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Gut function remains largely underinvestigated in undernutrition, despite its critical role in essential nutrient digestion, absorption and assimilation. In areas of high enteropathogen burden, alterations in gut barrier function and subsequent inflammatory effects are observable but remain poorly characterised. Environmental enteropathy (EE)—a condition that affects both gut morphology and function and is characterised by blunted villi, inflammation and increased permeability—is thought to play a role in impaired linear growth (stunting) and severe acute malnutrition. However, the lack of tools to quantitatively characterise gut functional capacity has hampered both our understanding of gut pathogenesis in undernutrition and evaluation of gut-targeted therapies to accelerate nutritional recovery. Here we survey the technology landscape for potential solutions to improve assessment of gut function, focussing on devices that could be deployed at point-of-care in low-income and middle-income countries (LMICs). We assess the potential for technological innovation to assess gut morphology, function, barrier integrity and immune response in undernutrition, and highlight the approaches that are currently most suitable for deployment and development. This article focuses on EE and undernutrition in LMICs, but many of these technologies may also become useful in monitoring of other gut pathologies.

Approximately 5% of individuals infected with hepatitis B virus (HBV) are coinfected with hepatitis D virus (HDV). Chronic HBV/HDV coinfection is associated with an unfavourable outcome, with many patients developing liver cirrhosis, liver failure and eventually hepatocellular carcinoma within 5–10 years. The identification of the HBV/HDV receptor and the development of novel in vitro and animal infection models allowed a more detailed study of the HDV life cycle in recent years, facilitating the development of specific antiviral drugs. The characterisation of HDV-specific CD4+ and CD8+T cell epitopes in untreated and treated patients also permitted a more precise understanding of HDV immunobiology and possibly paves the way for immunotherapeutic strategies to support upcoming specific therapies targeting viral or host factors. Pegylated interferon-α has been used for treating HDV patients for the last 30 years with only limited sustained responses. Here we describe novel treatment options with regard to their mode of action and their clinical effectiveness. Of those, the entry-inhibitor bulevirtide (formerly known as myrcludex B) received conditional marketing authorisation in the European Union (EU) in 2020 (Hepcludex). One additional drug, the prenylation inhibitor lonafarnib, is currently under investigation in phase III clinical trials. Other treatment strategies aim at targeting hepatitis B surface antigen, including the nucleic acid polymer REP2139Ca. These recent advances in HDV virology, immunology and treatment are important steps to make HDV a less difficult-to-treat virus and will be discussed.

Colorectal cancer (CRC) is one of the most common and lethal malignancies in Western countries. Its development is a multistep process that spans more than 15 years, thereby providing an opportunity for prevention and early detection. The high incidence and mortality rates emphasise the need for prevention and screening. Many countries have therefore introduced CRC screening programmes. It is expected, and preliminary evidence in some countries suggests, that this screening effort will decrease CRC-related mortality rates. CRC prevention involves a healthy lifestyle and chemoprevention—more specifically, oral chemoprevention that can interfere with progression from a normal colonic mucosa to adenocarcinoma. This preventive effect is important for individuals with a genetic predisposition, but also in the general population. The ideal chemopreventive agent, or combination of agents, remains unknown, especially when considering safety during long-term use. This review evaluates the evidence across 80 meta-analyses of interventional and observational studies of CRC prevention using medications, vitamins, supplements and dietary factors. This review suggests that the following factors are associated with a decreased incidence of CRC: aspirin, non-steroidal anti-inflammatory drugs, magnesium, folate, a high consumption of fruits and vegetables, fibre and dairy products. An increased incidence of CRC was observed with frequent alcohol or meat consumption. No evidence of a protective effect for tea, coffee, garlic, fish and soy products was found. The level of evidence is moderate for aspirin, β-carotene and selenium, but is low or very low for all other exposures or interventions.

Key messages The number of patients with type 2 diabetes (T2D) worldwide is expected to increase from 463 million in 2019 to 700 million in 2045, with a prevalence of more than 10% in Europe. Besides a role for genetics, causative factors include obesity, diet high in refined sugar and fat, and sedentary lifestyle. These factors may contribute to increased hepatic and peripheral insulin resistance, and thereafter pancreatic beta cells increase their insulin production to facilitate glucose uptake. …

Patients with Crohn’s disease commonly develop ileal and less commonly colonic strictures, containing various degrees of inflammation and fibrosis. While predominantly inflammatory strictures may benefit from a medical anti-inflammatory treatment, predominantly fibrotic strictures currently require endoscopic balloon dilation or surgery. Therefore, differentiation of the main components of a stricturing lesion is key for defining the therapeutic management. The role of endoscopy to diagnose the nature of strictures is limited by the superficial inspection of the intestinal mucosa, the lack of depth of mucosal biopsies and by the risk of sampling error due to a heterogeneous distribution of inflammation and fibrosis within a stricturing lesion. These limitations may be in part overcome by cross-sectional imaging techniques such as ultrasound, CT and MRI, allowing for a full thickness evaluation of the bowel wall and associated abnormalities. This systematic literature review provides a comprehensive summary of currently used radiologic definitions of strictures. It discusses, by assessing only manuscripts with histopathology as a gold standard, the accuracy for diagnosis of the respective modalities as well as their capability to characterise strictures in terms of inflammation and fibrosis. Definitions for strictures on cross-sectional imaging are heterogeneous; however, accuracy for stricture diagnosis is very high. Although conventional cross-sectional imaging techniques have been reported to distinguish inflammation from fibrosis and grade their severity, they are not sufficiently accurate for use in routine clinical practice. Finally, we present recent consensus recommendations and highlight experimental techniques that may overcome the limitations of current technologies.

Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) are ligand-activated transcriptional regulators of key metabolic processes including hepatic lipid and glucose metabolism, energy expenditure and bile acid (BA) homoeostasis, as well as inflammation, fibrosis and cellular proliferation. Dysregulation of these processes contributes to the pathogenesis and progression of cholestatic as well as fatty liver disease, placing NRs at the forefront of novel therapeutic approaches. This includes BA and fatty acid activated NRs such as farnesoid-X receptor (FXR) and peroxisome proliferator-activated receptors, respectively, for which high affinity therapeutic ligands targeting specific or multiple isoforms have been developed. Moreover, novel liver-specific ligands for thyroid hormone receptor beta 1 complete the spectrum of currently available NR-targeted drugs. Apart from FXR ligands, BA signalling can be targeted by mimetics of FXR-activated fibroblast growth factor 19, modulation of their enterohepatic circulation through uptake inhibitors in hepatocytes and enterocytes, as well as novel BA derivatives undergoing cholehepatic shunting (instead of enterohepatic circulation). Other therapeutic approaches more directly target inflammation and/or fibrosis as critical events of disease progression. Combination strategies synergistically targeting metabolic disturbances, inflammation and fibrosis may be ultimately necessary for successful treatment of these complex and multifactorial disorders.

Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of cirrhosis with the burden of NASH-related complications projected to increase massively over the coming years. Several molecules with different mechanisms of action are currently in development to treat NASH, although reported efficacy to date has been limited. Given the complexity of the pathophysiology of NASH, it will take the engagement of several targets and pathways to improve the results of pharmacological intervention, which provides a rationale for combination therapies in the treatment of NASH. As the field is moving towards combination therapy, this article reviews the rationale for such combination therapies to treat NASH based on the current therapeutic landscape as well as the advantages and limitations of this approach.

The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.

Complex rearrangement patterns and mitotic errors are hallmarks of most pancreatic ductal adenocarcinomas (PDAC), a disease with dismal prognosis despite some therapeutic advances in recent years. DNA double-strand breaks (DSB) bear the greatest risk of provoking genomic instability, and DNA damage repair (DDR) pathways are crucial in preserving genomic integrity following a plethora of damage types. Two major repair pathways dominate DSB repair for safeguarding the genome integrity: non-homologous end joining and homologous recombination (HR). Defective HR, but also alterations in other DDR pathways, such as BRCA1, BRCA2, ATM and PALB2, occur frequently in both inherited and sporadic PDAC. Personalised treatment of pancreatic cancer is still in its infancy and predictive biomarkers are lacking. DDR deficiency might render a PDAC vulnerable to a potential new therapeutic intervention that increases the DNA damage load beyond a tolerable threshold, as for example, induced by poly (ADP-ribose) polymerase inhibitors. The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency., publishedVersion

Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD in isolation, but are of value in determining need for further investigation. Conclusive evidence for reflux on oesophageal testing include advanced grade erosive oesophagitis (LA grades C and D), long-segment Barrett's mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET) >6% on ambulatory pH or pH-impedance monitoring. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal AET

Lactose is the main source of calories in milk, an essential nutriedigestion, patients with visceral hypersensitivity nt in infancy and a key part of the diet in populations that maintain the ability to digest this disaccharide in adulthood. Lactase deficiency (LD) is the failure to express the enzyme that hydrolyses lactose into galactose and glucose in the small intestine. The genetic mechanism of lactase persistence in adult Caucasians is mediated by a single C→T nucleotide polymorphism at the LCTbo -13'910 locus on chromosome-2. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. This includes primary genetic and also secondary LD due to infection or other conditions that affect the mucosal integrity of the small bowel. Lactose intolerance (LI) is defined as the onset of abdominal symptoms such as abdominal pain, bloating and diarrhoea after lactose ingestion by an individual with LM. The likelihood of LI depends on the lactose dose, lactase expression and the intestinal microbiome. Independent of lactose digestion, patients with visceral hypersensitivity associated with anxiety or the Irritable Bowel Syndrome (IBS) are at increased risk of the condition. Diagnostic investigations available to diagnose LM and LI include genetic, endoscopic and physiological tests. The association between self-reported LI, objective findings and clinical outcome of dietary intervention is variable. Treatment of LI can include low-lactose diet, lactase supplementation and, potentially, colonic adaptation by prebiotics. The clinical outcome of these treatments is modest, because lactose is just one of a number of poorly absorbed carbohydrates which can cause symptoms by similar mechanisms. ispartof: GUT vol:68 issue:11 pages:2080-2091 ispartof: location:England status: published

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption-distribution-metabolism-elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public-private partnerships.

