Showing papers in "Nature Reviews Gastroenterology & Hepatology in 2014"
TL;DR: An expert panel was convened in October 2013 by the International Scientific Association for Probiotics and Prebiotics (ISAPP) to discuss the field of probiotics and the appropriate use and scope of the term probiotic.
Abstract: An expert panel was convened in October 2013 by the International Scientific Association for Probiotics and Prebiotics (ISAPP) to discuss the field of probiotics. It is now 13 years since the definition of probiotics and 12 years after guidelines were published for regulators, scientists and industry by the Food and Agriculture Organization of the United Nations and the WHO (FAO/WHO). The FAO/WHO definition of a probiotic--"live microorganisms which when administered in adequate amounts confer a health benefit on the host"--was reinforced as relevant and sufficiently accommodating for current and anticipated applications. However, inconsistencies between the FAO/WHO Expert Consultation Report and the FAO/WHO Guidelines were clarified to take into account advances in science and applications. A more precise use of the term 'probiotic' will be useful to guide clinicians and consumers in differentiating the diverse products on the market. This document represents the conclusions of the ISAPP consensus meeting on the appropriate use and scope of the term probiotic.
5,114 citations
TL;DR: The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades, and hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases.
Abstract: The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications.
545 citations
TL;DR: The genetic basis of gastric cancer will offer insights into its pathogenesis, help identify new biomarkers and novel treatment targets, aid prognostication and could be central to developing individualized treatment strategies in the future.
Abstract: Gastric cancer remains highly prevalent and accounts for a notable proportion of global cancer mortality. This cancer is also associated with poor survival rates. Understanding the genetic basis of gastric cancer will offer insights into its pathogenesis, help identify new biomarkers and novel treatment targets, aid prognostication and could be central to developing individualized treatment strategies in the future. An inherited component contributes to <3% of gastric cancers; the majority of genetic changes associated with gastric cancer are acquired. Over the past few decades, advances in technology and high-throughput analysis have improved understanding of the molecular aspects of the pathogenesis of gastric cancer. These aspects are multifaceted and heterogeneous and represent a wide spectrum of several key genetic influences, such as chromosomal instability, microsatellite instability, changes in microRNA profile, somatic gene mutations or functional single nucleotide polymorphisms. These genetic aspects of the pathogenesis of gastric cancer will be addressed in this Review.
294 citations
TL;DR: The evidence implicating the gut microbiota in not only the expression of the intestinal manifestations of IBS, but also the psychiatric morbidity that coexists in up to 80% of patients with IBS is described.
Abstract: The gut microbiota is now acknowledged to have a profound effect on human health and disease. Here, Stephen Collins explores the role of the gut microbiota in the development of IBS, describing experimental evidence and clinical observational and trial data that implicates the gut microbiota in the manifestation of IBS.
275 citations
TL;DR: By adding insight into molecular and cellular mechanisms of related bowel disorders, gastroenterologists can substantially strengthen efforts to prevent, diagnose and manage adverse effects of cancer therapy, in general and those of radiation therapy specifically.
Abstract: Radiation enteropathy remains an important obstacle to uncomplicated cancer cures after radiation therapy of pelvic and abdominal malignancies. Moreover, the prevalence of radiation enteropathy in the population exceeds that of IBD. This Review introduces the clinical problem of radiation enteropathy, discusses contemporary concepts in pathogenesis, current therapeutic options and strategies for development of new radioprotective agents.
267 citations
TL;DR: Several commonly prescribed medications seem promising as chemopreventive agents against HCC, including statins, antidiabetic medications and aspirin, and dietary agents such as coffee, vitamin E and fish oil as well as phytochemicals might be associated with reduced risk of HCC.
Abstract: In light of the high mortality rate associated with hepatocellular carcinoma (HCC), chemopreventive strategies to prevent or delay the development of this disease are attractive. This Review outlines advances in the field of HCC chemoprevention, in particular focusing on the potential of antiviral therapy against HBV and HCV, the cancer-modifying effects of statins, antidiabetic medications and aspirin, as well as dietary strategies.
