The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-previously described as nonalcoholic fatty liver disease-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 noninvasive 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 and other patient-reported outcomes (PROs), particularly in physical functioning domains, fatigue, and vitality. 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.

Over 300 million individuals worldwide are chronically infected with hepatitis B virus and at risk for progressive liver disease. Due to the lack of a therapy that reliably achieves viral elimination and the variability of liver disease progression, treatment decisions are guided by the degree of liver disease and viral biomarkers as the viral life-cycle is well characterized and largely conserved between individuals. In contrast, the immunological landscape is much more heterogeneous and diverse and the measurement of its components is less well standardized. Due to the lack of a universal and easily measurable set of biomarkers, clinical practice guidelines remain controversial, aiming for a balance between simplifying treatment decisions by reducing biomarker requirements and using all available biomarkers to avoid overtreatment of patients with low risk for disease progression. While approved therapies such as nucleos(t)ide analogs improve patient outcomes, the inability to achieve a complete cure highlights the need for novel therapies. Since no treatment candidate has demonstrated universal efficacy, biomarkers will remain important for treatment stratification. Here, we summarize the current knowledge on virological and immunological biomarkers with a specific focus on how they might be beneficial in guiding treatment decisions in chronic hepatitis B.

Acute-on-chronic liver failure (ACLF) is defined as a clinical syndrome that develops in patients with chronic liver disease characterized by the presence of organ failure and high short-term mortality, although there is still no worldwide consensus on diagnostic criteria. Management of ACLF is mainly based on treatment of "precipitating factors" (the most common are infections, alcohol-associated hepatitis, hepatitis B flare, and bleeding) and support of organ failure, which often requires admission to the intensive care unit. Liver transplantation should be considered in patients with ACLF grades 2 to 3 as a potentially life-saving treatment. When a transplant is not indicated, palliative care should be considered after 3 to 7 days of full organ support in patients with at least four organ failures or a CLIF-C ACLF score of >70. This review summarizes the current knowledge on the management of organ failure in patients with ACLF, focusing on recent advances.

The Wilson disease (WD) research field is rapidly evolving, and new diagnostic and therapeutical approaches are expected to be change-gamers in the disease for the incoming years, after decades of slow changing options. Non-ceruloplasmin bound copper assays for circulating bioavailable copper are being tested for use in monitoring therapy and may also help in the diagnosis of new cases of WD. Other diagnostic advances include use of quantitative detection of ATP7B peptides in dried blood spots, a method that is being tested for use in newborn screening for WD, and the use of metallothionein immuno-staining of liver biopsy specimens to differentiate WD from other liver diseases. Ongoing and future trials of gene therapy and use of methanobactin are expected to restore biliary copper excretion from the liver, thus making a cure for WD a plausible therapeutic objective. With the aim of helping updating physicians, this review summarizes the novel methods for WD diagnosis and future therapies. Advancing understanding of the scientific advances that can be applied to WD will be critical for ensuring that our patients will receive the best current and future care.

There continues to be an ongoing need for fair and equitable organ allocation. The Model for End-stage Liver Disease (MELD) score has evolved as a calculated framework to evaluate and allocate patients for liver transplantation objectively. The original MELD score has undergone multiple modifications as it is continuously scrutinized for its accuracy in objectively representing the clinical context of patients with liver disease. Several refinements and iterations of the score have been developed, including the widely accepted MELD-Na score. In addition, the most recent updated iteration, MELD 3.0, has been created. The MELD 3.0 calculator incorporates new variables such as patient sex and serum albumin levels and assigns new weights for serum sodium, bilirubin, international normalized ratio, and creatinine levels. It is anticipated that the use of MELD 3.0 scores will reduce overall waitlist mortality and enhance access for female liver transplant candidates. However, despite the emergence of the MELD score as one of the most objective measures for fair organ allocation, various countries and healthcare systems employ alternative methods for stratification and organ allocation. This review article highlights the origins of the MELD score, its iterations, the current MELD 3.0, and future directions for managing liver transplantation organ allocation.

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.

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.

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.

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.

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.

The new nomenclature of metabolic dysfunction-associated steatotic liver disease (MASLD) emphasizes a positive diagnosis based on cardiometabolic risk factors. This definition is not only less stigmatizing but also allows for subclassification and stratification, thereby addressing the heterogeneity of what was historically referred to as nonalcoholic fatty liver disease. The heterogeneity within this spectrum is influenced by several factors which include but are not limited to demographic/dietary factors, the amount of alcohol use and drinking patterns, metabolic status, gut microbiome, genetic predisposition together with epigenetic factors. The net effect of this dynamic and intricate system-level interaction is reflected in the phenotypic presentation of MASLD. Therefore, the application of precision medicine in this scenario aims at complex phenotyping with consequent individual risk prediction, development of individualized preventive strategies, and improvements in the clinical trial designs. In this review, we aim to highlight the importance of precision medicine approaches in MASLD, including the use of novel biomarkers of disease, and its subsequent utilization in future study designs.