Acute-on-chronic liver failure (ACLF) is a syndrome characterised by acute decompensation of chronic liver disease associated with organ failures and high short-term mortality. Alcohol and chronic viral hepatitis are the most common underlying liver diseases. Up to 40%–50% of the cases of ACLF have no identifiable trigger; in the remaining patients, sepsis, active alcoholism and relapse of chronic viral hepatitis are the most common reported precipitating factors. An excessive systemic inflammatory response seems to play a crucial role in the development of ACLF. Using a liver-adapted sequential organ assessment failure score, it is possible to triage and prognosticate the outcome of patients with ACLF. The course of ACLF is dynamic and changes over the course of hospital admission. Most of the patients will have a clear prognosis between day 3 and 7 of hospital admission and clinical decisions such as evaluation for liver transplant or discussion over goals of care could be tailored using clinical scores. Bioartificial liver support systems, granulocyte-colony stimulating factors or stem-cell transplant are in the horizon of medical care of this patient population; however, data are too premature to implement them as standard of care.

Colonoscopy is a widely performed procedure with procedural volumes increasing annually throughout the world. Many procedures are now performed as part of colorectal cancer screening programmes. Colonoscopy should be of high quality and measures of this quality should be evidence based. New UK key performance indicators and quality assurance standards have been developed by a working group with consensus agreement on each standard reached. This paper reviews the scientific basis for each of the quality measures published in the UK standards.

In 1990 we asked clinicians attending a symposium during the annual meeting of the American Gastroenterological Association how many were using psychopharmacological agents, specifically antidepressants, to treat functional gastrointestinal disorders.1 Very few raised their hands. Over the subsequent 15 years, these agents increasingly have become used in the management of functional gastrointestinal symptoms, despite a limited amount of scientific information supporting this practice. It is now estimated that at least 1 in 8 patients with irritable bowel syndrome (IBS) is offered an antidepressant.2,3 Nearly every comprehensive current review of management strategies for IBS and other mainstream functional gastrointestinal disorders mentions their use, and prescribing among gastroenterologists has become commonplace.3–10 In parallel with this change, primary care physicians have become sufficiently comfortable in using antidepressants for treating not only anxiety and depression but also a host of somatic symptoms and syndromes that their use has nearly tripled in the past decade.11 Enhanced appreciation for the relative importance of central mechanisms (for example, signal processing alterations) in many if not most patients with IBS and other painful functional gastrointestinal disorders is an important factor responsible for prescribing shifts among gastroenterologists—more so than a new or improved understanding of the relationship of symptoms to anxiety or depression.8 The composite body of investigation over the past 15 years involving visceral stimulation, brain imaging, multidimensional clinical studies, and treatment trials designed to answer mechanistic questions has led us closer to understanding the pathways by which psychopharmacological agents may interrupt the symptomatic process in these common gastrointestinal disorders. Complemented by clinical observations, improved recommendations for their use have evolved.6,12 This review describes the types of psychopharmacological agents used in functional gastrointestinal disorders, new models for their potential benefits, a summary of the reported efficacy, and practical aspects …

Barrett’s oesophagus or columnar lined oesophagus is among the most intriguing of gastroenterological conditions. This is because of its pathogenesis, prevalence, association with reflux disease, male sex and, in particular, the potential for neoplastic degeneration to adenocarcinoma. The current and dramatic rise in the incidence of oesophageal adenocarcinoma is centred on the UK (5–8.7/100 000), over double that of the USA (3.7/100 0000). This epidemic is fairly localised and is not evident in Asia, where squamous cell cancer remains the predominant oesophageal malignancy. Large rises in incidence, up to 30% per year, have been seen in West European White men, a rise not mirrored in Eastern Europe.1,2 At present the incidence remains paralleled by mortality. The prognosis of oesophageal cancer remains universally poor; median survival has hardly changed from 0.75 years between 1973 and 1977 to 0.9 years between 1993 and 1999. This almost trivial change has led some to suggest that the change could be accounted for by improved reporting and detection bias rather than any important therapeutic advance.3 Gradual malignant degeneration within a segment of Barrett’s oesophagus occurs in a probabilistic rather than in a deterministic manner. Barrett’s appears to be a necessary intermediary step. The relatively long time sequence to cancer may allow early intervention with endoscopic ablation, thus offering the possibility of preventing the lethal development of symptomatic oesophageal adenocarcinoma. Stark choices face patient and clinician in the presence of a degenerating “possibly” premalignant Barrett’s mucosa. Radical therapy offers an overaggressive, “possibly” flawed approach if the diagnosis and prognosis remain uncertain. It cannot be considered a triumph to have a millimetre of worrying but superficial disease and remove a whole oesophagus. The alternative of surveillance presents other concerns. It offers intermittent endoscopic inspection at proscribed, economically viable, and societal designated intervals, and awaits …

