Seminars in liver disease最新文献

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.

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.

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.

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.

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.

Chronic liver disease (CLD) is a major contributor to global mortality, morbidity, and healthcare burden. Progress in pharmacotherapeutic for CLD management is lagging given its impact on the global population. While statins are indicated for the management of dyslipidemia and cardiovascular disease, their role in CLD prevention and treatment is emerging. Beyond their lipid-lowering effects, their liver-related mechanisms of action are multifactorial and include anti-inflammatory, antiproliferative, and immune-protective effects. In this review, we highlight what is known about the clinical benefits of statins in viral and nonviral etiologies of CLD and hepatocellular carcinoma (HCC), and explore key mechanisms and pathways targeted by statins. While their benefits may span the spectrum of CLD and potentially HCC treatment, their role in CLD chemoprevention is likely to have the largest impact. As emerging data suggest that genetic variants may impact their benefits, the role of statins in precision hepatology will need to be further explored.

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.