"The liver is the origin of the veins and the source of the blood." - Galen, De Usu Partium Galen's hepatocentric physiology foreshadowed the liver-brain axis, a network linking vagal signaling, cytokines, metabolites, and migratory immune cells. Central to the immune arm of this axis, the liver generates 25-50% of thoracic duct lymph, positioning hepatic lymphatic output as a significant, though not yet fully characterized, source of T cells and cytokines in systemic circulation, a contribution that increases with hepatic inflammation in chronic metabolic diseases. We propose that T lymphocytes are the key cellular effectors through which inflammation originating in the liver, propagating systemically, a process we term hepatosystemic inflammation (see Glossary), reaches the central nervous system (CNS). In metabolic dysfunction-associated steatotic liver disease (MASLD), hepatosystemic inflammation generates peripheral 'push signals' that may license T cells for CNS access, while neuroinflammatory 'pull signals' at CNS barrier interfaces may establish permissive entry points. In conclusion, we propose that T cell licensing by hepatosystemic signals represents the immune arm of the liver-brain axis and a mechanistic bridge between metabolic liver disease and neuroimmune dysfunction and associated cognitive decline, and identify candidate therapeutic targets along this cascade.

Endothelial cell dysfunction and loss are key drivers of acute and chronic liver disease, underscoring a critical unmet need for liver vascular-targeted therapies. Liver sinusoidal endothelial cells are specialized endothelial cells that form a fenestrated microvascular niche regulating hepatocyte metabolism, immune homeostasis, and hepatic stellate cell activation. Repopulating this niche through transplantation of primary liver sinusoidal endothelial cells, endothelial progenitor cells, induced-pluripotent stem cell-derived liver sinusoidal endothelial cells, or engineered endothelial cells delivered within biomaterial aims to restore microvascular architecture, reestablish supportive angiocrine signaling, attenuate fibrosis, and promote liver regeneration. This review summarizes the biological rationale for endothelial cell-based therapy, compares cell sources and engineering strategies, evaluates cell delivery and engraftment approaches, and synthesizes preclinical evidence demonstrating therapeutic benefits across diverse animal models of liver injury. Finally, we highlight key translational challenges and propose future directions to accelerate the clinical development of endothelial cell-based therapies for liver disease.

This review explores the pivotal and multifaceted roles of neutrophils in the context of liver pathophysiology. While traditionally recognized as primary effectors of antibacterial immunity, recent evidence reveals that these abundant leukocytes function as complex regulators in the development and progression of various hepatic conditions. Neutrophils act as double-edged swords: they serve as critical instigators of inflammatory cascades and fibrogenesis, yet simultaneously provide essential contributions to immune defense and the orchestration of tissue repair. This paper synthesizes current research regarding neutrophil behavior within diverse hepatic microenvironments and evaluates their specific contributions to disease resolution versus exacerbation. Furthermore, we deliberate on the emerging potential of targeting neutrophil-specific pathways as a novel therapeutic strategy for liver diseases. Understanding these intricate balances is essential for transitioning from broad anti-inflammatory approaches to precise, neutrophil-modulated interventions. In conclusion, given their status as a dynamic research hotspot, a deeper mechanical understanding of neutrophil functions is imperative for the development of targeted clinical treatments for liver disorders.

The clinical management of hepatocellular carcinoma (HCC) has evolved significantly over the past decade. Key advances include the introduction of immune-based treatment options, which now serve as the foundation for systemic therapies. Additionally, innovations in surgical techniques, such as robotic surgery, have broadened the scope of resection to include selected patients previously deemed unsuitable due to factors like tumor location or the presence of portal hypertension. HCC downstaging has also gained recognition as a viable strategy in appropriately selected patients, demonstrating outcomes comparable to those achieved under conventional listing criteria. Consequently, the management of HCC has become increasingly complex, underscoring the critical importance of multidisciplinary collaboration and shared decision-making. In this review, we provide a concise overview of practical recommendations for HCC management, encompassing aspects such as risk stratification, early detection, diagnosis, and treatment strategies.

Hepatocellular carcinoma (HCC) care is rapidly evolving, driven by a relentless pursuit of improved patient outcomes, enhanced quality of life, and increased patient empowerment. This transformation draws inspiration from innovative concepts originating in the corporate world, notably the insights of Rita McGrath, and their application to medicine, particularly within the Barcelona Clinic Liver Cancer (BCLC) system. This review explores pivotal advancements in shared decision-making, cross-disease insights, remote monitoring and telehealth, dynamics of multidisciplinary teamwork, and patient empowerment. These innovations signify a fundamental shift in our commitment to alleviating patient distress, fostering treatment adherence, and elevating the overall patient experience. This approach not only optimizes established practices but also broadens the horizons of HCC care by transferring expertise to new domains. Advanced practice nurses (APNs) play an essential role in spearheading this transformation through patient-centered care coordination and educational initiatives, fundamentally improving the management and outcomes of HCC care within the BCLC framework. · Value-based Coordination: Dynamic scheduling, team coordination, and personalized care reduce inefficiencies, ensuring timely, patient-centered interventions.. · Empowering Nurses and Patients: Advanced practice nurses (APNs) play a central role in educating and guiding patients, boosting adherence and autonomy.. · Leveraging Technology: Tools like telemedicine and real-time alerts streamline communication, reduce hospitalizations, and optimize resource allocation.. · Scalable Solutions: The Barcelona Clinic Liver Cancer (BCLC) model offers replicable practices adaptable to broader healthcare systems..