Histopathological characteristics distinguish steatohepatitis from other causes of chronic liver injury. For years, the main cause of steatohepatitis was thought to be excessive consumption of alcohol. Increasingly, steatohepatitis is being diagnosed in individuals who deny alcohol abuse. Arbitrarily, “non-alcoholic” steatohepatitis (NASH) is subcategorised into “primary” and “secondary” NASH.1 Primary NASH refers to steatohepatitis that is associated with the dysmetabolic syndrome (that is, obesity, type 2 diabetes, dyslipidaemia).2 Primary NASH is thought to be the predominant form of NASH, afflicting at least as many individuals in the USA as chronic hepatitis C. Secondary NASH refers to steatohepatitis that accompanies other syndromes (for example, lipodystrophy) or that is caused by certain drugs (for example, amiodarone).3 Accumulating evidence suggests that common mechanisms may mediate the pathogenesis of alcohol induced steatohepatitis and primary NASH.4 Although unproven, it is likely that primary and secondary NASH also share common pathogenic mechanisms. ### Obesity Obesity, especially visceral adiposity, is a major risk factor for NASH in humans.5 Even if they do not have an elevated body mass index, patients with NASH are very likely to be insulin resistant.2 Basic research on fat cell (adipocyte) biology provides some clues about why obesity, insulin resistance, and NASH may be interrelated. Obesity increases adipose tissue mass. It has long been known that adipose tissue is a source of free fatty acids that are delivered to the liver and a depot for triglycerides that are synthesised by hepatocytes and released into the blood. Only recently however has the neuroendocrine role of adipose tissue been appreciated. Fat produces hormones, such as leptin, resistin, and adiponectin, that regulate metabolism in other tissues, as well as fat itself. Fat is also a source of neurotransmitters, such as noradrenaline and angiotensin II. In addition, because adipocytes produce immunomodulatory cytokines, such as …

During the past three decades, prolonged monitoring of oesophageal pH has become increasingly popular among physicians. Most of the studies carried out with this technique focused on oesophageal acid exposure, defined as percentage of time with pH below 4. However, in most cases acid exposure variables are not very useful in the evaluation of patients with symptoms and signs of gastro-oesophageal reflux disease (GORD). An often neglected aspect of 24 hour pH recording is assessment of the temporal relation between reflux and symptoms. Various methods to quantify this relationship were developed. Here, we review these methods and the contribution of symptom association analysis to the evaluation of patients with symptoms suggestive of GORD.

Rather than a unique disorder, Crohn’s disease is regarded as a common denominator for various immune mediated inflammatory diseases of the gastrointestinal tract. These various subforms of Crohn’s disease are characterised by T cell mediated tissue destruction in the gut. In contrast with autoimmune diseases where autoantibodies react with self antigens, inflammation in Crohn’s disease is directed against antigens that are mainly derived from the environment.1 Although it may sound trivial, this adjustment in the understanding of the pathogenetic mechanisms has a vast number of consequences for the search of the disease causing factors and identification of therapeutic targets. The various subforms of Crohn’s disease have not been recognised until recently. Historically, colonic Crohn’s disease was not distinguished from ulcerative colitis. Approximately 30 years ago, the first studies highlighted the diverse natural history of colonic and ileal Crohn’s disease.2 Inherent differences in disease behaviour (obstructing versus perforating) were later recognised by a group of physicians at Mount Sinai Hospital in New York.3 Biological discrimination between various subgroups of Crohn’s patients led to a proposal for a phenotypic classification,4 which was taken up and further developed and evaluated by an international working group, leading to the Vienna classification.5 Accordingly, Crohn’s disease is separated into three categories: age at diagnosis, location, and behaviour (table 1). Several teams have now tested the Vienna classification in their databases6–8 and found that it is feasible and reproducible. The behaviour and age categories earned some criticism which will be discussed later. The location category was found to be very useful and was also stable over time, with only one of seven patients having changes over a 10 year observation period.7 View this table: Table 1 Vienna classification of Crohn’s disease The best classification would be by cause of disease, but unfortunately this is …

The majority of pancreatic diseases are associated with genetic polymorphisms. Recent breakthroughs in understanding the origin and pathways toward pancreatic diseases, and especially acute and chronic pancreatitis, reveal that specific variation in the genomic DNA sequence of individuals strongly influence their susceptibility to pancreatitis, the severity and nature of the inflammatory process, and the likelihood of various complications. Acute pancreatitis is an event, and chronic pancreatitis is a process. They are sequentially linked with chronic pancreatitis reflecting a pathophysiological response to acute pancreatitis events. The triggers, thresholds, mechanism of injury, and immunological responses of individuals with acute and chronic pancreatitis are being organised and defined. In the future, early use of genetic testing will likely play a critical role in early diagnosis and prognosis of pancreatic diseases, and could guide new and effective preventative and therapeutic interventions. The benefits and risk of limited genetic testing have been defined by consensus conference, while the framework for future and more extensive genetic evaluation is still developing.