242 citations
TL;DR: Evidence for neuroplasticity (structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function is discussed, which is evident during inflammation and, in many cases, long after healing of the damaged tissues, when the nervous system fails to reset back to normal.
Abstract: The gastrointestinal tract is innervated by several distinct populations of neurons, whose cell bodies either reside within (intrinsic) or outside (extrinsic) the gastrointestinal wall. Normally, most individuals are unaware of the continuous, complicated functions of these neurons. However, for patients with gastrointestinal disorders, such as IBD and IBS, altered gastrointestinal motility, discomfort and pain are common, debilitating symptoms. Although bouts of intestinal inflammation underlie the symptoms associated with IBD, increasing preclinical and clinical evidence indicates that infection and inflammation are also key risk factors for the development of other gastrointestinal disorders. Notably, a strong correlation exists between prior exposure to gut infection and symptom occurrence in IBS. This Review discusses the evidence for neuroplasticity (structural, synaptic or intrinsic changes that alter neuronal function) affecting gastrointestinal function. Such changes are evident during inflammation and, in many cases, long after healing of the damaged tissues, when the nervous system fails to reset back to normal. Neuroplasticity within distinct populations of neurons has a fundamental role in the aberrant motility, secretion and sensation associated with common clinical gastrointestinal disorders. To find appropriate therapeutic treatments for these disorders, the extent and time course of neuroplasticity must be fully appreciated.
218 citations
TL;DR: The incidence, risk factors and outcomes of HBV reactivation, and the efficacy of antiviral therapy in preventing its occurrence are reviewed and an algorithm for managing patients with HBV infection who require immunosuppressive therapy is proposed.
Abstract: Patients with chronic HBV infection are at risk of reactivation of HBV should they require immunosuppressive therapies for a variety of clinical settings, including chemotherapy for patients with cancer, immunosuppression for solid organ and stem cell transplant recipients, and use of anti-CD20 antibodies, TNF inhibitors, or corticosteroids in patients with oncological, gastrointestinal, rheumatological or dermatological conditions. The key to preventing HBV reactivation is the identification of patients with HBV infection prior to immunosuppressive therapy, initiation of prophylactic antiviral therapy in patients at moderate or high risk of HBV reactivation, and close monitoring of other patients so that antiviral therapy can be initiated at the first sign of HBV reactivation. Unfortunately, many patients infected with HBV are unaware of their infection or risk factors, and physicians often do not have sufficient time to systematically assess patients for risk factors for HBV prior to starting immunosuppressive therapy. In this article, we review the incidence, risk factors and outcomes of HBV reactivation, and the efficacy of antiviral therapy in preventing its occurrence. We also propose an algorithm for managing patients with HBV infection who require immunosuppressive therapy.
199 citations
TL;DR: An emerging body of research now demonstrates the efficacy of fermentable carbohydrate restriction in IBS; however, limitations still exist with this approach owing to a limited number of randomized trials, in part due to the fundamental difficulty of placebo control in dietary trials.
Abstract: IBS is a debilitating condition that markedly affects quality of life. The chronic nature, high prevalence and associated comorbidities contribute to the considerable economic burden of IBS. The pathophysiology of IBS is not completely understood and evidence to guide management is variable. Interest in dietary intervention continues to grow rapidly. Ileostomy and MRI studies have demonstrated that some fermentable carbohydrates increase ileal luminal water content and breath hydrogen testing studies have demonstrated that some carbohydrates also increase colonic hydrogen production. The effects of fermentable carbohydrates on gastrointestinal symptoms have also been well described in blinded, controlled trials. Dietary restriction of fermentable carbohydrates (popularly termed the 'low FODMAP diet') has received considerable attention. An emerging body of research now demonstrates the efficacy of fermentable carbohydrate restriction in IBS; however, limitations still exist with this approach owing to a limited number of randomized trials, in part due to the fundamental difficulty of placebo control in dietary trials. Evidence also indicates that the diet can influence the gut microbiota and nutrient intake. Fermentable carbohydrate restriction in people with IBS is promising, but the effects on gastrointestinal health require further investigation.
