Seminars in liver disease最新文献

Biliary atresia (BA) is the most prevalent serious liver disease of infancy and childhood, and the principal indication for liver transplantation in pediatrics. BA is best considered as an idiopathic panbiliary cholangiopathy characterized by obstruction of bile flow and consequent cholestasis presenting during fetal and perinatal periods. While several etiologies have been proposed, each has significant drawbacks that have limited understanding of disease progression and the development of effective treatments. Recently, modern genetic analyses have uncovered gene variants contributing to BA, thereby shifting the paradigm for explaining the BA phenotype from an acquired etiology (e.g., virus, toxin) to one that results from genetically altered cholangiocyte development and function. Herein we review recently reported genetic contributions to BA, highlighting the enhanced representation of variants in biological pathways involving ciliary function, cytoskeletal structure, and inflammation. Finally, we blend these findings as a new framework for understanding the resultant BA phenotype as a developmental cholangiopathy.

First discovered over 40 years ago, the hepatitis delta virus (HDV) is a unique RNA virus, requiring hepatitis B virus (HBV) antigens for its assembly, replication, and transmission. HBV and HDV can be acquired at the same time (coinfection) or HDV infection can occur in persons with chronic HBV (superinfection). Screening guidelines for HDV are inconsistent. While some guidelines recommend universal screening for all people with HBV, others recommend risk-based screening. Estimates of the global HDV prevalence range from 4.5 to 14.6% among persons with HBV; thus, there may be up to 72 million individuals with HDV worldwide. HDV is the most severe form of viral hepatitis. Compared to HBV monoinfection, HDV coinfection increases the risk of cirrhosis, hepatocellular carcinoma, hepatic decompensation, mortality, and necessity for liver transplant. Despite the severity of HDV, there are few treatment options. Pegylated interferon (off-label use) has long been the only available treatment, although bulevirtide is conditionally approved in some European countries. There are many potential treatments in development, but as yet, there are few effective and safe therapies for HDV infection. In conclusion, given the severity of HDV disease and the paucity of treatments, there is a great unmet need for HDV therapies.

Alpha-1 antitrypsin deficiency (AATD) arises due to inherited variants in SERPINA1, the AAT gene that impairs the production or secretion of this hepatocellular protein and leads to a gain-of-function liver proteotoxicity. Homozygous Pi*Z pathogenic variant (Pi*ZZ genotype) is the leading cause of severe AATD. It manifests in 2 to 10% of carriers as neonatal cholestasis and 20 to 35% of adults as significant liver fibrosis. Both children and adults may develop an end-stage liver disease requiring liver transplantation. Heterozygous Pi*Z pathogenic variant (Pi*MZ genotype) constitutes an established disease modifier. Our review summarizes the natural history and management of subjects with both pediatric and adult AATD-associated liver disease. Current findings from a phase 2 clinical trial indicate that RNA silencing may constitute a viable therapeutic approach for adult AATD. In conclusion, AATD is an increasingly appreciated pediatric and adult liver disorder that is becoming an attractive target for modern pharmacologic strategies.

Liver sinusoidal endothelial cells (LSECs) are key players in maintaining hepatic homeostasis. They also play crucial roles during liver injury by communicating with liver cell types as well as immune cells and promoting portal hypertension, fibrosis, and inflammation. Cutting-edge technology, such as single cell and spatial transcriptomics, have revealed the existence of distinct LSEC subpopulations with a clear zonation in the liver. The signals released by LSECs are commonly called "angiocrine signaling." In this review, we summarize the role of angiocrine signaling in health and disease, including zonation in healthy liver, regeneration, fibrosis, portal hypertension, nonalcoholic fatty liver disease, alcohol-associated liver disease, aging, drug-induced liver injury, and ischemia/reperfusion, as well as potential therapeutic advances. In conclusion, sinusoidal endotheliopathy is recognized in liver disease and promising preclinical studies are paving the path toward LSEC-specific pharmacotherapies.

Chronic liver diseases encompass a wide spectrum of hepatic maladies that often result in cholestasis or altered bile acid secretion and regulation. Incidence and cost of care for many chronic liver diseases are rising in the United States with few Food and Drug Administration-approved drugs available for patient treatment. Farnesoid X receptor (FXR) is the master regulator of bile acid homeostasis with an important role in lipid and glucose metabolism and inflammation. FXR has served as an attractive target for management of cholestasis and fibrosis; however, global FXR agonism results in adverse effects in liver disease patients, severely affecting quality of life. In this review, we highlight seminal studies and recent updates on the FXR proteome and identify gaps in knowledge that are essential for tissue-specific FXR modulation. In conclusion, one of the greatest unmet needs in the field is understanding the underlying mechanism of intestinal versus hepatic FXR function.

