Seminars in liver disease最新文献

Idiosyncratic drug-induced liver injury (DILI) is a rare and unpredictable form of hepatotoxicity. While its clinical course is usually benign, cases leading to liver transplantation or death can occur. Based on modern prospective registries, antimicrobials including antibiotics and antifungals are frequently implicated as common causes. Amoxicillin-clavulanate ranks as the most common cause for DILI in the Western World. Although the absolute risk of hepatotoxicity of these agents is low, as their usage is quite high, it is not uncommon for practitioners to encounter liver injury following the initiation of antibiotic or antifungal therapy. In this review article, mechanisms of hepatoxicity are presented. The adverse hepatic effects of well-established antibiotic and antifungal agents are described, including their frequency, severity, and pattern of injury and their HLA risks. We also review the drug labeling and prescription guidance from regulatory bodies, with a focus on individuals with hepatic impairment.

Primary liver cancer, represented mainly by hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (CCA), is one of the most common and deadliest tumors worldwide. While surgical resection or liver transplantation are the best option in early disease stages, these tumors often present in advanced stages and systemic treatment is required to improve survival time. The emergence of immune checkpoint inhibitor (ICI) therapy has had a positive impact especially on the treatment of advanced cancers, thereby establishing immunotherapy as part of first-line treatment in HCC and CCA. Nevertheless, low response rates reflect on the usually cold or immunosuppressed tumor microenvironment of primary liver cancer. In this review, we aim to summarize mechanisms of resistance leading to tumor immune escape with a special focus on the composition of tumor microenvironment in both HCC and CCA, also reflecting on recent important developments in ICI combination therapy. Furthermore, we discuss how combination of ICIs with established primary liver cancer treatments (e.g. multikinase inhibitors and chemotherapy) as well as more complex combinations with state-of-the-art therapeutic concepts may reshape the tumor microenvironment, leading to higher response rates and long-lasting antitumor immunity for primary liver cancer patients.

This review examines the latest epidemiological and molecular pathogenic findings of metabolic-associated hepatocellular carcinoma (HCC). Its increasing prevalence is a significant concern and reflects the growing burden of obesity and metabolic diseases, including metabolic dysfunction-associated steatotic liver disease, formerly known as nonalcoholic fatty liver disease, and type 2 diabetes. Metabolic-associated HCC has unique molecular abnormality and distinctive gene expression patterns implicating aberrations in bile acid, fatty acid metabolism, oxidative stress, and proinflammatory pathways. Furthermore, a notable frequency of single nucleotide polymorphisms in genes such as patatin-like phospholipase domain-containing 3, transmembrane 6 superfamily member 2, glucokinase regulator, and membrane-bound O-acyltransferase domain-containing 7 has been observed. The tumor immune microenvironment of metabolic-associated HCC is characterized by unique phenotypes of macrophages, neutrophils, and T lymphocytes. Additionally, the pathogenesis of metabolic-associated HCC is influenced by abnormal lipid metabolism, insulin resistance, and dysbiosis. In conclusion, deciphering the intricate interactions among metabolic processes, genetic predispositions, inflammatory responses, immune regulation, and microbial ecology is imperative for the development of novel therapeutic and preventative measures against metabolic-associated HCC.

Primary liver cancer is a solid malignancy with a high mortality rate. The success of immunotherapy has shown great promise in improving patient care and highlights a crucial need to understand the complexity of the liver tumor immune microenvironment (TIME). Recent advances in single-cell and spatial omics technologies, coupled with the development of systems biology approaches, are rapidly transforming the landscape of tumor immunology. Here we review the cellular landscape of liver TIME from single-cell and spatial perspectives. We also discuss the cellular interaction networks within the tumor cell community in regulating immune responses. We further highlight the challenges and opportunities with implications for biomarker discovery, patient stratification, and combination immunotherapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent condition with a broad spectrum defined by liver biopsy. This gold standard method evaluates three features: steatosis, activity (ballooning and lobular inflammation), and fibrosis, attributing them to certain grades or stages using a semiquantitative scoring system. However, liver biopsy is subject to numerous restrictions, creating an unmet need for a reliable and reproducible method for MASLD assessment, grading, and staging. Noninvasive imaging modalities, such as magnetic resonance imaging (MRI), offer the potential to assess quantitative liver parameters. This review aims to provide an overview of the available MRI techniques for the three criteria evaluated individually by liver histology. Here, we discuss the possibility of combining multiple MRI parameters to replace liver biopsy with a holistic, multiparametric MRI protocol. In conclusion, the development and implementation of such an approach could significantly improve the diagnosis and management of MASLD, reducing the need for invasive procedures and paving the way for more personalized treatment strategies.