Primary liver cancer remains a global health challenge due to rising incidence, limited curative options, and poor overall survival. Poor outcomes stem from tumor heterogeneity, limited efficacy of current therapies, and comorbid chronic liver disease. Despite recent advances in immunotherapy and combination treatments, response rates remain low, and predictive biomarkers are lacking. As a result, there is an urgent need for preclinical models that capture the molecular, cellular, and immune landscape of primary liver cancer. This review discusses the strengths and limitations of patient-derived models of liver cancer, including two-dimensional patient-derived cell lines (PDCL), three-dimensional (3D) patient-derived tumor organoids (PDTOs), and patient-derived xenografts (PDXs). While PDCLs and PDTOs enable high throughput studies, they lack a representative tumor microenvironment. PDXs, including PDXs in animals with humanized immune systems, may more effectively mimic tumor-environment interactions but are costly, complex, and still contain mouse stromal cells. Ex vivo tissue culture preserves tissue structure and cell-cell interactions in an immunocompetent environment; however, short duration of viable culture limits broader application. Continued innovation in the development of multicellular three-dimensional culture systems and in vivo humanization strategies will play a critical role in enabling the development of more personalized and effective therapies for primary liver cancer.

Primary liver cancer, or hepatocellular carcinoma (HCC), typically emerges in fibrotic livers where persistent inflammation and extracellular matrix (ECM) remodeling create a permissive niche for malignant transformation. Although cirrhosis remains a major risk factor, mounting data show that fibrosis itself, often in the context of metabolic dysfunction-associated steatotic liver disease (MASLD), can promote hepatocarcinogenesis even before cirrhosis develops. This review synthesizes mechanistic insights from hepatic stellate cell (HSC) biology and tumor immunology that position fibrosis as an instigator of HCC. Fibrotic remodeling increases ECM stiffness, distorts sinusoidal architecture, and promotes abnormal angiogenesis, while HSCs reprogram immune surveillance toward immune cell exclusion and immunosuppression. Aging and cellular senescence amplify these effects through a senescence-associated secretory phenotype in HSCs and hepatocytes, which fuels chronic inflammation and immune dysfunction. Metabolic crosstalk and extracellular vesicle exchange further couple stromal and epithelial programs, reinforcing stemness, therapy resistance, and metastatic fitness. In conclusion, the convergence of fibrogenic and oncogenic signaling drives HCC, uncovering actionable targets for its prevention and treatment.

The liver is a dynamic organ that plays a central role in metabolism and serves several critical functions in maintaining overall nutritional health, including helping maintain metabolic homeostasis by ensuring energy needs are met, eliminating waste products, and maintaining nutrient balance. Hepatic injury/liver dysfunction can compromise multiple metabolic processes and lead to complications such as malnutrition (deficiencies, excesses, or imbalances in a person's nutritional or caloric intake). The adverse clinical consequences of malnutrition vary widely from global malnutrition that can result in frailty, cachexia, and/or sarcopenia to micronutrient imbalances that can lead to individual functional alterations. Malnutrition is associated with a higher rate of complications including ascites, hepatic encephalopathy, and variceal bleeding, progressing to liver failure and poor survival outcomes. Malnutrition prior to liver transplantation is associated with worse postoperative quality of life, worse outcomes following decompensation events, and higher recurrence rates of hepatocellular carcinoma. Several treatment options are discussed.

