Seminars in liver disease最新文献

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 co-morbid 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 (3-D) 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 multi-cellular 3-D 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.

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.

A new paradigm for drug development and patient therapeutic strategies is required, especially for complex, heterogeneous diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Heterogeneity in MASLD patients is driven by genetics, various comorbidities, gut microbiota composition, lifestyle, environment, and demographics that produce multiple patient disease presentations and outcomes. Existing drug development methods have had limited success for complex, heterogeneous diseases like MASLD where only a fraction of patients respond to specific treatments, prediction of a therapeutic response is not presently possible, and the cost of the new classes of drugs is high. However, it is now possible to generate patient digital twins (PDTs) that are computational models of patients using clinomics and other "omics" data collected from patients to make various predictions, including responses to therapeutics. PDTs are then integrated with patient biomimetic twins (PBTs) that are patient-derived organoids or induced pluripotent stem cells that are then differentiated into the optimal number of organ-specific cells to produce organ experimental models. The PBTs mimic key aspects of the patient's pathophysiology, enabling predictions to be tested. In conclusion, integration of PTDs and PBTs has the potential to create a powerful precision medicine platform, yet there are challenges.

Aging is characterized by the progressive deterioration of cell and tissue functions. The liver, which regulates metabolic homeostasis, detoxification, and immune responses, undergoes structural and functional changes with age. These include increasing genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing and intracellular communication, mitochondrial dysfunction, cell senescence, stem cell exhaustion, chronic inflammation, disabled macroautophagy, and dysbiosis. These alterations contribute to hepatocyte dysfunction, impaired regenerative responses, and fibrosis risk, which all exacerbate existing liver diseases. Senescence involves irreversible cell cycle arrest resulting in an inflammatory, senescence-associated secretory cell phenotype. Senescent hepatocytes, liver sinusoidal endothelial cells, hepatic stellate cells, and Kupffer cells accumulate in the aged liver, creating an inflammatory and fibrotic microenvironment that promotes tumorigenesis. As the burden of aging-related liver disease increases, therapeutic strategies targeting hepatic senescence have gained attention. We review these, along with the mechanisms and pathogenic effects of liver aging.

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.

Portosinusoidal vascular disorders (PSVD) represent a group of rare conditions characterized by abnormalities in the liver's vascular architecture, often manifesting with clinical features of portal hypertension (PH), in the absence of cirrhosis. The pathophysiology of PSVD remains unclear, but it is frequently linked to underlying immunological disorders, medications, hematological disorders, and thrombophilia. Laboratory tests typically show preserved liver function with or without slight alteration on the transaminase profile. A key diagnostic feature is the presence of clear signs of PH alongside normal or only slightly elevated liver stiffness and hepatic venous pressure gradient. Liver biopsy remains essential for confirming the diagnosis and excluding other causes of PH and cirrhosis. However, histological examination may reveal subtle or mild changes, making expert pathological analysis and high-quality specimens crucial for an accurate diagnosis. In some cases, characteristic histological findings may be identified in patients without overt PH, which could represent an early stage of the disease. The long-term prognosis for patients with PSVD is mainly influenced by severity of the underlying condition and development of PH. However, treatments that modify the disease's natural history are still lacking, and management primarily focuses on controlling complications related to PH. Further research into the pathogenesis and potential therapeutic strategies for PSVD is needed to improve patient outcomes.

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.

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.