Semin Liver Dis
· 2022 May · PMID 35738255
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Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality a...Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality associated with chronic liver disease, and NAFLD patients are at a higher risk of developing cirrhosis and hepatocellular carcinoma. While there is a consensus that inflammation plays a key role in promoting NAFLD progression, the underlying mechanisms are not well understood. Recent clinical and experimental evidence suggest that increased hepatic translocation of gut microbial antigens, secondary to diet-induced impairment of the intestinal barrier may be important in driving hepatic inflammation in NAFLD. Here, we briefly review various endogenous and exogenous factors influencing the intestinal barrier and present recent advances in our understanding of cellular and molecular mechanisms underlying intestinal barrier dysfunction in NAFLD.
Nonalcoholic steatohepatitis (NASH) is a burgeoning global health crisis that mirrors the obesity pandemic. This global health crisis has stimulated active research to develop novel NASH pharmacotherapies targeting dysre...Nonalcoholic steatohepatitis (NASH) is a burgeoning global health crisis that mirrors the obesity pandemic. This global health crisis has stimulated active research to develop novel NASH pharmacotherapies targeting dysregulated inflammatory, cellular stress, and fibrogenetic processes that include (1) metabolic pathways to improve insulin sensitivity, de novo lipogenesis, and mitochondrial utilization of fatty acids; (2) cellular injury or inflammatory targets that reduce inflammatory cell recruitment and signaling; (3) liver-gut axis targets that influence bile acid enterohepatic circulation and signaling; and (4) antifibrotic targets. In this review, we summarize several of the therapeutic agents that have been studied in phase 2 and 3 randomized trials. In addition to reviewing novel therapeutic drugs targeting nuclear receptor pathways, liver chemokine receptors, liver lipid metabolism, lipotoxicity or cell death, and glucagon-like peptide-1 receptors, we also discuss the rationale behind the use of combination therapy and the lessons learned from unsuccessful or negative clinical trials.
During biliary tree homeostasis, BECs are largely in a quiescent state and their turnover is slow for maintaining normal tissue homeostasis. BTSCs continually replenish new BECs in the luminal surface of EHBDs. In respon...During biliary tree homeostasis, BECs are largely in a quiescent state and their turnover is slow for maintaining normal tissue homeostasis. BTSCs continually replenish new BECs in the luminal surface of EHBDs. In response to various types of biliary injuries, distinct cellular sources, including HPCs, BTSCs, hepatocytes, and BECs, repair or regenerate the injured bile duct. BEC, biliary epithelial cell; BTSC, biliary tree stem/progenitor cell; EHBD, extrahepatic bile ducts; HPC, hepatic progenitor cell.The biliary tree comprises intrahepatic bile ducts and extrahepatic bile ducts lined with epithelial cells known as biliary epithelial cells (BECs). BECs are a common target of various cholangiopathies for which there is an unmet therapeutic need in clinical hepatology. The repair and regeneration of biliary tissue may potentially restore the normal architecture and function of the biliary tree. Hence, the repair and regeneration process in detail, including the replication of existing BECs, expansion and differentiation of the hepatic progenitor cells and biliary tree stem/progenitor cells, and transdifferentiation of the hepatocytes, should be understood. In this paper, we review biliary tree homeostasis, repair, and regeneration and discuss the feasibility of regenerative therapy strategies for cholangiopathy treatment.
Strategies to prevent infection and improve outcomes in patients with cirrhosis. HAV, hepatitis A virus; HBV, hepatitis B virus; COVID-19, novel coronavirus disease 2019; NSBB, nonselective β-blocker; PPI, proton pump in...Strategies to prevent infection and improve outcomes in patients with cirrhosis. HAV, hepatitis A virus; HBV, hepatitis B virus; COVID-19, novel coronavirus disease 2019; NSBB, nonselective β-blocker; PPI, proton pump inhibitors.Cirrhosis is a risk factor for infections. Majority of hospital admissions in patients with cirrhosis are due to infections. Sepsis is an immunological response to an infectious process that leads to end-organ dysfunction and death. Preventing infections may avoid the downstream complications, and early diagnosis of infections may improve the outcomes. In this review, we discuss the pathogenesis, diagnosis, and biomarkers of infection; the incremental preventive strategies for infections and sepsi; and the consequent organ failures in cirrhosis. Strategies for primary prevention include reducing gut translocation by selective intestinal decontamination, avoiding unnecessary proton pump inhibitors' use, appropriate use of β-blockers, and vaccinations for viral diseases including novel coronavirus disease 2019. Secondary prevention includes early diagnosis and a timely and judicious use of antibiotics to prevent organ dysfunction. Organ failure support constitutes tertiary intervention in cirrhosis. In conclusion, infections in cirrhosis are potentially preventable with appropriate care strategies to then enable improved outcomes.
