The key factor in preventing and treating nonalcoholic fatty liver disease (NAFLD) is a holistic lifestyle modification approach, encompassing diet based on healthy eating patterns of unprocessed foods, exercise, balance...The key factor in preventing and treating nonalcoholic fatty liver disease (NAFLD) is a holistic lifestyle modification approach, encompassing diet based on healthy eating patterns of unprocessed foods, exercise, balanced drinking, and smoking habits. The Mediterranean diet and other healthy dietary patterns can reduce liver fat and may be related with lower disease progression. The type of diet should be tailored to the patient's cultural and personal preferences. Changing dietary composition without reducing caloric intake may offer an additional and sometimes more feasible alternative, so that the nutritional treatment incorporates, but is not focused on, weight reduction goals. The growing global consumption of ultra-processed foods, which is the polar opposite of the Mediterranean diet and its concept of home-based cooking, poses a great challenge in the prevention of NAFLD and probably hepatocellular carcinoma.This review will cover the most updated clinical and epidemiological evidence for lifestyle treatment in NAFLD and provide practical treatment tools.
Owing to species-specific differences in liver pathways, in vitro human liver models are utilized for elucidating mechanisms underlying disease pathogenesis, drug development, and regenerative medicine. To mitigate limit...Owing to species-specific differences in liver pathways, in vitro human liver models are utilized for elucidating mechanisms underlying disease pathogenesis, drug development, and regenerative medicine. To mitigate limitations with de-differentiated cultures, bioengineers have developed advanced techniques/platforms, including micropatterned cocultures, spheroids/organoids, bioprinting, and microfluidic devices, for perfusing cell cultures and liver slices. Such techniques improve mature functions and culture lifetime of primary and stem-cell human liver cells. Furthermore, bioengineered liver models display several features of liver diseases including infections with pathogens (e.g., malaria, hepatitis C/B viruses, Zika, dengue, yellow fever), alcoholic/nonalcoholic fatty liver disease, and cancer. Here, we discuss features of bioengineered human liver models, their uses for modeling aforementioned diseases, and how such models are being augmented/adapted for fabricating implantable human liver tissues for clinical therapy. Ultimately, continued advances in bioengineered human liver models have the potential to aid the development of novel, safe, and efficacious therapies for liver disease.
Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advanceme...Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advancement in systemic therapy also provides new opportunities of reducing recurrence after curative therapy through adjuvant therapy or improving resectability through neoadjuvant therapy. Improved recurrence-free survival by adjuvant or neoadjuvant ICI-based therapy has been reported in other cancer types. In this article, developments of systemic therapy in adjuvant and neoadjuvant settings for HCC were reviewed. The design of adjuvant and neoadjuvant therapy using ICI-based regimens and potential challenges of trial conduct and result analysis was discussed. Results from these trials may extend the therapeutic benefit of ICI-based systemic therapy beyond the advanced-stage disease and lead to a new era of multidisciplinary management for HCC.
This review will discuss the etiologies of kidney disease in liver transplant candidates, provide a historical background of the prior evolution of simultaneous liver-kidney (SLK) transplant indications, discuss the curr...This review will discuss the etiologies of kidney disease in liver transplant candidates, provide a historical background of the prior evolution of simultaneous liver-kidney (SLK) transplant indications, discuss the current indications for SLK including Organ Procurement and Transplantation Network policies and Model for End Stage Liver Disease exception points, as well as provide an overview of the safety net kidney transplant policy. Finally, the authors explore unanswered questions and future research needed in SLK transplantation.