This present review is timely with the increasing use of the molecular adsorbents recirculating system (MARS) for the management of liver failure, with over 3000 patients having been treated with this device worldwide. In the UK, MARS is being used for the treatment of individual patients both in the National Health Service and also in the private sector. In order to investigate the latest position with respect to bioartificial liver devices, a meeting was held at University College London Hospital in September 2003 and this article is based on the most up to date data presented there. Liver failure, whether of the acute variety with no pre-existing liver disease (acute liver failure (ALF)) or an acute episode of decompensation superimposed on a chronic liver disorder (acute on chronic liver failure (ACLF)), carries a high mortality. In patients with ALF, lack of detoxification, metabolic, and regulatory functions of the liver leads to life threatening complications, including kidney failure, encephalopathy, cerebral oedema, severe hypotension, and susceptibility to infections culminating in multiorgan failure.1 The only established therapy for such patients is liver transplantation (LTx) but currently one third of these patients die while waiting for a transplant and the organ shortage is increasing (fig 1).2 However, liver failure, whether of the acute or acute on chronic variety, is potentially reversible, and considerable work has been carried out over many years to develop effective liver support devices. Figure 1 Annual death rates on the waiting list for liver transplantation between 1997 and 2001 in UNOS categories 1 (acute/fulminant liver failure), 2a (decompensated chronic liver disease urgently requiring transplant), and 2b (decompensated chronic liver disease requiring transplant less urgently). (Source: OPTN/SRTR data, as of 1 August 2002.) The development of these devices has been approached in two very different ways. The biological devices, which aim …

In the last few years, there have developments in many aspects of liver transplantation. This review will focus on those areas where adult clinical practice has developed1–3; the topics selected are those which, it is hoped, will be of interest and relevance to those health care professionals who refer patients to transplant centres and share in their follow up. In such a review, it is not possible to be comprehensive. View this table: Table 1 Transplant activity and indications in Europe (data from the European Liver Transplant Registry, kindly provided by Dr Vincent Karam) Indications for transplantation are evolving: liver failure from hepatitis C virus (HCV) infection and alcohol now represent the commonest indications for liver transplantation both in Europe and North America (table 1). ### Alcoholic liver disease (ALD) ALD remains a controversial indication for liver transplantation and adverse publicity surrounding selected high profile cases can impact on organ donation. None the less, both short and long term outcomes in those transplanted for ALD are similar to those seen in patients transplanted for other causes of cirrhosis, with respect to survival and quality of life. However, this simplistic analysis takes no account of case mix (see box 1). ### Box 1 Alcoholic liver disease

Understanding the genetic basis of "complex disease" has been heralded as one of the major challenges of the post genome era. However what are "complex diseases" and how will understanding the genetics of such diseases advance medical science? There has been a great deal of "hype" about the potential of the human genome mapping project. The three major claims are that this information will: (a) be used in diagnosis; (b) provide useful prognostic indices for disease management (including the development of individualised treatment regimens, based on the findings of both immunogenetic and pharmacogenetic studies); and (c) provide insight into the pathogenesis of these diseases. Of these three objectives the last has the greatest potential and is the least exaggerated claim. In this review I shall highlight major associations, discuss some of the practical issues that arise, and outline how current knowledge of the immunogenetic basis of chronic liver disease is beginning to inform the debate about disease pathogenesis.

The worldwide incidence of GORD and its complications is increasing along with the exponentially increasing problem of obesity. Of particular concern is the relationship between central adiposity and GORD complications, including oesophageal adenocarcinoma. Driven by progressive insight into the epidemiology and pathophysiology of GORD, the earlier belief that increased gastroesophageal reflux mainly results from one dominant mechanism has been replaced by acceptance that GORD is multifactorial. Instigating factors, such as obesity, age, genetics, pregnancy and trauma may all contribute to mechanical impairment of the oesophagogastric junction resulting in pathological reflux and accompanying syndromes. Progression of the disease by exacerbating and perpetuating factors such as obesity, neuromuscular dysfunction and oesophageal fibrosis ultimately lead to development of an overt hiatal hernia. The latter is now accepted as a central player, impacting on most mechanisms underlying gastroesophageal reflux (low sphincter pressure, transient lower oesophageal sphincter relaxation, oesophageal clearance and acid pocket position), explaining its association with more severe disease and mucosal damage. Since the introduction of proton pump inhibitors (PPI), clinical management of GORD has markedly changed, shifting the therapeutic challenge from mucosal healing to reduction of PPI-resistant symptoms. In parallel, it became clear that reflux symptoms may result from weakly acidic or non-acid reflux, insight that has triggered the search for new compounds or minimally invasive procedures to reduce all types of reflux. In summary, our view on GORD has evolved enormously compared to that of the past, and without doubt will impact on how to deal with GORD in the future.