The map and global disease burden of chronic liver diseases are markedly changing, with nonalcoholic fatty liver disease (NAFLD) becoming the most common cause of liver diseases coinciding with the current epidemics of o...The map and global disease burden of chronic liver diseases are markedly changing, with nonalcoholic fatty liver disease (NAFLD) becoming the most common cause of liver diseases coinciding with the current epidemics of obesity, type 2 diabetes, and metabolic syndrome. Understanding the incidence and prevalence of NAFLD is critical because of its linkage to a significant economic burden of hospitalization and changing patterns in consequences, such as liver transplantation. Moreover, the long-term average health care expenses of NAFLD patients have exceeded those of other liver diseases. To lessen the imminent burden of NAFLD, immediate actions to raise worldwide awareness and address metabolic risk factors are required. This review summarizes key data about the global disease burden of NAFLD, modifiable and nonmodifiable risk factors, and current preventive approaches.
Chronic infection with the hepatitis B virus (HBV) is one of the most common causes of liver disease worldwide. Chronic HBV infection is currently incurable because of the persistence of the viral template for the viral...Chronic infection with the hepatitis B virus (HBV) is one of the most common causes of liver disease worldwide. Chronic HBV infection is currently incurable because of the persistence of the viral template for the viral transcripts, covalently closed circular deoxyribonucleic acid (cccDNA). Detecting changes in cccDNA transcriptional activity is key to understanding fundamental virology, determining the efficacy of new therapies, and deciding the optimal clinical management of HBV patients. In this review, we summarize surrogate circulating biomarkers that have been used to infer cccDNA levels and activity in people with chronic hepatitis B. Moreover, we outline the current shortcomings of the current biomarkers and highlight the clinical importance in improving them and expanding their use.
Alcohol use disorder (AUD) is one of the main causes of global death and disability. The liver represents the main target of alcohol damage, and alcohol-associated liver disease (ALD) represents the first cause of liver...Alcohol use disorder (AUD) is one of the main causes of global death and disability. The liver represents the main target of alcohol damage, and alcohol-associated liver disease (ALD) represents the first cause of liver cirrhosis in Western countries. Alcohol abstinence is the main goal of treatment in AUD patients with ALD, as treatments for ALD are less effective when drinking continues. Moreover, the persistence of alcohol consumption is associated with higher mortality, increased need for liver transplantation, and graft loss. The most effective treatment for AUD is the combination of psychosocial interventions, pharmacological therapy, and medical management. However, the effectiveness of these treatments in patients with ALD is doubtful even because AUD patients with ALD are usually excluded from pharmacological trials due to concerns on liver safety. This narrative review will discuss the treatment options for AUD-ALD patients focusing on controversies in pharmacological therapy.
Semin Liver Dis
· 2022 May · PMID 35263797
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Circadian rhythms are approximately 24-hour cycles of variation in physiological processes, gene expression, and behavior. They result from the interplay of internal biological clocks with daily environmental rhythms, in...Circadian rhythms are approximately 24-hour cycles of variation in physiological processes, gene expression, and behavior. They result from the interplay of internal biological clocks with daily environmental rhythms, including light/dark and feeding/fasting. Note that 24-hour rhythms of liver metabolic processes have been known for almost 100 years. Modern studies reveal that, like metabolism, hepatic gene expression is highly rhythmic. Genetic or environmental changes can disrupt the circadian rhythms of the liver, leading to metabolic disorders and hepatocellular carcinoma. In this review, we summarize the current understanding of mechanisms regulating rhythmic gene expression in the liver, highlighting the roles of transcription factors that comprise the core clock molecular as well as noncanonical regulators. We emphasize the plasticity of circadian rhythms in the liver as it responds to multiple inputs from the external and internal environments as well as the potential of circadian medicine to impact liver-related diseases.
Liver transplantation (LT) is the only curative therapy in patients with end-stage liver disease with excellent long-term survival; however, LT recipients are at risk of significant complications. Among these complicatio...Liver transplantation (LT) is the only curative therapy in patients with end-stage liver disease with excellent long-term survival; however, LT recipients are at risk of significant complications. Among these complications are biliary complications with an incidence ranging from 5 to 32% and associated with significant post-LT morbidity and mortality. Prompt recognition and management are critical as these complications have been associated with mortality rates up to 19% and retransplantation rates up to 13%. An important limitation of published studies is that a large proportion does not discriminate between anastomotic strictures and nonanastomotic strictures. This review aims to summarize our current understanding of risk factors and natural history, diagnostic testing, and treatment options for post-LT biliary strictures.