Single-cell technologies are revolutionizing our understanding of cellular heterogeneity and functional diversity in health and disease. Here, we review the current knowledge and advances in liver biology using single-ce...Single-cell technologies are revolutionizing our understanding of cellular heterogeneity and functional diversity in health and disease. Here, we review the current knowledge and advances in liver biology using single-cell approaches. We focus on the landscape of the composition and the function of cells in a healthy liver in the context of its spatial organization. We also highlight the alterations of the molecular landscape in chronic liver disease and liver cancer, which includes the identification of disease-related cell types, altered cellular functions, dynamic cell-cell interactions, the plasticity of malignant cells, the collective behavior of a cell community, and microenvironmental reprogramming. We anticipate that the uncovered liver cell atlas will help deciphering the molecular and cellular mechanisms driving a healthy liver into a disease state. It also offers insight into the detection of new therapeutic targets and paves the way for effective disease interventions.
Interleukin 17A (IL-17A)-producing T helper 17 (Th17) cells were identified as a subset of T helper cells that play a critical role in host defense against bacterial and fungal pathogens. Th17 cells differentiate from Th...Interleukin 17A (IL-17A)-producing T helper 17 (Th17) cells were identified as a subset of T helper cells that play a critical role in host defense against bacterial and fungal pathogens. Th17 cells differentiate from Th0 naïve T-cells in response to transforming growth factor β1 (TGF-β1) and IL-6, the cytokines which also drive development of liver fibrosis, require activation of transcription factor retinoic acid receptor-related orphan nuclear receptor gamma (RORγ). IL-17A signals through the ubiquitously expressed receptor IL-17RA. Expression of IL-17RA is upregulated in patients with hepatitis B virus/hepatitis C virus (HBV/HCV) infections, nonalcoholic steatohepatitis (NASH), alcohol-associated liver disease (AALD), hepatocellular carcinoma (HCC), and experimental models of chronic toxic liver injury. The role of IL-17 signaling in the pathogenesis of NASH- and AALD-induced metabolic liver injury and HCC will be the focus of this review. The role of IL-17A-IL-17RA axis in mediation of the cross-talk between metabolically injured hepatic macrophages, hepatocytes, and fibrogenic myofibroblasts will be discussed.
The most concerned issue in the context of drug/herb-induced chronic cholestasis is vanishing bile duct syndrome. The progressive destruction of intrahepatic bile ducts leading to ductopenia is usually not dose dependent...The most concerned issue in the context of drug/herb-induced chronic cholestasis is vanishing bile duct syndrome. The progressive destruction of intrahepatic bile ducts leading to ductopenia is usually not dose dependent, and has a delayed onset that should be suspected when abnormal serum cholestasis enzyme levels persist despite drug withdrawal. Immune-mediated cholangiocyte injury, direct cholangiocyte damage by drugs or their metabolites once in bile, and sustained exposure to toxic bile salts when biliary epithelium protective defenses are impaired are the main mechanisms of cholangiolar damage. Current therapeutic alternatives are scarce and have not shown consistent beneficial effects so far. This review will summarize the current literature on the main diagnostic tools of ductopenia and its histological features, and the differential diagnostic with other ductopenic diseases. In addition, pathomechanisms will be addressed, as well as the connection between them and the supportive and curative strategies for ductopenia management.
Nonalcoholic fatty liver disease (NAFLD) is a systemic, dynamic, heterogeneous, and multiaxis entity, the pathogenesis of which is still uncertain. The gut-liver axis is regulated and stabilized by a complex network enco...Nonalcoholic fatty liver disease (NAFLD) is a systemic, dynamic, heterogeneous, and multiaxis entity, the pathogenesis of which is still uncertain. The gut-liver axis is regulated and stabilized by a complex network encompassing a metabolic, immune, and neuroendocrine cross-talk between the gut, the microbiota, and the liver. Changes in the gut-liver axis affect the metabolism of lipids and carbohydrates in the hepatocytes, and they impact the balance of inflammatory mediators and cause metabolic deregulation, promoting NAFLD and its progression to nonalcoholic steatohepatitis. Moreover, the microbiota and its metabolites can play direct and indirect roles in gut barrier function and fibrosis development. In this review, we will highlight findings from the recent literature focusing on the gut-liver axis and its relation to NAFLD. Finally, we will discuss the impact of technical issues, design bias, and other limitations on current knowledge of the gut microbiota in the context of NAFLD.