197 citations
TL;DR: Cirrhotic cardiomyopathy designates a cardiac dysfunction that includes impaired cardiac contractility with systolic and diastolic dysfunction, as well as electromechanical abnormalities in the absence of other known causes of cardiac disease.
Abstract: Cirrhosis is known to cause alterations in the systemic haemodynamic system. Cirrhotic cardiomyopathy designates a cardiac dysfunction that includes impaired cardiac contractility with systolic and diastolic dysfunction, as well as electromechanical abnormalities in the absence of other known causes of cardiac disease. This condition is primarily revealed by inducing physical or pharmacological stress, but echocardiography is excellent at revealing diastolic dysfunction and might also be used to detect systolic dysfunction at rest. Furthermore, measurement of circulating levels of cardiac biomarkers could improve the diagnostic assessm+ent. Cirrhotic cardiomyopathy contributes to various complications in cirrhosis, especially as an important factor in the development of hepatic nephropathy. Additionally, cirrhotic cardiomyopathy seems to be associated with the development of heart failure in relation to invasive procedures such as shunt insertion and liver transplantation. Current pharmacological treatment is nonspecific and directed towards left ventricular failure, and liver transplantation is currently the only proven treatment with specific effect on cirrhotic cardiomyopathy.
191 citations
TL;DR: The knowledge of the differences in epidemiology, clinical characteristics, and natural history of paediatric, adult and elderly-onset IBD are updated and potential differences in host–gene–microbial interactions according to age are highlighted.
Abstract: IBD is a chronic disorder with disease onset ranging from early childhood to beyond the sixth decade of life. The factors that determine the age of onset currently remain unexplained. Is timing of occurrence a random event or is it indicative of different pathophysiological pathways leading to different phenotypes across the age spectrum? Over the past decade, several studies have suggested that the characteristics and natural history of IBD seem to be different according to age of onset. This heterogeneity suggests that the respective contributions of genetics, host immune system and environment to the aetiology and phenotype of Crohn's disease and ulcerative colitis are different across ages. Critical reviews that focus on differences characterizing IBD between age groups are scarce. Therefore, this Review updates the knowledge of the differences in epidemiology, clinical characteristics, and natural history of paediatric, adult and elderly-onset IBD. In addition, potential differences in host-gene-microbial interactions according to age are highlighted.
TL;DR: Aetiological factors associated with liver cancer are well understood; however, their effects on the accumulation of somatic changes and the influence of ethnic variation in risk factors still remain unknown.
Abstract: Liver cancer is the third leading cause of cancer-related death worldwide. Advances in sequencing technologies have enabled the examination of liver cancer genomes at high resolution; somatic mutations, structural alterations, HBV integration, RNA editing and retrotransposon changes have been comprehensively identified. Furthermore, integrated analyses of trans-omics data (genome, transcriptome and methylome data) have identified multiple critical genes and pathways implicated in hepatocarcinogenesis. These analyses have uncovered potential therapeutic targets, including growth factor signalling, WNT signalling, the NFE2L2-mediated oxidative pathway and chromatin modifying factors, and paved the way for new molecular classifications for clinical application. The aetiological factors associated with liver cancer are well understood; however, their effects on the accumulation of somatic changes and the influence of ethnic variation in risk factors still remain unknown. The international collaborations of cancer genome sequencing projects are expected to contribute to an improved understanding of risk evaluation, diagnosis and therapy for this cancer.
TL;DR: With multiple direct-acting antiviral agents in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients, which incorporates data on fibrosis stage as well as potential drug interactions with antiretroviral therapy.