The complex immune system of the liver has a major role in tumor surveillance, but also partly explains why current immune therapies are poorly effective against liver cancers. Known primarily for its tolerogenic capacit...The complex immune system of the liver has a major role in tumor surveillance, but also partly explains why current immune therapies are poorly effective against liver cancers. Known primarily for its tolerogenic capacity, the hepatic immune repertoire also comprises diverse populations of armored immune cells with tumor surveillant roles. In healthy people, these work together to successfully identify malignant cells and prevent their proliferation, thus halting tumor formation. When frontline hepatic immune surveillance systems fail, compromised hepatic immunity, driven by obesity, infection, or other pathological factors, allows primary or secondary liver cancers to develop. Tumor growth promotes the normal tolerogenic immunological milieu of the liver, perhaps explaining why current immunotherapies fail to work. This review explores the complex local liver immune system with the hope of identifying potential therapeutic targets needed to best overcome immunological barriers in the liver to create an environment no longer hostile to immunotherapy for the treatment of liver cancer.
Microelimination targets specific subpopulations and/or geographic settings for hepatitis C virus (HCV) elimination. This review reports on global HCV microelimination literature published from 2013 to 2020. Data were ex...Microelimination targets specific subpopulations and/or geographic settings for hepatitis C virus (HCV) elimination. This review reports on global HCV microelimination literature published from 2013 to 2020. Data were extracted from publications to report a score based on the four key components defining microelimination. Sustained virologic response (SVR) and treatment initiation proportions were calculated for each manuscript and grouped means of these estimates were compared depending on microelimination score and care setting. A total of 83% of the studies were from high-income settings and mainly included people who use drugs or those incarcerated. Among manuscripts, 18 had "low" microelimination scores, 11 had "high" scores, and the differences in mean proportion who initiated treatment and achieved SVR between low and high score groups were statistically significant. Microelimination can be a useful complementary strategy for driving engagement in HCV treatment and cure. Our analysis suggests that adhering to more of the core microelimination components can improve outcomes. This study is registered with Prospero, registration identification: CRD42020175211.
The World Health Organization describes antimicrobial resistance as one of the biggest threats to global health, food security, and development with indiscriminate use of antimicrobials globally driving the emergence of...The World Health Organization describes antimicrobial resistance as one of the biggest threats to global health, food security, and development with indiscriminate use of antimicrobials globally driving the emergence of multidrug-resistant bacteria, resistant to 60% of antimicrobials in some countries. Infections with multidrug-resistant organisms (MDROs) have increased in recent decades in patients with cirrhosis, who are frequently prescribed antibiotics, regularly undergo invasive procedures such as large volume paracentesis, and have recurrent hospitalizations, posing a particular risk in this already immunocompromised cohort of patients. In this review, we explore mechanisms underlying this vulnerability to MDRO infection; the effect of bacterial infections on disease course in cirrhosis; prevalence of MDROs in patients with cirrhosis; outcomes following MDRO infection; fungal infections; antibiotics and their efficacy; and management of MDRO infections in terms of detection, antimicrobial and nonantimicrobial treatments, prophylaxis, antibiotic stewardship, the gut microbiome, and technological interventions.
As blood flows from the portal triad to the central vein, cell-mediated depletion establishes gradients of soluble factors such as oxygen, nutrients, and hormones, which act through molecular pathways (e.g., Wnt/β-cateni...As blood flows from the portal triad to the central vein, cell-mediated depletion establishes gradients of soluble factors such as oxygen, nutrients, and hormones, which act through molecular pathways (e.g., Wnt/β-catenin, hedgehog) to spatially regulate hepatocyte functions along the sinusoid. Such "zonation" can lead to the compartmentalized initiation of several liver diseases, including alcoholic/non-alcoholic fatty liver diseases, chemical/drug-induced toxicity, and hepatocellular carcinoma, and can also modulate liver regeneration. Transgenic rodent models provide valuable information on the key molecular regulators of zonation, while in vitro models allow for subjecting cells to precisely controlled factor gradients and elucidating species-specific differences in zonation. Here, we discuss the latest advances in both in vivo and in vitro models of liver zonation and pending questions to be addressed moving forward. Ultimately, obtaining a deeper understanding of zonation can lead to the development of more effective therapeutics for liver diseases, microphysiological systems, and scalable cell-based therapies.
