Seminars in liver disease最新文献

Alcohol-associated liver disease (ALD) is one of the leading causes of chronic liver disease and a major cause of liver-related death. ALD is a multifactorial disease triggered by the oxidative metabolism of alcohol which leads to the activation of multiple factors that promote the progression from steatosis to more advanced stages like alcohol-associated steatohepatitis (AH) that culminate in alcohol-associated cirrhosis and hepatocellular carcinoma. Poor understanding of the complex heterogeneous pathology of ALD has limited drug development for this disease. Alterations in mitochondrial performance are considered a crucial event in paving the progression of ALD due to the crucial role of mitochondria in energy production, intermediate metabolism, calcium homeostasis, and cell fate decisions. Therefore, understanding the role of mitochondria in eliciting steatosis and progression toward AH may open the door to new opportunities for treatment. In this review, we will cover the physiological function of mitochondria, its contribution to ALD in experimental models and human disease, and explore whether targeting mitochondria may represent a game changer in the treatment of ALD.

Drug-induced liver injury (DILI) continues to be a major concern in clinical practice, thus necessitating a need for novel therapeutic approaches to alleviate its impact on hepatic function. This review investigates the therapeutic potential of nutraceuticals against DILI, focusing on examining the underlying molecular mechanisms and cellular pathways. In preclinical and clinical studies, nutraceuticals, such as silymarin, curcumin, and N-acetylcysteine, have demonstrated remarkable efficacy in attenuating liver injury induced by diverse pharmaceutical agents. The molecular mechanisms underlying these hepatoprotective effects involve modulation of oxidative stress, inflammation, and apoptotic pathways. Furthermore, this review examines cellular routes affected by these nutritional components focusing on their influence on hepatocytes, Kupffer cells, and stellate cells. Key evidence highlights that autophagy modulation as well as unfolded protein response are essential cellular processes through which nutraceuticals exert their cytoprotective functions. In conclusion, nutraceuticals are emerging as promising therapeutic agents for mitigating DILI, by targeting different molecular pathways along with cell processes involved in it concurrently.

The prevalence of Metabolic dysfunction-associated steatotic liver disease (MASLD) - previously described as non-alcoholic fatty liver disease (NAFLD) - continues to rise globally. Despite this, therapeutic measures for MASLD remain limited. Recently, there has been a growing interest in the gut microbiome's role in the pathogenesis of MASLD. Understanding this relationship may allow for the administration of therapeutics that target the gut microbiome and/or its metabolic function to alleviate MASLD development or progression. This review will discuss the interplay between the gut microbiome's structure and function in relation to the development of MASLD, assess the diagnostic yield of gut microbiome-based signatures as a non-invasive tool to identify MASLD severity, and examine current and emerging therapies targeting the gut microbiome-liver axis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and can progress to serious complications, including metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Predisposing risk factors for MASH include obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome. Patients with MASH often experience significant impairments in their health-related quality of life (HRQoL) and other patient-reported outcomes (PROs), particularly in physical functioning domains. Incorporating PROs offers valuable insights into patients' perspectives on their symptoms, treatment efficacy, and overall well-being, thereby guiding more holistic and patient-centered care strategies. This review aims to investigate the utilization of patient-reported outcome measures (PROMs) in the context of MASLD and MASH care, identify which PROMs are employed, and summarize the outcomes reported.

Portal vein thrombosis (PVT) is one of the common complications of cirrhosis. The incidence of PVT correlates with liver disease severity-higher incidence in patients with Child-Turcotte-Pugh (CTP) C, large spontaneous portosystemic shunts, hepatofugal portal flow, and in the presence of hepatocellular carcinoma. PVT may worsen ascites, increase the risk and poor control of variceal bleeding. The occurrence of PVT may increase morbidity and lower survival after a liver transplant. Using statins prevents the occurrence of PVT, whereas beta-blockers may aggravate its occurrence. Cross-sectional imaging is mandatory for the precise diagnosis and classification of PVT. Symptomatic, occlusive PVT and candidacy for liver transplantation are the main indications for anticoagulation. Vitamin K antagonists, low-molecular-weight heparin, and newer anticoagulants are effective and safe in cirrhosis. Direct-acting oral anticoagulants are agents of choice in early cirrhosis (CTP A, B). The duration of anticoagulant therapy, predictors of response, and management of complications of cirrhosis while on therapy require in-depth knowledge and individualized treatment. Transjugular intrahepatic porto-systemic shunt can be considered in nonresponsive cases or when anticoagulants are contraindicated. This manuscript reviews the latest updated knowledge about managing PVT in cirrhosis.