Traditional concepts have classically viewed resolution of inflammation as a passive process yet insight into the pathways by which inflammation is resolved has challenged this idea. Resolution has been revealed as a hig...Traditional concepts have classically viewed resolution of inflammation as a passive process yet insight into the pathways by which inflammation is resolved has challenged this idea. Resolution has been revealed as a highly dynamic and active event that is essential to counteract the dysregulated inflammatory response that drives diverse disease states. Abrogation of the hepatic inflammatory response through the stimulation of proresolving mechanisms represents a new paradigm in the setting of chronic inflammatory-driven liver diseases. Elucidation of the role of different cells of the innate and adaptive immune system has highlighted the interplay between them as an important orchestrator of liver repair. A finely tuned interaction between neutrophils and macrophages has risen as revolutionary mechanism that drives the restoration of hepatic function and architecture. Specialized proresolving mediators have also been shown to act as stop signals of the inflammatory response and promote resolution as well as tissue regeneration. In this review, we discuss the discovery and understanding of the mechanisms by which inflammation is resolved and highlight novel proresolving pathways that represent promising therapeutic strategies.
Nonalcoholic fatty liver disease (NAFLD) denotes a condition with excess fat in the liver. The prevalence of NAFLD is increasing, averaging > 25% of the Western population. In 25% of the patients, NAFLD progresses to its...Nonalcoholic fatty liver disease (NAFLD) denotes a condition with excess fat in the liver. The prevalence of NAFLD is increasing, averaging > 25% of the Western population. In 25% of the patients, NAFLD progresses to its more severe form: nonalcoholic steatohepatitis and >25% of these progress to cirrhosis following activation of inflammatory and fibrotic processes. NAFLD is associated with obesity, type 2 diabetes, and the metabolic syndrome and represents a considerable and increasing health burden. In the near future, NAFLD cirrhosis is expected to be the most common cause for liver transplantation. NAFLD patients have an increased risk of developing cardiovascular disease as well as liver-related morbidity. In addition, hepatic steatosis itself appears to represent an independent cardiovascular risk factor. In the present review, we provide an overview of the overlapping mechanisms and prevalence of NAFLD and cardiovascular disease.
Haep N, Florentino RM, Squires JE
… +2 more, Bell A, Soto-Gutierrez A
Semin Liver Dis
· 2021 May · PMID 33992030
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Chronic liver injury results in cirrhosis and end-stage liver disease (ESLD) which represents a leading cause of death worldwide, affecting people in their most productive years of life. Medical therapy can extend life,...Chronic liver injury results in cirrhosis and end-stage liver disease (ESLD) which represents a leading cause of death worldwide, affecting people in their most productive years of life. Medical therapy can extend life, but the only definitive treatment is liver transplantation (LT). However, LT remains limited by access to quality donor organs and suboptimal long-term outcomes. The degeneration from healthy-functioning livers to cirrhosis and ESLD involves a dynamic process of hepatocyte damage, diminished hepatic function, and adaptation. However, the mechanisms responsible for deterioration of hepatocyte function and ultimately hepatic failure in man are poorly understood. We review the current understanding of cirrhosis and ESLD as a dynamic process and outline the current mechanisms associated with the development of hepatic failure from the clinical manifestations to energy adaptations, regeneration, and regulation of nuclear transcription factors. A new generation of therapeutics could target stabilization of hepatocyte differentiation and function to avoid the need for transplantation in patients with cirrhosis and ESLD.