It is increasingly perceived that gut host-microbial interactions are important elements in the pathogenesis of functional gastrointestinal disorders (FGID). The most convincing evidence to date is the finding that functional dyspepsia and irritable bowel syndrome (IBS) may develop in predisposed individuals following a bout of infectious gastroenteritis. There has been a great deal of interest in the potential clinical and therapeutic implications of small intestinal bacterial overgrowth in IBS. However, this theory has generated much debate because the evidence is largely based on breath tests which have not been validated. The introduction of culture-independent molecular techniques provides a major advancement in our understanding of the microbial community in FGID. Results from 16S rRNA-based microbiota profiling approaches demonstrate both quantitative and qualitative changes of mucosal and faecal gut microbiota, particularly in IBS. Investigators are also starting to measure host-microbial interactions in IBS. The current working hypothesis is that abnormal microbiota activate mucosal innate immune responses which increase epithelial permeability, activate nociceptive sensory pathways and dysregulate the enteric nervous system. While we await important insights in this field, the microbiota is already a therapeutic target. Existing controlled trials of dietary manipulation, prebiotics, probiotics, synbiotics and non-absorbable antibiotics are promising, although most are limited by suboptimal design and small sample size. In this article, the authors provide a critical review of current hypotheses regarding the pathogenetic involvement of microbiota in FGID and evaluate the results of microbiota-directed interventions. The authors also provide clinical guidance on modulation of gut microbiota in IBS.

Hepatic steatosis is a common histological feature of chronic hepatitis C. Various factors are associated with hepatic steatosis, including obesity, high alcohol consumption, diabetes type II, and hyperlipidaemia. These factors may contribute to steatosis in patients with chronic hepatitis C. In humans, hepatitis C virus (HCV) genotype 3 is more commonly associated with steatosis. In vitro studies and the transgenic mouse model have suggested that the HCV core protein (genotype 1) can induce lipid accumulation within hepatocytes. However, what is the relevance of steatosis in chronic hepatitis C? It seems that in certain populations, steatosis may be associated with fibrosis progression and this may be genotype specific. The mechanisms underlying this association are unknown; neither is it clear whether this holds true for all patients or only a subgroup. Indeed, after antiviral treatment, virus related steatosis disappears whereas the host associated steatosis remains unaffected. This review describes and discusses the basic and clinical aspects of the relationship between steatosis and progression of fibrosis, and response to treatment in patients with chronic hepatitis C.

A variety of pulmonary and ear, nose, and throat (ENT) symptoms and disorders are considered to be extraoesophageal manifestations of gastro-oesophageal reflux disease (GORD). These extraoesophageal manifestations include asthma, chronic cough, laryngeal disorders, and various ENT symptoms. Recent studies have established that GORD underlies or contributes to chronic sinusitis, chronic otitis media, paroxysmal laryngospasm, excessive throat phlegm, and postnasal drip. Traditionally, management of extraoesophageal GORD manifestations relies on prolonged empiric therapy with high doses of proton pump inhibitors (PPI), followed by pH monitoring under PPI in refractory cases. Recent studies found no benefit of empiric long term high dose PPI therapy. The diagnostic yield of endoscopy in extraoesophageal GORD manifestations seems higher than previously appreciated while pH monitoring under PPI therapy has a low yield. Based on these new findings, a new management algorithm can be proposed that uses short term empiric PPI therapy and GORD investigations off PPI. Well designed controlled studies evaluating the proposed management algorithms and treatment approaches in this area are urgently needed.

Recent estimates for cancer incidence and mortality in Europe continue to rank colorectal cancer as the second most common cause for cancer related death. Every year more than 376 000 patients are newly diagnosed with colorectal cancer and approximately 200 000 people die from the disease.1 Even though these numbers show a slight decrease,2,3 partially due to more effective screening programmes, they still represent a major medical and economic challenge. During the past 10 years, intensive clinical studies helped to establish the value of adjuvant therapy for colorectal cancer. The introduction of new chemotherapeutic agents such as irinotecan and oxaliplatin has led to a significant increase in tumour response and median survival. In advanced colorectal cancer, impressive prolongation of overall survival can be achieved through sequential application of combined systemic chemotherapy. In addition, targeted manipulation of molecular tumour mechanisms with new substances such as monoclonal antibodies against the epidermal growth factor receptor or vascular endothelial growth factor shows promising effects. Apart from the encouraging improvement in treatment results, introduction of new drugs and strategies has multiplied the available treatment options, which are much more complex and sometimes confusing in their variety. This review aims to summarise the current systemic treatment options of colorectal cancer with an additional focus on new classes of targeted compounds recently introduced into clinical management. The only curative strategy in the treatment of colorectal cancer is, and so far remains, complete surgical resection. Despite the fact that approximately 70–80% of patients are eligible for curative surgical resection at the time of diagnosis,4,5 five year overall survival is only 50–60%.6–8 Two out of three patients who undergo curative resection will experience local recurrence or distant metastases. In 85%, relapse is diagnosed within the first 2.5 years after surgery.9 This …

