the building up of biological membranes. Besides this structural function, they also display crucial roles in signaling, acting as second messengers that activate specific pathways. Mitochondria are fundamental for cells as they participate in several pivotal functions, such as ATP synthesis, cell survival, metabolic pathways, and calcium homeostasis. Thus, the lipid composition of mitochondrial membranes can affect specific proteins and impact vital functions of mitochondria, such as oxidative phosphorylation and dynamics. The liver possesses a critical function in lipid homeostasis, involving the generation, oxidation, and trafficking of free fatty acids (FFA), triglycerides (TG), cholesterol, and bile acids (BAs). Mitochondria play a key role in lipid storage regulation in hepatocytes, which can control liver function. Their diverse tasks are affected by the lipid composition of mitochondrial membranes, characterized by low cholesterol content and enrichment of specific lipids such as cardiolipin. As mitochondria determine the bioenergetic status of cells and are key regulators of cell viability, alterations of mitochondrial lipid composition can contribute to the induction and progression of chronic diseases, including alcohol-related liver disease (ARLD) and metabolic dysfunction-associated steatotic liver disease (MASLD), two of the most common forms of liver diseases characterized by steatosis, necroinflammation, and fibrosis, which can progress to hepatocellular carcinoma (HCC). Thus, the disruption of lipid metabolism and membrane composition of mitochondria are characteristic features of cancer cells, and altered mitochondrial lipid composition may be a critical player in the progression of chronic liver diseases toward HCC. This review will address the mechanisms whereby alterations of mitochondrial lipid composition lead to the onset and progression of chronic liver diseases. Thus, a better characterization of the alterations of lipid composition in mitochondria may be a crucial step to design strategies and novel therapeutic opportunities for the treatment of MASLD and ARLD.

Ascites is a frequent complication in patients with cirrhosis, associated with a bad prognosis. Ascites is associated with severe complications, such as spontaneous bacterial peritonitis and kidney dysfunction, which must be diagnosed and managed rapidly. First-line management is based on diuretics use. Beta-blockers role remains debated but an early administration could probably decrease complications associated with portal hypertension. Albumin infusion is validated in large volume paracenteses, spontaneous bacterial peritonitis, or kidney dysfunction, but is debated in other situations. Technical progresses allow the worldwide use of TIPS (transjugular intrahepatic portosystemic shunt), but patient selection must be rigorous because of potential severe complications. An alternative treatment, automated low-flow ascites pump, can be offered in patients without TIPS possibility: It is a recent technique, whose patients’ selection and installation conditions were improved, with interesting results. Liver transplantation remains the gold standard, but the lack of grafts, and specific side effects, lead to prefer other methods. In case of acute kidney injury due to hepatorenal syndrome, terlipressin remains the standard of care; continuous infusion is associated with fewer side effects.

One of the primary complications of cirrhosis and portal hypertension is the occurrence of hepatocellular carcinoma (HCC), which is among the most common malignancies worldwide. There is limited availability of predictive non-invasive markers for primary HCC development in compensated advanced chronic liver disease (cACLD) patients. The reference standard method of assessing prognosis for cACLD patients, beyond liver fibrosis assessed by histology, is the measurement of the hepatic venous pressure gradient (HVPG). HVPG ≥ 10 mmHg is associated with an increased risk of HCC in these patients. However, these methods are expensive and invasive and are available only at referral centers. In the last decade, several studies have focused on the evaluation of several, simple, non-invasive tests (NITs) as predictors of HCC development. Among these methods, attention has particularly been paid to the elastographic techniques for the assessment of liver and spleen stiffness. We have reviewed the current literature about vibration-controlled transient elastography (VCTE), magnetic resonance elastography (MRE), and other ultrasound-based elastographic techniques (e.g., SWE) in predicting primary HCC occurrence and recurrence. Despite promising results, the overall heterogeneity resulting from the variability in the populations analyzed, the differences in the elastographic techniques used, the design and methodological quality of the available studies, prevented us from drawing definite conclusions on the liver and spleen stiffness role for predicting HCC occurrence and recurrence in chronic liver disease patients.

Chronic hepatitis B (CHB) disease caused by persistent infection with hepatitis B virus (HBV) is a global health problem affecting almost 300 million people worldwide, resulting in up to 1 million deaths each year. The factors contributing to HBV mediated liver disease are yet to be fully resolved, however, multiple studies have suggested that HBV splice variants may be a contributing factor. Recent studies have indicated that novel fusion proteins encoded by splice variants, or the splice-derived RNA itself, may impact replication of wild-type HBV, although the direct mechanisms for these interactions are largely unknown. This review explores the latest knowledge regarding the contribution of splice variants to liver disease and their impact on HBV replication.

Patients with advanced chronic liver disease can develop specific pulmonary complications related or unrelated to pre-existing lung disease. The three major pulmonary complications in this patient population include hepatopulmonary syndrome (HPS), portopulmonary hypertension (PoPH), and hepatic hydrothorax (HH). These entities are most often revealed by increasing dyspnea together with signs of portal hypertension. The prevalence of these complications remains underestimated due to the lack of routine screening of the cirrhotic population. The pathophysiology of HH is better understood than that of HPS and PoPH. The clinical features, diagnosis, and therapeutic options of these pulmonary complications are extensively discussed in this chapter. Liver transplantation may offer a curative therapy in highly-selected cases and MELD exception points allow priority access to liver transplantation, thus avoiding potential deterioration while awaiting transplant and providing a better post liver transplant survival. The complexity of managing these pulmonary complications requires a multidisciplinary team approach, especially when liver transplantation is indicated.