Abstract: HCV and HIV co-infection is associated with accelerated hepatic fibrosis progression and higher rates of liver decompensation and death compared to HCV monoinfection, and liver disease is a leading cause of non-AIDS-related mortality among HIV-infected patients. New insights have revealed multiple mechanisms by which HCV and HIV lead to accelerated disease progression, specifically that HIV infection increases HCV replication, augments HCV-induced hepatic inflammation, increases hepatocyte apoptosis, increases microbial translocation from the gut and leads to an impairment of HCV-specific immune responses. Treatment of HIV with antiretroviral therapy and treatment of HCV have independently been shown to delay the progression of fibrosis and reduce complications from end-stage liver disease among co-infected patients. However, rates of sustained virologic response with PEG-IFN and ribavirin have been significantly inferior among co-infected patients compared with HCV-monoinfected patients, and treatment uptake has remained low given the limited efficacy and tolerability of current HCV regimens. With multiple direct-acting antiviral agents in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients, which incorporates data on fibrosis stage as well as potential drug interactions with antiretroviral therapy.
TL;DR: The different types of hepatic autophagy, their role in maintaining homeostasis in a healthy liver and the contribution of autophagic malfunction to liver disease are described.
Abstract: Studies performed in the liver in the 1960s led to the identification of lysosomes and the discovery of autophagy, the process by which intracellular proteins and organelles are degraded in lysosomes. Early studies in hepatocytes also uncovered how nutritional status regulates autophagy and how various circulating hormones modulate the activity of this catabolic process in the liver. The intensive characterization of hepatic autophagy over the years has revealed that lysosome-mediated degradation is important not only for maintaining liver homeostasis in normal physiological conditions, but also for an adequate response of this organ to stressors such as proteotoxicity, metabolic dysregulation, infection and carcinogenesis. Autophagic malfunction has also been implicated in the pathogenesis of common liver diseases, suggesting that chemical manipulation of this process might hold potential therapeutic value. In this Review--intended as an introduction to the topic of hepatic autophagy for clinical scientists--we describe the different types of hepatic autophagy, their role in maintaining homeostasis in a healthy liver and the contribution of autophagic malfunction to liver disease.
TL;DR: Con conceptual limitations of clinically available liver support therapy systems are discussed and alternative concepts, such as hepatocyte transplantation, and cutting-edge developments in the field of liver support strategies are analysed, raising hope for bioengineered liver support therapies in the future.
Abstract: The treatment of end-stage liver disease and acute liver failure remains a clinically relevant issue. Although orthotopic liver transplantation is a well-established procedure, whole-organ transplantation is invasive and increasingly limited by the unavailability of suitable donor organs. Artificial and bioartificial liver support systems have been developed to provide an alternative to whole organ transplantation, but despite three decades of scientific efforts, the results are still not convincing with respect to clinical outcome. In this Review, conceptual limitations of clinically available liver support therapy systems are discussed. Furthermore, alternative concepts, such as hepatocyte transplantation, and cutting-edge developments in the field of liver support strategies, including the repopulation of decellularized organs and the biofabrication of entirely new organs by printing techniques or induced organogenesis are analysed with respect to clinical relevance. Whereas hepatocyte transplantation shows promising clinical results, at least for the temporary treatment of inborn metabolic diseases, so far data regarding implantation of engineered hepatic tissue have only emerged from preclinical experiments. However, the evolving techniques presented here raise hope for bioengineered liver support therapies in the future.
TL;DR: An overview of the studies assessing circulating MV levels in patients with liver diseases, together with an insight into the mechanisms that could account for these changes, and a detailed analysis of the implication of MVs in key processes of liver diseases are presented.