Familial adenomatous polyposis (FAP) is one of two well described forms of hereditary colorectal cancer. The primary cause of death from this syndrome is colorectal cancer which inevitably develops usually by the fifth decade of life. Screening by genetic testing and endoscopy in concert with prophylactic surgery has significantly improved the overall survival of FAP patients. However, less well appreciated by medical providers is the second leading cause of death in FAP, duodenal adenocarcinoma. This review will discuss the clinicopathological features, management, and prevention of duodenal neoplasia in patients with familial adenomatous polyposis. FAP is an autosomal dominant disorder caused by a germline mutation in the adenomatous polyposis coli ( APC ) gene. FAP is characterised by the development of multiple (⩾100) adenomas in the colorectum. Colorectal polyposis develops by age 15 years in 50% and age 35 years in 95% of patients. The lifetime risk of colorectal carcinoma is virtually 100% if patients are not treated by colectomy.1 Patients with FAP can also develop a wide variety of extraintestinal findings. These include cutaneous lesions (lipomas, fibromas, and sebaceous and epidermoid cysts), desmoid tumours, osteomas, occult radio-opaque jaw lesions, dental abnormalities, congenital hypertrophy of the retinal pigment epithelium, and nasopharyngeal angiofibroma. In addition, FAP patients are at increased risk for several malignancies, such as hepatoblastoma, pancreatic, thyroid, biliary-tree, and brain tumours.1 Other gastrointestinal manifestations commonly found in FAP patients are duodenal adenomas, and gastric fundic gland and adenomatous polyps. Of concern, duodenal cancer is the second leading cause of death after colorectal cancer in these individuals. After the colorectum, the duodenum is the second most commonly affected site of polyp development in FAP (fig 1).2,3 Duodenal adenomas can be found in 30–70% of FAP patients2–4 and the lifetime risk of these lesions approaches 100%.4,5 …

Bacterial infections in cirrhotic patients are common. There is a predisposition to intestinal bacterial overgrowth, intestinal dysmotility, and increased intestinal permeability, all leading to an increase in bacterial translocation. Bacterial translocation is the probable mechanism for some of the most common infections in cirrhosis, such as spontaneous bacterial peritonitis, but is also the source of bacterial byproducts such as endotoxin which can cause an increase in portal pressure, impairment of liver function, and worsening of haemostasis. The effects of bacterial infection and bacterial products on portal and systemic haemodynamics in cirrhosis and clinical data on infection, from both retrospective and prospective studies of variceal bleeding and other settings, demonstrate the importance of infection in pathophysiological mechanisms in cirrhosis. This has been followed by recent clinical evidence that antibiotic therapy reverses systemic vasodilation and prevents early variceal rebleeding. In cirrhotic patients there is an increased susceptibility to bacterial infection, related to the degree of liver dysfunction1 leading to several abnormalities of defence mechanisms, all of which increase the susceptibility to infection, including deficiency of bactericidal and opsonic activities, impaired monocyte function, depressed phagocytic activity of the reticuloendothelial system (RES), defective chemotaxis, and low levels of complement in serum. A particularly important role is played by the reduced RES activity, due to the presence of extrahepatic and intrahepatic shunts through sinusoids without Kupffer cells, reduced number of Kupffer cells, and impaired Kupffer cell function. Thus cirrhotics with impaired RES phagocytic activity (as assessed by elimination of 99 m technetium-sulphur colloid) develop acute bacterial infections more frequently than cirrhotics with normal RES phagocytic activity.2 Both community and hospital acquired bacterial infections are frequently diagnosed in cirrhotics, most frequently spontaneous bacterial peritonitis (SBP), urinary tract infections, pneumonia, and skin infections.3 Their incidence rises with worsening liver function.3 Importantly, half of …

In recent years, treatment of severe acute pancreatitis has shifted away from early surgical treatment to aggressive intensive care. While the treatment is conservative in the early phase, surgery might be considered in the later phase of the disease. Surgical debridement is still the “gold standard” for treatment of infected pancreatic and peripancreatic necrosis. Advances in radiological imaging, new developments in interventional radiology, and other minimal access interventions have revolutionised the management of many surgical conditions over the past decades. Several interventional therapy regimens, including endoscopic retrograde cholangiopancreatography (ERCP) and sphincterotomy, fine needle aspiration for bacteriology (FNAB), percutaneous or endoscopic drainage of peripancreatic fluid collections, pseudocysts, and late abscesses, as well as selective angiography and catheter directed embolisation of acute pancreatitis associated bleeding complications have been well established as diagnostic and therapeutic standards in the management of acute pancreatitis. Secondary to recent technical improvements in interventional therapy and minimally invasive surgery, even infected pancreatic necrosis has successfully been treated in selected patients. However, technical feasibility does not obviate sound clinical judgement. We must be cautious in the application of new technologies in the absence of well designed clinical trials. Thus minimally invasive surgery and interventional therapy for infected necrosis should be limited to clinical trials and specific indications in patients who are critically ill and otherwise unfit for conventional surgery. The management of acute pancreatitis has been controversial over the past decades, varying between a conservative medical approach on the one hand and an aggressive surgical approach on the other. There has been great improvement in knowledge of the natural course and pathophysiology of acute pancreatitis over the past decade.1–4 The clinical course of acute pancreatitis varies from a mild transitory form to a severe necrotising disease. Most episodes of acute pancreatitis (80%) are mild and self limiting, …