Patients with acute-on-chronic liver failure (ACLF) have a devastating prognosis and therapeutic options are limited. Granulocyte-colony stimulating factor (G-CSF) mobilizes immune and stem cells and possess immune-modul...Patients with acute-on-chronic liver failure (ACLF) have a devastating prognosis and therapeutic options are limited. Granulocyte-colony stimulating factor (G-CSF) mobilizes immune and stem cells and possess immune-modulatory and proregenerative capacities. In this review, we aim to define the current evidence for the treatment with G-CSF in end-stage liver disease. Several smaller clinical trials in patients with different severity grades of end-stage liver disease have shown that G-CSF improves survival and reduces the rate of complications. Adequately powered multicenter European trials could not confirm these beneficial effects. In mouse models of ACLF, G-CSF increased the toll-like receptor (TLR)-mediated inflammatory response which led to an increase in mortality. Adding a TLR4 signaling inhibitor allowed G-CSF to unfold its proregenerative properties in these ACLF models. These data suggest that G-CSF requires a noninflammatory environment to exert its protective properties.
Current treatments for hepatitis B virus (HBV) using nucleos(t)ide analogs cannot eliminate the risk of hepatocellular carcinoma (HCC) development. As HBV-associated HCC can develop even in the absence of liver cirrhosis...Current treatments for hepatitis B virus (HBV) using nucleos(t)ide analogs cannot eliminate the risk of hepatocellular carcinoma (HCC) development. As HBV-associated HCC can develop even in the absence of liver cirrhosis, HBV is regarded to possess direct oncogenic potential. HBV regulatory protein X (HBx) has been identified as a primary mediator of HBV-mediated hepatocarcinogenesis. A fragment of the HBV genome that contains the coding region of HBx is commonly integrated into the host genome, resulting in the production of aberrant proteins and subsequent hepatocarcinogenesis. Besides, HBx interferes with the host DNA or deoxyribonucleic acid damage repair pathways, signal transduction, epigenetic regulation of gene expression, and cancer immunity, thereby promoting carcinogenesis in the noncirrhotic liver. However, numerous molecules and pathways have been implicated in the development of HBx-associated HCC, suggesting that the mechanisms underlying HBx-mediated hepatocarcinogenesis remain to be elucidated.
The past decade has seen a rise in the availability of breakthrough therapeutic strategies for treatment of hepatocellular carcinoma (HCC). A tumor microenvironment in HCC is regulated by various immunotolerance mechanis...The past decade has seen a rise in the availability of breakthrough therapeutic strategies for treatment of hepatocellular carcinoma (HCC). A tumor microenvironment in HCC is regulated by various immunotolerance mechanisms; therefore, therapeutic strategies aiming at disrupting tumor immune tolerance are becoming attractive curative options in HCC. Immune checkpoint inhibitors have demonstrated impressive effectiveness in HCC, including in sorafenib-unresponsive patients. Synergistic approaches with checkpoint inhibitors (anti-PD-1/PD-L1 and CTLA-4) and antiangiogenic drugs are burgeoning as first-line treatment therapeutic modalities in HCC.
Translational studies in human cholestatic diseases have for years been hindered by various challenges, including the rarity of the disorders, the difficulty in obtaining biliary tissue from across the spectrum of the di...Translational studies in human cholestatic diseases have for years been hindered by various challenges, including the rarity of the disorders, the difficulty in obtaining biliary tissue from across the spectrum of the disease stage, and the difficulty culturing and maintaining primary cholangiocytes. Organoid technology is increasingly being viewed as a technological breakthrough in translational medicine as it allows the culture and biobanking of self-organizing cells from various sources that facilitate the study of pathophysiology and therapeutics, including from individual patients in a personalized approach. This review describes current research using biliary organoids for the study of human cholestatic diseases and the emerging applications of organoids to regenerative medicine directed at the biliary tree. Challenges and possible solutions to the current hurdles in this emerging field, particularly the need for standardization of terminology and clarity on source materials and techniques, are also discussed.
Within the field of randomized clinical trials (RCTs), the randomized double-blind placebo-controlled clinical trial is considered the most efficient means of simultaneously assessing the efficacy and safety of a medical...Within the field of randomized clinical trials (RCTs), the randomized double-blind placebo-controlled clinical trial is considered the most efficient means of simultaneously assessing the efficacy and safety of a medical therapy in a single trial. While many RCTs are conducted without blinding (open label), it is rare to encounter a blinded trial that does not randomize its subjects. Clinical trials for chronic liver diseases have adopted many of the practices set forth by RCTs in other chronic diseases, but blinding has often been difficult to properly implement. This review examines the rationale for blinding, common challenges to successful blinding, different mechanisms of unintentional unblinding in clinical trials for viral hepatitis and nonalcoholic steatohepatitis, and recommendations for blinding and design in future trials of treatments for liver disease.