Abstract: Microvesicles (MVs) are extracellular vesicles released by virtually all cells, under both physiological and pathological conditions They contain lipids, proteins, RNAs and microRNAs and act as vectors of information that regulate the function of target cells This Review provides an overview of the studies assessing circulating MV levels in patients with liver diseases, together with an insight into the mechanisms that could account for these changes We also present a detailed analysis of the implication of MVs in key processes of liver diseases MVs have a dual role in fibrosis as certain types of MVs promote fibrolysis by increasing expression of matrix metalloproteinases, whereas others promote fibrosis by stimulating processes such as angiogenesis MVs probably enhance portal hypertension by contributing to intrahepatic vasoconstriction, splanchnic vasodilation and angiogenesis As MVs can modulate vascular permeability, vascular tone and angiogenesis, they might contribute to several complications of cirrhosis including hepatic encephalopathy, hepatopulmonary syndrome and hepatorenal syndrome Several results also suggest that MVs have a role in hepatocellular carcinoma Although MVs represent promising biomarkers in patients with liver disease, methods of isolation and subsequent analysis must be standardized
TL;DR: Measuring drug and anti-drug antibody levels which develop in some patients has emerged as a valuable tool in understanding the mechanisms responsible for some of these clinical scenarios but knowledge on how to use these measurements to guide clinical decisions in daily practice is still in its nascency and awaits prospective validation trials.
Abstract: Despite the proven and often clinically marked efficacy of anti-TNF drugs for IBD, these biologic agents are not immune to treatment failures. Tailoring anti-TNF treatment in IBD mandates considerations of the different clinical scenarios in which therapy failure might occur while bearing in mind an opposite group of patients in whom intensive therapy might be unnecessary.
TL;DR: An overview of the success of clinical research on H. pylori to date is given and some future trends in this area are highlighted, which might have a clinical effect in the near future.
Abstract: The discovery of Helicobacter pylori three decades ago is a modern medical success story. It markedly changed our understanding of the pathophysiology of gastroduodenal diseases and led to an improvement in the treatment of diseases related to H. pylori infection. Many of these diseases (such as ulcer disease and mucosal associated lymphoid tissue lymphoma) have become curable, and others (gastric cancer) might be preventable with the application of H. pylori eradication therapy. Since its discovery, H. pylori has also been identified as a trigger for some extragastric diseases. Promising results in this exciting field might have a clinical effect in the near future. This Timeline gives an overview of the success of clinical research on H. pylori to date and highlights some future trends in this area.
TL;DR: Advances in glycoprofiling technology make it technically feasible and affordable to perform high-throughput glycan pattern analyses and to build on previous work investigating a much wider range of glycan parameters in large numbers of patients.
Abstract: A number of genetic and immunological studies give impetus for investigating the role of glycosylation in IBD. Experimental mouse models have helped to delineate the role of glycosylation in intestinal mucins and to explore the putative pathogenic role of glycosylation in colitis. These experiments have been extended to human studies investigating the glycosylation patterns of intestinal mucins as well as levels of glycans of serum glycoproteins and expression of glycan receptors. These early human studies have generated interesting hypotheses regarding the pathogenic role of glycans in IBD, but have generally been restricted to fairly small underpowered studies. Decreased glycosylation has been observed in the intestinal mucus of patients with IBD, suggesting that a defective inner mucus layer might lead to increased bacterial contact with the epithelium, potentially triggering inflammation. In sera, decreased galactosylation of IgG has been suggested as a diagnostic marker for IBD. Advances in glycoprofiling technology make it technically feasible and affordable to perform high-throughput glycan pattern analyses and to build on previous work investigating a much wider range of glycan parameters in large numbers of patients.
TL;DR: The possibility of spontaneous resolution of partial PVT questions the necessity of anticoagulation for the treatment ofpartial PVT, and a relatively low recanalization rate of complete PVT after antICOagulation therapy suggests its limited usefulness in patients with complete PVt.