Sepsis is a systemic inflammatory response to the presence of infection, mediated via the production of many cytokines, including tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-6, and IL-1, which cause changes in the circulation and in the coagulation cascade. There is stagnation of blood flow and poor oxygenation, subclinical coagulopathy with elevated D-dimers, and increased production of superoxide from nitric oxide synthase. All of these changes favour endothelial apoptosis and necrosis as well as increased oxidant stress. Reduced levels of activated protein C, which is normally anti-inflammatory and antiapoptotic, can lead to further tissue injury. Cirrhotic patients are particularly susceptible to bacterial infections because of increased bacterial translocation, possibly related to liver dysfunction and reduced reticuloendothelial function. Sepsis ensues when there is overactivation of pathways involved in the development of the sepsis syndrome, associated with complications such as renal failure, encephalopathy, gastrointestinal bleed, and shock with decreased survival. Thus the treating physician needs to be vigilant in diagnosing and treating bacterial infections in cirrhosis early, in order to prevent the development and downward spiral of the sepsis syndrome. Recent advances in management strategies of infections in cirrhosis have helped to improve the prognosis of these patients. These include the use of prophylactic antibiotics in patients with gastrointestinal bleed to prevent infection and the use of albumin in patients with spontaneous bacterial peritonitis to reduce the incidence of renal impairment. The use of antibiotics has to be judicious, as their indiscriminate use can lead to antibiotic resistance with potentially disastrous consequences.

The function of the oesophagus is relatively straightforward—to transport the swallowed food into the stomach. In order to meet this functional need, the design of the oesophagus is simple; a relatively straight muscular tube that is guarded at it two ends by the upper and lower oesophageal sphincters. Following a voluntary act of a swallow, the two sphincters relax and open and a contraction wave or peristalsis sweeps behind the bolus autonomously. The contraction wave sweeps through the entire length of the oesophagus followed by closure of the two sphincters. Neuromuscular control mechanisms that bring about normal functioning of the two sphincters and oesophageal peristalsis are complex and require fine coordination of the muscles and nerves at the level of the central and peripheral nervous system. Disturbance of sphincters and peristalsis causes symptoms of dysphagia and oesophageal pain. The latter may manifest either as chest pain (pressure-like sensation) or heartburn (retrosternal burning). The nature of dysfunction in oesophageal motor disorders has been the subject of intense investigation for several decades. In this paper, we will review briefly the physiology of oesophageal peristalsis and lower oesophageal sphincter and then attempt to understand what may be wrong in motor disorders of the oesophagus. Novel pharmacological approaches to treat oesophageal motor disorders are also discussed. The anatomy of the oesophagus is unique; it is made up of skeletal muscle in the upper one third, a mixture of skeletal and smooth muscle in the middle one third, and smooth muscle only in the distal one third in humans. The upper oesophageal sphincter is composed of all skeletal muscle and the lower oesophageal sphincter of all smooth muscle. The muscularis propria of the oesophagus, similar to the rest of the gastrointestinal tract, is made of two distinct muscle layers that are arranged in a circular …

Obesity is defined as a body mass index (BMI) of 30 kg/m2 or more, where a person’s BMI is defined as their weight in kg divided by the square of their height in metres. Overweight is defined as a BMI between 25 and 29.9 kg/m2. In 1980, 6% of men and 8% of women in the UK were obese. In 2000, the respective figures had increased to 21% and 21.4%. Approximately 55% of the adult population is overweight or obese.1 Obesity causes or exacerbates a large number of health problems, both independently and in association with other diseases.2 In particular, it is associated with the development of type 2 diabetes mellitus, coronary heart disease, an increased incidence of certain forms of cancer, obstructive sleep apnoea, and osteoarthritis of large and small joints. The Build and Blood Pressure Study has shown that the adverse effects of excess weight tend to be delayed, sometimes for 10 years or longer.3 Life insurance data and epidemiological studies confirm that increasing degrees of overweight and obesity are important predictors of decreased longevity. In the Framingham Heart Study, the risk of death within 26 years increased by 1% for each extra pound (0.45 kg) increase in weight between the ages of 30 years and 42 years, and by 2% between the ages of 50 years and 62 years.4 Despite this evidence, many clinicians continue to consider obesity to be a self-inflicted condition of little medical significance. Increasing body fatness is accompanied by profound changes in physiological function. These changes are, to a certain extent, dependent on the regional distribution of adipose tissue. Generalised obesity results in alterations in total blood volume and cardiac function while the distribution of fat around the thoracic cage and abdomen restricts respiratory excursion and …