Semin Liver Dis
· 2022 Feb · PMID 35073587
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Yes-associated protein 1 (YAP1) is a transcriptional coactivator that activates transcriptional enhanced associate domain transcription factors upon inactivation of the Hippo signaling pathway, to regulate biological pro...Yes-associated protein 1 (YAP1) is a transcriptional coactivator that activates transcriptional enhanced associate domain transcription factors upon inactivation of the Hippo signaling pathway, to regulate biological processes like proliferation, survival, and differentiation. YAP1 is most prominently expressed in biliary epithelial cells (BECs) in normal adult livers and during development. In the current review, we will discuss the multiple roles of YAP1 in the development and morphogenesis of bile ducts inside and outside the liver, as well as in orchestrating the cholangiocyte repair response to biliary injury. We will review how biliary repair can occur through the process of hepatocyte-to-BEC transdifferentiation and how YAP1 is pertinent to this process. We will also discuss the liver's capacity for metabolic reprogramming as an adaptive mechanism in extreme cholestasis, such as when intrahepatic bile ducts are absent due to YAP1 loss from hepatic progenitors. Finally, we will discuss the roles of YAP1 in the context of pediatric pathologies afflicting bile ducts, such as Alagille syndrome and biliary atresia. In conclusion, we will comprehensively discuss the spatiotemporal roles of YAP1 in biliary development and repair after biliary injury while describing key interactions with other well-known developmental pathways.
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and affects 25% of the population in Western countries. NAFLD is the hepatic manifestation of the metabolic syndrome, linked to insu...Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and affects 25% of the population in Western countries. NAFLD is the hepatic manifestation of the metabolic syndrome, linked to insulin resistance, which is the common pathogenetic mechanism. In approximately 40% of NAFLD patients, steatosis is associated with necro-inflammation and fibrosis, resulting in nonalcoholic steatohepatitis (NASH), a severe condition that may progress to cirrhosis and liver cancer. Although the hepatocyte represents the main target of the disease, involvement of the bile ducts occurs in a subset of patients with NASH, and is characterized by ductular reaction and activation of the progenitor cell compartment, which incites portal fibrosis and disease progression. We aim to dissect the multiple biological effects that adipokines and metabolic alterations exert on cholangiocytes to derive novel information on the mechanisms driven by insulin resistance, which promote fibro-inflammation and carcinogenesis in NASH.
Patten DA, Wilkinson AL, O'Keeffe A
… +1 more, Shetty S
Semin Liver Dis
· 2022 Feb · PMID 34553345
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The scavenger receptor superfamily represents a highly diverse collection of evolutionarily-conserved receptors which are known to play key roles in host homeostasis, the most prominent of which is the clearance of unwan...The scavenger receptor superfamily represents a highly diverse collection of evolutionarily-conserved receptors which are known to play key roles in host homeostasis, the most prominent of which is the clearance of unwanted endogenous macromolecules, such as oxidized low-density lipoproteins, from the systemic circulation. Members of this family have also been well characterized in their binding and internalization of a vast range of exogenous antigens and, consequently, are generally considered to be pattern recognition receptors, thus contributing to innate immunity. Several studies have implicated scavenger receptors in the pathophysiology of several inflammatory diseases, such as Alzheimer's and atherosclerosis. Hepatic resident cellular populations express a diverse complement of scavenger receptors in keeping with the liver's homeostatic functions, but there is gathering interest in the contribution of these receptors to hepatic inflammation and its complications. Here, we review the expression of scavenger receptors in the liver, their functionality in liver homeostasis, and their role in inflammatory liver disease and cancer.
Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis when diagnosed at advanced stages in which curative treatments are no longer applicable. A small group of these patients may still benefit from transarte...Hepatocellular carcinoma (HCC) is a malignancy with poor prognosis when diagnosed at advanced stages in which curative treatments are no longer applicable. A small group of these patients may still benefit from transarterial chemoembolization. The only therapeutic option for most patients with advanced HCC is systemic pharmacological treatments based on tyrosine kinase inhibitors (TKIs) and immunotherapy. Available drugs only slightly increase survival, as tumor cells possess additive and synergistic mechanisms of pharmacoresistance (MPRs) prior to or enhanced during treatment. Understanding the molecular basis of MPRs is crucial to elucidate the genetic signature underlying HCC resistome. This will permit the selection of biomarkers to predict drug treatment response and identify tumor weaknesses in a personalized and dynamic way. In this article, we have reviewed the role of MPRs in current first-line drugs and the combinations of immunotherapeutic agents with novel TKIs being tested in the treatment of advanced HCC.
Fontan-associated liver disease is the term used to encompass the disorders arising from abnormal hemodynamic alterations and systemic venous congestion after the Fontan procedure. The histological changes produced in th...Fontan-associated liver disease is the term used to encompass the disorders arising from abnormal hemodynamic alterations and systemic venous congestion after the Fontan procedure. The histological changes produced in the liver are similar but not equivalent to those seen in other forms of cardiac liver disease. While the natural history of this form of liver disease is poorly established, many Fontan patients ultimately develop portal hypertension-related complications such as ascites, esophageal varices, malnutrition, and encephalopathy. Fontan survivors also show an elevated risk of hepatocellular carcinoma. Adequate staging of the liver damage is essential to anticipate screening strategies and improve global management.