Risk of disease progression and clinical outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with fibrosis stage and presence of "at-risk metabolic dysfunction-associated steatohepatitis (MASH)." Although liver biopsy is considered the gold standard to diagnose MASH and stage of fibrosis, biopsy is infrequently performed in clinical practice and has associated sampling error, lack of interrater reliability, and risk for procedural complications. Noninvasive tests (NITs) are routinely used in clinical practice for risk stratification of patients with MASLD. Several NITs are being developed for detecting "at-risk MASH" and cirrhosis. Clinical care guidelines apply NITs to identify patients needing subspecialty referral. With recently approved Food and Drug Administration treatment for MASH and additional emerging pharmacotherapy, NITs will identify patients who will most benefit from treatment, monitor treatment response, and assess risk for long-term clinical outcomes. In this review, we examine the performance of NITs to detect "at-risk MASH," fibrosis stage, response to treatment, and risk of clinical outcomes in MASLD and MASH.

Transplantation of the liver in combination with other organs is an increasingly performed procedure. Over the years, continuous improvement in survival could be realized through careful patient selection and refined organ preservation techniques, in spite of the challenges posed by aging recipients and donors, as well as the increased use of steatotic liver grafts. Herein, we revisit the epidemiology, allocation policies in different transplant zones, indications, and outcomes with regard to simultaneous organ transplants involving the liver, that is combined heart-liver, liver-lung, liver-kidney, and multivisceral transplantation. We address challenges surrounding combined organ transplantation such as equity, utility, and logistics of dual organ implantation, but also advantages that come along with combined transplantation, thereby focusing on molecular mechanisms underlying immunoprotection provided by the liver to the other allografts. In addition, the current standing and knowledge of machine perfusion in combined organ transplantation, mostly based on center experience, will be reviewed. Notwithstanding all the technical advances, shortage of organs, and the lack of universal eligibility criteria for certain multi-organ combinations are hurdles that need to be tackled in the future.

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.

Gallstones are common and affect up to 20% of the general adult population and >20% of them will develop symptoms or complications of cholelithiasis. The high risk of gallbladder stone formation can be reduced by ursodeoxycholic acid in the case of significant weight reduction resulting from diet or bariatric surgery. Laparoscopic cholecystectomy is indicated for symptomatic gallstones, as the risk of recurrence or complications increases over the course of the disease. Biliary colic is treated with nonsteroidal anti-inflammatory drugs and spasmolytics; opioids can also be used in cases of severe acute pain. Acute cholecystitis represents a common complication of gallbladder stones and a cholecystectomy should be performed early electively, i.e., within 24 hours of admission to hospital. Symptomatic bile duct stones are primarily treated endoscopically. Immediate anti-infective therapy is mandatory in acute cholangitis. Although knowledge on the genetics and pathophysiology of gallstones has increased, current treatment algorithms remain predominantly invasive, based on interventional endoscopy and surgery. Future efforts should focus on novel strategies to prevent the development of gallstones.

This review explores the biological aspects of neutrophils, their contributions to the development of steatotic liver disease, and their potential as therapeutic targets for the disease. Although alcohol-associated and metabolic dysfunction-associated liver diseases originate from distinct etiological factors, the two diseases frequently share excessive lipid accumulation as a common contributor to their pathogenesis, thereby classifying them as types of steatotic liver disease. Dysregulated lipid deposition in the liver induces hepatic injury, triggering the activation of the innate immunity, partially through neutrophil recruitment. Traditionally recognized for their role in microbial clearance, neutrophils have recently garnered attention for their involvement in sterile inflammation, a pivotal component of steatotic liver disease pathogenesis. In conclusion, technological innovations, including single-cell RNA sequencing, have gradually disclosed the existence of various neutrophil subsets; however, how the distinct subsets of neutrophil population contribute differentially to the development of steatotic liver disease remains unclear.

Liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and the incidence of HCC is on the rise. Liver cancers in general and HCC in particular do not respond to chemotherapy. Radiological ablation, surgical resection, and liver transplantation are the only medical therapies currently available. Hepatocyte nuclear factor 4 α (HNF4α) is an orphan nuclear receptor expressed only in hepatocytes in the liver. HNF4α is considered the master regulator of hepatic differentiation because it regulates a significant number of genes involved in various liver-specific functions. In addition to maintaining hepatic differentiation, HNF4α also acts as a tumor suppressor by inhibiting hepatocyte proliferation by suppressing the expression of promitogenic genes and inhibiting epithelial to mesenchymal transition in hepatocytes. Loss of HNF4α expression and function is associated with rapid progression of chronic liver diseases that ultimately lead to liver cirrhosis and HCC, including metabolism-associated steatohepatitis, alcohol-associated liver disease, and hepatitis virus infection. This review summarizes the role of HNF4α in liver cancer pathogenesis and highlights its potential as a potential therapeutic target for HCC.

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.