Excessive alcohol consumption represents an important burden for health systems worldwide and is a major cause of liver- and cancer-related deaths. Alcohol consumption is mostly assessed by self-report that often underestimates the amount of drinking. While alcohol use disorders identification test - version C is the most widely used test for alcohol use screening, in patients with liver disease the use of alcohol biomarker could help an objective assessment. The amount of alcohol that leads to significant liver disease depends on gender, genetic background, and coexistence of comorbidities (i.e., metabolic syndrome factors). All patients with alcohol-associated liver disease are recommended to follow complete abstinence and they should be treated within multidisciplinary teams. Abstinence slows down and even reverses the progression of liver fibrosis and can help recompensate patients with complicated cirrhosis. Whether there is a safe amount of alcohol in the general population is a matter of intense debate. Large epidemiological studies showed that the safe amount of alcohol to avoid overall health-related risks is lower than expected even in the general population. Even one drink per day can increase cancer-related death. In patients with any kind of chronic liver disease, especially in those with metabolic-associated steatotic liver disease, no alcohol intake is recommended. This review article discusses the current evidence supporting the deleterious effects of small-to-moderate amounts of alcohol in the general population and in patients with underlying chronic liver disease.

In June 2023, under the patronage of the American Association for Study of Liver Disease, the European Association for Study of the Liver, and the Asociación Latinoamericana para el Estudio del Hígado with the involvement of 236 participants from around the world, a new nomenclature and definition for nonalcoholic fatty liver disease (NAFLD) has been proposed. Metabolic dysfunction-associated steatotic liver disease (MASLD) was defined as presence of hepatic steatosis and at least one of the cardiometabolic risk factors with alcohol intake less than 140 g/wk for women and 210 g/wk for men and no other causes of steatosis. A new entity called combined metabolic dysfunction- and alcohol-associated liver disease (MetALD) was created outside of pure MASLD for patients with metabolic dysfunction and alcohol intake greater than that allowed for MASLD (i.e., 140-350 g/wk for women and 210-420 g/wk for men). Recent studies have confirmed a 95% overlap between NAFLD and the new MASLD diagnostic criteria. Natural history, biomarkers, and thresholds of alcohol intake in MetALD group remains to be studied and validated.

Liver transplantation (LT) is a highly effective treatment for carefully selected patients with hepatocellular carcinoma (HCC). In this review, we explored the development of LT selection criteria and organ allocation policies, comparing original data to underscore their historical progression into the intricate task of quantitatively estimating pre- and post-LT survivals. We emphasized the role of biomarkers such as serum alpha-fetoprotein, Des-gamma-carboxy-prothrombin, circulating tumor cells, and circulating tumor DNA in predicting patient outcomes. Additionally, we examined the transplant-associated survival benefits and the difficulties in accurately calculating these benefits. We also reviewed recent advancements in targeted therapy and checkpoint inhibitors for advanced, inoperable HCC and projected their integration into LT for HCC. We further discussed the growing use of living donor liver transplants in the United States and compared its outcomes with those of deceased donor liver transplants. Furthermore, we examined the progress in machine perfusion techniques, which have shown potential in improving patient outcomes and enlarging the donor pool. These advancements present opportunities to enhance LT patient survivals, refine selection criteria, establish new priority metrics, develop innovative bridging and downstaging strategies, and formulate redesigned LT strategies for HCC treatments.

Drug-induced liver injury (DILI) is an adverse reaction to medications and other xenobiotics that leads to liver dysfunction. Based on differential clinical patterns of injury, DILI is classified into hepatocellular, cholestatic, and mixed types; although hepatocellular DILI is associated with inflammation, necrosis, and apoptosis, cholestatic DILI is associated with bile plugs and bile duct paucity. Ursodeoxycholic acid (UDCA) has been empirically used as a supportive drug mainly in cholestatic DILI, but both curative and prophylactic beneficial effects have been observed for hepatocellular DILI as well, according to preliminary clinical studies. This could reflect the fact that UDCA has a plethora of beneficial effects potentially useful to treat the wide range of injuries with different etiologies and pathomechanisms occurring in both types of DILI, including anticholestatic, antioxidant, anti-inflammatory, antiapoptotic, antinecrotic, mitoprotective, endoplasmic reticulum stress alleviating, and immunomodulatory properties. In this review, a revision of the literature has been performed to evaluate the efficacy of UDCA across the whole DILI spectrum, and these findings were associated with the multiple mechanisms of UDCA hepatoprotection. This should help better rationalize and systematize the use of this versatile and safe hepatoprotector in each type of DILI scenarios.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is increasing globally, creating a growing public health concern. However, this disease is often not diagnosed, and accurate data on its epidemiology are limited in many geographical regions, making it challenging to provide proper care and implement effective national plans. To combat the increasing disease burden, screening and diagnosis must reach a significant number of high-risk subjects. Addressing MASLD as a health care challenge requires a multidisciplinary approach involving prevention, diagnosis, treatment, and care, with collaboration between multiple stakeholders in the health care system. This approach must be guided by national and global strategies, to be combined with efficient models of care developed through a bottom-up process. This review article highlights the pillars of the MASLD model of care (MoC), including screening, risk stratification, and establishing a clinical care pathway for management, in addition to discussing the impact of nomenclature change on the proposed MoC.