Abstract: Portal vein thrombosis (PVT) is a fairly common complication of liver cirrhosis. Importantly, occlusive PVT might influence the prognosis of patients with cirrhosis. Evidence from a randomized controlled trial has shown that anticoagulation can prevent the occurrence of PVT in patients with cirrhosis without prior PVT. Evidence from several case series has also demonstrated that anticoagulation can achieve portal vein recanalization in patients with cirrhosis and PVT. Early initiation of anticoagulation therapy and absence of previous portal hypertensive bleeding might be positively associated with a high rate of portal vein recanalization after anticoagulation. However, the possibility of spontaneous resolution of partial PVT questions the necessity of anticoagulation for the treatment of partial PVT. In addition, a relatively low recanalization rate of complete PVT after anticoagulation therapy suggests its limited usefulness in patients with complete PVT. Successful insertion of a transjugular intrahepatic portosystemic shunt (TIPS) not only recanalizes the thrombosed portal vein, but also relieves the symptomatic portal hypertension. However, the technical difficulty of TIPS potentially limits its widespread application, and the risk and benefits should be fully balanced. Notably, current recommendations regarding the management of PVT in liver cirrhosis are insufficient owing to low-quality evidence.
TL;DR: This Review summarizes the results of the most important studies performed to date surrounding the association of H. pylori infection with extragastric diseases, as well as the strength of the evidence, and provides information concerning bacterial–host interactions and the mechanisms implicated in the pathogenesis of each of these extragasts.
Abstract: The discovery of Helicobacter pylori infection in the stomach could be considered as one of the most important events of modern gastroenterology. Understanding of the natural history of many disorders of the upper gastrointestinal tract, including chronic gastritis, peptic ulcer disease, gastric cancer and MALT lymphoma, was altered by this discovery. Interestingly, epidemiological studies have also revealed a correlation between H. pylori infection and some diseases localized outside the stomach, especially those characterized by persistent and low‑grade systemic inflammation. Of note, H. pylori has an important role in iron deficiency anaemia, idiopathic thrombocytopenic purpura and vitamin B 12 deficiency. Moreover, the association of this bacterial pathogen with many other diseases, including hepatobiliary, pancreatic, cardiovascular and neurodegenerative disorders is currently under investigation. In this Review, we summarize the results of the most important studies performed to date surrounding the association of H. pylori infection with extragastric diseases, as well as the strength of the evidence. We also provide information concerning bacterial-host interactions and the mechanisms implicated in the pathogenesis of each of these extragastric diseases.
TL;DR: How genetic association studies have informed understanding of the pathogenesis of IBD by focusing research efforts on key pathways involved in innate immunity, autophagy, lymphocyte differentiation and chemotaxis is highlighted.
Abstract: IBD is a spectrum of chronic disorders that constitute an important health problem worldwide. The hunt for genetic determinants of disease onset and course has culminated in the Immunochip project, which has identified >160 loci containing IBD susceptibility genes. In this Review, we highlight how genetic association studies have informed our understanding of the pathogenesis of IBD by focusing research efforts on key pathways involved in innate immunity, autophagy, lymphocyte differentiation and chemotaxis. Several of these novel genetic markers and cellular pathways are promising candidates for patient stratification and therapeutic targeting.
TL;DR: Refinement of phase II–III trial designs with a biomarker-enriched patient-selection process and stratification according to prognostic baseline factors is indispensable to prevent another 5-year vain endeavour in systemic therapy of HCC.
Abstract: Advancing the field of therapeutics for hepatocellular carcinoma has been far more challenging than initially anticipated; sorafenib is the only approved systemic therapy in more than 5 years. Marcus-Alexander Worns and Peter Galle elucidate the current landscape of phase III trials in advanced HCC, with a special focus on future challenges.
TL;DR: Reducing the HCV burden has been hampered by limited access to treatment, largely owing to the cost of drugs, in countries where antibody screening, disposable materials and effective sterilization procedures are not routinely available.