For patients with early-stage hepatocellular carcinoma (HCC), liver transplantation offers the best chance of cure. Over the past two decades, selection criteria to determine eligibility for liver transplantation have be...For patients with early-stage hepatocellular carcinoma (HCC), liver transplantation offers the best chance of cure. Over the past two decades, selection criteria to determine eligibility for liver transplantation have been constantly refined but a fair allocation strategy of liver grafts to HCC patients remains challenging. In Europe, over a dozen transplantation networks apply different liver transplantation criteria for HCC patients. In this review, we explore and compare candidate selection and liver graft allocation strategies for patients with HCC with a European perspective and discuss the ethical and technical challenges involved. In addition, we suggest possible paths for future improvement such as transitioning from fixed selection and allocation criteria to a more flexible model of benefit, which includes criteria concerning the graft, response to treatment, the biology of the tumor, and other relevant recipient factors.
Hepatitis B core-related antigen (HBcrAg) is a composite measure of the serum levels of hepatitis B e antigen, hepatitis B core antigen, and a 22-kDa precore protein. It has been shown to reflect the level and transcript...Hepatitis B core-related antigen (HBcrAg) is a composite measure of the serum levels of hepatitis B e antigen, hepatitis B core antigen, and a 22-kDa precore protein. It has been shown to reflect the level and transcriptional activity of covalently closed circular DNA in the liver. Longitudinal cohort studies have improved our understanding of the role of this novel viral marker in the natural history of chronic hepatitis B. HBcrAg kinetics reflect the response to peginterferon, and its role in defining guidelines for stopping peginterferon therapy has been evaluated. HBcrAg is a marker of intrahepatic viral activity, which may influence the risk of hepatocellular carcinoma. In this article, we review the virology and role of HBcrAg in defining phases of chronic hepatitis B. Furthermore, the function of HBcrAg in predicting treatment outcomes and its role in monitoring response to novel antiviral agents will be discussed.
Semin Liver Dis
· 2021 Jan · PMID 33957682
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Alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are important causes of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of b...Alcohol-associated liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are important causes of morbidity and mortality worldwide. The intestinal microbiota is involved in the development and progression of both ALD and NAFLD. Here we describe associated changes in the intestinal microbiota, and we detail randomized clinical trials in ALD and NAFLD which evaluate treatments modulating the intestinal microbiome including fecal microbiota transplantation, probiotics, prebiotics, synbiotics, and antibiotics. Finally, we discuss precision medicine approaches targeting the intestinal microbiome to ameliorate ALD and NAFLD.
The success of liver transplant (LT) for hepatocellular carcinoma (HCC) is dependent on accurate tumor staging using validated imaging criteria, and adherence to acceptable criteria based on tumor size and number. Other...The success of liver transplant (LT) for hepatocellular carcinoma (HCC) is dependent on accurate tumor staging using validated imaging criteria, and adherence to acceptable criteria based on tumor size and number. Other factors including α-fetoprotein (AFP) and response to local regional therapy (LRT) have now played a larger role in candidate selection. Tumor downstaging is defined as reduction in the size of viable tumors using LRT to meet acceptable criteria for LT, and serves as a selection tool for a subgroup of HCC with more favorable biology. The application of tumor downstaging requires a structured approach involving three key components in tumor staging-initial tumor stage and eligibility criteria, tumor viability assessment following LRT, and target tumor stage prior to LT-and incorporation of AFP into staging and treatment response assessments. In this review, we provide in-depth discussions of the key role of these staging definitions in ensuring successful outcome.