Acute decompensation is defined as the development of ascites, bleeding due to portal hypertension, jaundice, or hepatic encephalopathy in the presence of known or unknown chronic liver disease. Acute-on-chronic liver disease is defined as a clinical entity reflecting acute worsening in liver function along with extrahepatic organ failure with significantly higher 28-day mortality. In the common pathogenesis, severe systemic inflammation and portal hypertension and varying degrees of reaction to these conditions play a major role. Triggering factors act as accelerators in the development of acute decompensation and acute-on-chronic liver failure. The extrahepatic organ failure in acute-on-chronic liver failure is mainly due to tissue hypoxia due to decreased perfusion and cellular edema. The number of organ failure in acute-on-chronic liver failure is considered to be the most important prognostic indicator. Liver transplantation remains the most appropriate treatment option for selected patients, even though supportive therapies based on the severity of the disease and the clinical findings that have developed are at the forefront.

With the rising prevalence of chronic liver disease worldwide, the incidence and prevalence of acute-on-chronic liver failure (ACLF) are increasing and attribute to higher morbidity, mortality, and healthcare costs. Many of such patients die without being considered for the lifesaving treatment option of liver transplantation. The underutilization of liver transplantation as a therapeutic option in the setting of ACLF, is due to multiple reasons; with the heterogeneity of ACLF and the lack of universal definition being the key players. Liver transplantation listing and allocation are based on MELD score. As of now, we do not know where MELD score stands in regard to defining ACLF and the prognostication of such patients. This insight is very important for the efficient identification of potential liver transplantation candidates in the setting of ACLF. This review paper investigates the role of liver transplantation in the setting of ACLF. In light of recent evidence, MELD score is not the perfect model in the setting of ACLF either. The safety of liver transplantation, either deceased donor or living donor, among ACLF patients has been debated. The short-term mortality rate of ACLF patients has created a need for a standard liver transplant selection criterion for these patients. Based on published literature, we find that three commonly used ACLF definitions may be used in combination to define the sensitivity, specificity, and futility of ACLF and we propose an algorithm to best identify patients for urgent liver transplantation in the setting of ACLF. Moreover, we discuss the data on the safety of liver transplantation in the setting of ACLF. Future validation of this multifaceted approach could bridge the gap between ACLF patients and appropriately guided medical intervention.

Transabdominal ultrasound is a valuable diagnostic approach for evaluating the gastrointestinal tract and related disorders. This dynamic examination provides real-time visualization of the digestive tube and surrounding structures, assessment of peristaltic movements, estimation of compressibility of intestinal loops, and recognition of painful spots requiring specific attention. Since ultrasound imaging is non-invasive, painless, reproducible, inexpensive and requires no special preparation, it is used as a major diagnostic tool in emergency settings and in outpatient follow-up of several disorders. Costs, encompassing both accessibility and actual procedural expenses, are lower than those associated with other diagnostic techniques. However, the incorporation of gastro-intestinal ultrasound (GIUS) in clinical practice has not been widely used on a global scale. The purpose of this paper is to provide an overview of the execution techniques as well as the main areas of application for GIUS. Through illustrative iconographic representation, emphasis was placed on its potential within the diagnostic and therapeutic pathway of various acute and chronic gastrointestinal disorders.

Hepatitis C viral infections present a significant global health challenge, carrying substantial economic implications. These infections manifest in various clinical forms, including acute and chronic hepatitis, liver cirrhosis, hepatic failure, and hepatocellular carcinoma (HCC). Liver cirrhosis and HCC emerge as the primary contributors to mortality in hepatitis virus-induced liver diseases. To alleviate the public health impact of this disease, it is imperative to enhance the diagnosis and treatment rates among hepatitis C virus-infected individuals. The advent of direct-acting antivirals (DAAs), especially pan-genotypic regimens such as a combination of sofosbuvir and velpatasvir, has shown remarkable progress in achieving hepatitis C cure. However, potential obstacles, such as drug adverse effects and resistance-associated substitutions (RASs), warrant attention. Managing chronic hepatitis C (CHC) requires tailored treatment plans, vigilant monitoring, and judicious re-treatment strategies.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and its death rate is rising faster than that of any other cancer, while we still lack effective treatments. The increasing incidence of liver cancer in western countries is closely associated with the growing prevalence of metabolic dysfunction-associated steatohepatitis (MASH) linked to metabolic diseases. While the contribution of lipids in the progression of MASH pathogenesis and its progression to HCC is well recognized, the specific contribution of cholesterol is subject to controversy. The liver plays a central role in cholesterol metabolism, where the majority of its biosynthesis, storage, excretion, recycling, and conversion into bile acids occur. Moreover, cholesterol is implicated in numerous hepatocyte cellular processes, encompassing endoplasmic reticulum function, formation of lipid microdomains in the plasma membrane, metabolism of lipoproteins, and mitochondrial function and performance. Therefore, it is not surprising that cholesterol plays key roles in initiation, promotion, and survival of HCC cells and there are several lines of evidence pointing to that cancer cells are subverting cholesterol metabolism to foster their proliferation and survival through various mechanisms. This narrative review provides a concise overview of the physiological and pathological roles of cholesterol in the transition from healthy hepatocytes to HCC, in the context of MASH. Gaining further understanding of how hepatic cancer cells disrupt cholesterol homeostasis and how these perturbations impact cancer progression will facilitate the identification of novel and more effective cancer treatment strategies in this complex and devastating disease.