Abstract: Understanding HCV transmission routes is essential for designing and implementing control strategies to reduce the prevalence of HCV infection and the burden of hepatitis C. Here, the main routes of HCV transmission in industrialized and resource-constrained countries are presented, along with a global agenda on how the burden of HCV could be reduced.
TL;DR: Evidence indicates that bile acid diarrhoea accounts for a sizeable proportion of patients who would otherwise be diagnosed with IBS, and the role of the ileal hormone FGF19 in BAD has been strengthened: a prospective clinical study has confirmed low F GF19 levels in BAD, and so a test to measure these levels could be developed for diagnosis.
Abstract: Chronic diarrhoea induced by bile acids is common and the underlying mechanisms are linked to homeostatic regulation of hepatic bile acid synthesis by fibroblast growth factor 19 (FGF19). Increasing evidence, including that from several large case series using SeHCAT (selenium homocholic acid taurine) tests for diagnosis, indicates that bile acid diarrhoea (BAD) accounts for a sizeable proportion of patients who would otherwise be diagnosed with IBS. Studies of other approaches for diagnosis of BAD have shown increased bile acid synthesis, increased faecal levels of primary bile acids, dysbiosis and different urinary volatile organic compounds when compared with healthy controls or with other diseases. The role of the ileal hormone FGF19 in BAD has been strengthened: a prospective clinical study has confirmed low FGF19 levels in BAD, and so a test to measure these levels could be developed for diagnosis. In animal models, FGF19 depletion by antibodies produces severe diarrhoea. Bile acids affect colonic function through farnesoid X receptor (FXR) and TGR5 receptors. As well as these effects in the colon, FXR-dependent stimulation of ileal FGF19 production could be a logical mechanism to provide therapeutic benefit in BAD. Further studies of FGF19 in humans hold promise in providing novel treatments for this cause of chronic diarrhoea.
TL;DR: No single measure gives a reliable estimate of the risk of drinking relapses before or after liver transplantation, but careful evaluation by an addiction specialist with a particular interest in transplant medicine is the best available approach.
Abstract: This Review outlines the nomenclature of addiction to alcohol and details how patients who drink to excess should be assessed for liver transplantation. Michael Lucey also explores the controversies about predicting future drinking behaviour and offering liver transplantation to patients with severe alcoholic hepatitis. Alcoholic liver disease (ALD) is the major cause of life-threatening liver disease in Western countries. Abstinence from alcohol is the foundation of all treatment programmes for patients with ALD. Liver transplantation is a valuable option for patients with life-threatening ALD. Although the role of liver transplantation in the treatment of alcoholic hepatitis that is unresponsive to medical therapy is controversial, the latest prospective studies support this approach. No single measure gives a reliable estimate of the risk of drinking relapses before or after liver transplantation, but careful evaluation by an addiction specialist with a particular interest in transplant medicine is the best available approach. Survival, both on the waiting list and after the operation, is better in patients with ALD than in patients with HCV infection. Alcohol relapse may lead to liver damage and increased mortality, albeit usually after many years of renewed drinking. After liver transplantation, patients with ALD have increased rates of mortality and morbidity that are attributable to cardiovascular disease and new-onset cancers of the aerodigestive tract. The latter are probably linked to the high prevalence of smoking in this population. Cessation of smoking is thus an important goal in the care of patients with ALD after they have undergone liver transplantation.
TL;DR: MRI has markedly improved diagnosis and can identify the major hepatocellular adenomas subtypes, however, the use of biopsy results to inform the indication for resection remains questionable and percutaneous biopsy could help improve diagnostic accuracy.