This review is to evaluate how much alcohol is safe in the context of alcohol-related liver disease (ALD). In patients without an established diagnosis of ALD consuming alcohol at quantities below 12 to 20 g daily with alcohol-free days is associated with a very low risk of developing disease. This risk is mediated by the presence of cofactors such as sex, medical comorbidity, obesity, and genetic factors. A threshold effect below which liver disease will not occur is not seen, instead a dose-response relationship where risk ranges from low to high. Once ALD is present, natural history studies confirm that continued alcohol consumption is clearly associated with an increased risk of ill health and premature death. In conclusion, low-level alcohol consumption in the absence of liver disease is associated with a very small risk of developing ALD, but once ALD is present patients should be supported to achieve complete abstinence from alcohol.

Exposure to hepatotoxic chemicals is involved in liver disease-related morbidity and mortality worldwide. The liver responds to damage by triggering compensatory hepatic regeneration. Physical agent or chemical-induced liver damage disrupts hepatocyte proteostasis, including endoplasmic reticulum (ER) homeostasis. Post-liver injury ER experiences a homeostatic imbalance, followed by active ER stress response signaling. Activated ER stress response causes selective upregulation of stress response genes and downregulation of many hepatocyte genes. Acetaminophen overdose, carbon tetrachloride, acute and chronic alcohol exposure, and physical injury activate the ER stress response, but details about the cellular consequences of the ER stress response on liver regeneration remain unclear. The current data indicate that inhibiting the ER stress response after partial hepatectomy-induced liver damage promotes liver regeneration, whereas inhibiting the ER stress response after chemical-induced hepatotoxicity impairs liver regeneration. This review summarizes key findings and emphasizes the knowledge gaps in the role of ER stress in injury and regeneration.

Endoscopy is and remains an indispensable tool in diagnosing and managing liver disease and its complications. Due to the progress in advanced endoscopy, endoscopy has become an alternative route for many surgical, percutaneous, and angiographic interventions, not only as a backup tool when conventional interventions fail but increasingly as a first-line choice. The term endo-hepatology refers to the integration of advanced endoscopy in the practice of hepatology. Endoscopy is key in the diagnosis and management of esophageal and gastric varices, portal hypertensive gastropathy, and gastric antral vascular ectasia. Endoscopic ultrasound (EUS) can be used for the evaluation of the liver parenchyma, liver lesions, and surrounding tissues and vessels, including targeted biopsy and complemented with new software functions. Moreover, EUS can guide portal pressure gradient measurement, and assess and help manage complications of portal hypertension. It is crucial that each present-day hepatologist is aware of the (rapidly increasing) full spectrum of diagnostic and therapeutic tools that exist within this field. In this comprehensive review, we would like to discuss the current endo-hepatology spectrum, as well as future directions for endoscopy in hepatology.

Mast cells (MCs) contribute to the pathogenesis of cholestatic liver diseases (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). PSC and PBC are immune-mediated, chronic inflammatory diseases, characterized by bile duct inflammation and stricturing, advancing to hepatobiliary cirrhosis. MCs are tissue resident immune cells that may promote hepatic injury, inflammation, and fibrosis formation by either direct or indirect interactions with other innate immune cells (neutrophils, macrophages/Kupffer cells, dendritic cells, natural killer, and innate lymphoid cells). The activation of these innate immune cells, usually through the degranulation of MCs, promotes antigen uptake and presentation to adaptive immune cells, exacerbating liver injury. In conclusion, dysregulation of MC-innate immune cell communications during liver injury and inflammation can lead to chronic liver injury and cancer.

Nonalcoholic fatty liver disease (NAFLD) affects 30 to 40% of the population globally and is increasingly considered the most common liver disease. Patients with type 2 diabetes, obesity, and cardiovascular diseases are at especially increased risk for NAFLD. Although most patients with NAFLD do not have progressive liver disease, some patients progress to cirrhosis, liver cancer, and liver mortality. Given the sheer number of patients with NAFLD, the burden of disease is enormous. Despite this large and increasing burden, identification of NAFLD patients at risk for progressive liver disease in the primary care and diabetology practice settings remains highly suboptimal. In this review, our aim is to summarize a stepwise approach to risk stratify patients with NAFLD which should help practitioners in their management of patients with NAFLD.