Rodents are commonly employed to model human liver conditions, although species differences can restrict their translational relevance. To overcome some of these limitations, researchers have long pursued human hepatocyte transplantation into rodents. More than 20 years ago, the first primary human hepatocyte transplantations into immunodeficient mice with liver injury were able to support hepatitis B and C virus infections, as these viruses cannot replicate in murine hepatocytes. Since then, hepatocyte chimeric mouse models have transitioned into mainstream preclinical research and are now employed in a diverse array of liver conditions beyond viral hepatitis, including malaria, drug metabolism, liver-targeting gene therapy, metabolic dysfunction-associated steatotic liver disease, lipoprotein and bile acid biology, and others. Concurrently, endeavors to cotransplant other cell types and humanize immune and other nonparenchymal compartments have seen growing success. Looking ahead, several challenges remain. These include enhancing immune functionality in mice doubly humanized with hepatocytes and immune systems, efficiently creating mice with genetically altered grafts and reliably humanizing chimeric mice with renewable cell sources such as patient-specific induced pluripotent stem cells. In conclusion, hepatocyte chimeric mice have evolved into vital preclinical models that address many limitations of traditional rodent models. Continued improvements may further expand their applications.

Alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), two main types of steatotic liver disease (SLDs), are characterized by a wide spectrum of several different liver disorders, including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Multiple immune cell-mediated inflammatory responses not only orchestrate the killing and removal of infected/damaged cells but also exacerbate the development of SLDs when excessive or persistent inflammation occurs. In recent years, single-cell and spatial transcriptome analyses have revealed the heterogeneity of liver-infiltrated immune cells in ALD and MASLD, revealing a new immunopathological picture of SLDs. In this review, we will emphasize the roles of several key immune cells in the pathogenesis of ALD and MASLD and discuss inflammation-based approaches for effective SLD intervention. In conclusion, the study of immunological mechanisms, especially highly specific immune cell population functions, may provide novel therapeutic opportunities for this life-threatening disease.

The hepatic extracellular matrix (ECM) is most accurately depicted as a dynamic compartment that comprises a diverse range of players that work bidirectionally with hepatic cells to regulate overall homeostasis. Although the classic meaning of the ECM referred to only proteins directly involved in generating the ECM structure, such as collagens, proteoglycans, and glycoproteins, the definition of the ECM is now broader and includes all components associated with this compartment. The ECM is critical in mediating phenotype at the cellular, organ, and even organismal levels. The purpose of this review is to summarize the prevailing mechanisms by which ECM mediates hepatic phenotype and discuss the potential or established role of this compartment in the response to hepatic injury in the context of steatotic liver disease.

Ammonia is a product of amino acid metabolism that accumulates in the blood of patients with cirrhosis and plays a pivotal role in the pathogenesis of hepatic encephalopathy (HE). Despite being one of the main drivers of brain dysfunction, for many years international societies stated that increased blood ammonia does not add any diagnostic, staging, or prognostic value for HE in patients with cirrhosis. Nonetheless, in the last decades, evidence is emerging that supports the utility of ammonia for risk stratification, but its role in guiding HE diagnosis, staging, and treatment is unclear and there is equipoise in its use in clinical practice. This review provides the latest evidence on the value of ammonia as a biomarker in patients with cirrhosis. Although correct measurement of ammonia requires disciplined sample collection, it provides extremely useful clinical guidance for the diagnosis of HE, offers prognostic information, and it defines a therapeutic target.

The liver has the great ability to regenerate after partial resection or injury, and the mechanisms underlying liver regeneration have been extensively investigated. Interestingly, acute liver injuries triggered by various etiologies are associated with the formation of necrotic lesions, and such necrotic lesions are also rapidly resolved. However, how necrotic liver lesions are repaired has not been carefully investigated until recently. In this review, we briefly summarize the spatiotemporal process of necrotic liver lesion resolution in several liver injury models including immune-mediated liver injury and drug-induced liver injury. The roles of liver nonparenchymal cells and infiltrating immune cells in controlling necrotic liver lesion resolution are discussed, which may help identify potential therapies for acute liver injury and failure.