Abstract: More and more asymptomatic benign liver tumours are discovered incidentally and can be divided into regenerative lesions and true neoplastic lesions. The most common regenerative lesions include hemangioma, focal nodular hyperplasia and inflammatory pseudotumours of the liver. Neoplastic lesions include hepatocellular adenomas and angiomyolipomas. Regenerative lesions rarely increase in volume, do not yield a higher risk of complications and usually do not require treatment. By contrast, hepatocellular adenomas and angiomyolipomas can increase in volume and are associated with a risk of complications. Large hepatocellular adenomas (>5 cm in diameter) are undoubtedly associated with a risk of bleeding and malignant transformation, particularly the inflammatory (also known as telangiectatic) and β-catenin mutated subtypes. Accurate diagnosis needs to be obtained to select patients eligible for surgical resection. MRI has markedly improved diagnosis and can identify the major hepatocellular adenomas subtypes. The use of biopsy results to inform the indication for resection remains questionable. However, when diagnosis remains uncertain after imaging, percutaneous biopsy could help improve diagnostic accuracy.
TL;DR: D diseases that might be targets for stem cell therapies and the barriers that could limit treatment application are discussed and various sources of stem cells and the proof of concept for their use are explored.
Abstract: The enteric nervous system is vulnerable to a range of congenital and acquired disorders that disrupt the function of its neurons or lead to their loss. The resulting enteric neuropathies are some of the most challenging clinical conditions to manage. Neural stem cells offer the prospect of a cure given their potential ability to replenish missing or dysfunctional neurons. This article discusses diseases that might be targets for stem cell therapies and the barriers that could limit treatment application. We explore various sources of stem cells and the proof of concept for their use. The critical steps that remain to be addressed before these therapies can be used in patients are also discussed. Key milestones include the harvesting of neural stem cells from the human gut and the latest in vivo transplantation studies in animals. The tremendous progress in the field has brought experimental studies exploring the potential of stem cell therapies for the management of enteric neuropathies to the cusp of clinical application.
TL;DR: The genetic mechanisms underlying polycystic liver diseases and the most relevant molecular pathways of hepatic cystogenesis are discussed and the main clinical and preclinical studies are highlighted and future directions in basic as well as clinical research are indicated.
Abstract: Polycystic liver diseases are genetic disorders characterized by progressive bile duct dilatation and/or cyst development. The large volume of hepatic cysts causes different symptoms and complications such as abdominal distension, local pressure with back pain, hypertension, gastro-oesophageal reflux and dyspnea as well as bleeding, infection and rupture of the cysts. Current therapeutic strategies are based on surgical procedures and pharmacological management, which partially prevent or ameliorate the disease. However, as these treatments only show short-term and/or modest beneficial effects, liver transplantation is the only definitive therapy. Therefore, interest in understanding the molecular mechanisms involved in disease pathogenesis is increasing so that new targets for therapy can be identified. In this Review, the genetic mechanisms underlying polycystic liver diseases and the most relevant molecular pathways of hepatic cystogenesis are discussed. Moreover, the main clinical and preclinical studies are highlighted and future directions in basic as well as clinical research are indicated.
TL;DR: Endomicroscopy is also unique in its ability to dynamically visualize cellular processes in their native environment free of artefacts, which enables fundamental insights into mechanisms of human diseases in clinical and translational science.
Abstract: Performing real-time microscopy has been a vision of endoscopists since the very early phases of gastrointestinal endoscopy. Confocal endomicroscopy, an adaption of confocal laser scanning microscopy, and endocytoscopy, an adaption of white-light microscopy, have been introduced into the endoscopic armamentarium in the past decade. Both techniques yield on-site histological information. Multiple trials have demonstrated the ability of gastroenterologists to obtain and interpret microscopic images from the upper and lower gastrointestinal tract, and also the hepatobiliary-pancreatic system, during endoscopy. Such microscopic information has been successfully used in expert hands to minimize sampling error by 'smart', microscopically targeted biopsies and to guide endoscopic interventions. However, endomicroscopy is also unique in its ability to dynamically visualize cellular processes in their native environment free of artefacts. This ability enables fundamental insights into mechanisms of human diseases in clinical and translational science.