Alcohol-associated liver disease (ALD) is a leading cause of liver disease worldwide, caused by hazardous alcohol use. Many patients with ALD also have alcohol use disorder (AUD), a chronic mental health condition characterized by a cluster of behavioral, cognitive, and physiological symptoms that indicate continued alcohol use despite significant alcohol-related problems. Comprehensive care of ALD often requires treatment of AUD, and evidence has demonstrated that treating the latter improves patient outcomes. However, only a minority of patients with AUD/ALD receive treatment. Integrative care models where hepatologists work alongside AUD specialists have been developed. These partnerships have been associated with improved outcomes, including decreased rates of return to alcohol use, decreased healthcare utilization, and even improved mortality. We review the epidemiology, diagnosis, and treatment of AUD and ALD, examples of successful integrated care models, and outcomes. We also discuss knowledge gaps and areas where future research is needed, including the role of integrated care in the peri-transplantation period for ALD, harm reduction approaches, and the need for efforts to support collaboration for integrative care. In conclusion, the dual pathologies of AUD and ALD necessitate multidisciplinary care, and integrated care models have been shown to be both feasible and effective.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver malignancy characterized by the coexistence of both hepatocellular and biliary morphological differentiation. It is thought to represent less than 5% of all primary liver cancers and is associated with a dismal clinical course. Due to its rarity and inherent diagnostic challenges, consensus guidelines for the management of patients with cHCC-CCA are lacking, and treatments are usually extrapolated from HCC or CCA guidelines. This review provides an overview of the main clinical and histo-molecular features of cHCC-CCA, along with its diagnostic and therapeutic challenges. Technological advances have allowed researchers to progressively elucidate cHCC-CCA's unique biology and heterogeneity. Several major questions, however, remain, such as the cHCC-CCA cell of origin. Integration of multi-modal data and use of artificial intelligence provide interesting perspectives to further improve patient management; however, they will need to be carefully assessed and validated. A better definition and understanding of this entity will be key to further planning clinical trials.

Endohepatology is an emerging field that encompasses various diagnostic and therapeutic endoscopic ultrasound (EUS) techniques for the management of liver disease. It encompasses diagnostic techniques for fibrosis staging and portal hypertension evaluation, as well as therapeutic interventions for conditions like variceal bleeding. Given the medical complexity and fragility that are often encountered in patients with liver disease, careful attention is of paramount importance to minimize risk and invasiveness when possible while extracting maximal value with a therapeutic intent. EUS-guided access to liver, bile ducts, and the hepatic vasculature provides the ability for diagnostic evaluation and interventions, which are not limited by body habitus and the need for central vascular access. Established EUS-guided techniques include liver biopsy, direct portal pressure gradient measurements, and gastric variceal coiling and injection therapies. More emerging techniques, including liver palpation, shear wave elastography, portal venous sampling, rectal variceal coiling, and partial splenic artery embolization, have also been described in the literature. This review details the rationale and evidence behind both established and emerging EUS-guided techniques, highlighting their current and potential future impact on endohepatology.

Autoimmune liver diseases (AILDs), including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are chronic inflammatory conditions influenced by complex interactions among genetic, environmental, and immunological factors. Recent studies have highlighted the critical role of the gut microbiota in regulating immune responses beyond the gastrointestinal tract via the gut-liver axis. This review examines the interactions between intestinal microecology and AILDs, with a focus on mechanisms such as bacterial translocation, disruption of the intestinal barrier, and modulation of microbial metabolites. Dysbiosis, involving alterations in both bacterial and fungal communities, has been associated with immune dysregulation and hepatic inflammation. Evidence indicates that short-chain fatty acids, bile acids, and microbial products such as lipopolysaccharides influence hepatic immune tolerance and inflammatory signaling pathways. Several diagnostic and therapeutic approaches, including probiotics, fecal microbiota transplantation, and bile acid regulation, have shown potential to slow or alter disease progression. However, the clinical translation of these findings remains limited due to interindividual variability and the complex nature of the gut-liver axis. Continued research is needed to develop precision medicine strategies that can harness intestinal microecology for improved management of AILDs.

The porphyrias are a group of metabolic disorders that are caused by defects in one of the eight enzymes that synthesize heme. A common feature of all porphyrias is accumulation of porphyrin precursors or porphyrins, which are intermediates of the heme biosynthesis pathway. Approximately 15% of heme biosynthesis occurs in the liver, and excessive hepatic production of porphyrin precursors caused by heme enzyme deficiencies can lead to neurovisceral manifestations. Additionally, in erythropoietic protoporphyria, porphyrins accumulate in the liver, leading to hepatic injury. These rare diseases have few effective medical therapies, and disease mechanisms are not always well understood. Animal models have provided a platform to study the pathophysiology of disease and test emerging therapies. In this review, the last of a three-part series, we describe the animal models that have been generated to study porphyrias with hepatic involvement. For each model, we discuss mechanisms of injury, phenotypic features, and the similarities and contrasts to human porphyria. We also describe preclinical studies that have utilized the model for therapeutic interventions. Overall, animal-based studies have made significant contributions to our understanding of porphyria and may lead to innovative therapies in the future.

Patient-centered care for chronic liver disease is an approach that supports patient engagement and proactive interventions aimed at preserving quality of life and function and preventing adverse outcomes. Patient-centered care is fully realized by embracing multidisciplinary care, technological innovation, and fully optimized use of the electronic health record for remote monitoring and patient communication/education. It is best enabled using conducive payment models and may require adjustments to clinical structures. This review highlights key successful examples and areas for growth applicable to practices around the world.