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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.

Following the success of immune checkpoint blockers (ICBs) in different cancer types, a large number of studies are currently investigating ICBs in patients with hepatocellular carcinoma (HCC), alone or in combination with other treatments. Both nivolumab and pembrolizumab, as well as the combination of nivolumab plus ipilimumab have been granted accelerated approval by the United States Food and Drug Administration for sorafenib-pretreated patients. While nivolumab and pembrolizumab both failed to meet their primary endpoints in phase III trials, the combination of atezolizumab plus bevacizumab eventually improved overall and progression-free survival compared with sorafenib in a front-line phase III trial, and thus, will become the new standard of care in this setting. Despite this breakthrough, there are patient populations with certain underlying conditions that may not be ideal candidates for this new treatment either due to safety concerns or potential lack of efficacy. In this review, we discuss the safety of ICBs in patients with pre-existing autoimmune disease, IBD or a history of solid organ transplantation. Moreover, we summarise emerging preclinical and clinical data suggesting that ICBs may be less efficacious in patients with underlying non-alcoholic steatohepatitis or HCCs with activated Wnt/β-catenin signalling.

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. …

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

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.

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 …

The discovery that Helicobacter pylori infection is the main cause of most gastroduodenal diseases has been a major breakthrough in gastroenterology. It has dramatically changed the management of these diseases which are now considered as infectious diseases and are treated with antibiotics. Triple therapy, including two antibiotics, amoxicillin and clarithromycin, and a proton pump inhibitor given for a week has been recommended as the treatment of choice at several consensus conferences.1–6 However, this treatment may fail for several reasons, as reported elsewhere.7 In fact, the main reason for failure was found to be H pylori resistance to one of the antibiotics used (that is, clarithromycin). Other treatments have also been proposed, including metronidazole, a drug for which resistance is also a problem although to a lesser extent, as well as tetracycline, fluoroquinolones, and rifamycins for which resistance has become an emerging issue.8,9 Our aim was to review the prevalence of H pylori resistance to these various antibiotics, their clinical importance, and methods of testing, especially in light of the resistance mechanism which allows application of molecular methods. Numerous studies have been performed to determine the prevalence of H pylori resistance to antibiotics. However, many of them have drawbacks, in particular concerning the number and representativeness of the strains tested. Most of the studies were performed in specialised centres, with recruitment of special cases which are not always representative of patients as a whole and, because these studies are monocentric, the number of patients may be low, leading to wide confidence intervals of the prevalence rates obtained. Ideal studies involving patients who are representative of a given region are few. An alternative has been to analyse prevalence data obtained from clinical trials aiming to evaluate new regimens. As prevalence is in essence an evolving phenomenon, only …

Gastro-oesophageal reflux disease (GORD) is a common chronic disorder that has severe impact on quality of life. Moreover, GORD may also cause reflux oesophagitis and sometimes severe complications, such as ulceration, strictures, Barrett’s mucosa, and adenocarcinoma of the oesophagus.1 Surveys revealed that up to 15–20% of adults experience heartburn on a weekly basis and therefore the cost of drugs prescribed for the treatment of GORD represents a heavy economic burden for society.2 Although proton pump inhibitors (PPIs) are extremely effective in healing oesophagitis and improving typical reflux symptoms, they also have shortcomings and limitations.3 Firstly, they do not restore the normal antireflux barrier at the gastro-oesophageal junction and there is frequently a rebound acid hypersecretion after cessation of drug intake which both contribute to the high relapse rate observed after discontinuation of PPI therapy.4 Additionally, even though PPIs are usually extremely well tolerated drugs they can interact with Helicobacter pylori infection and occasionally be responsible for some rare side effects or drug interferences. In contrast with short term administration of H2 antagonists, PPIs are less potent in reducing nocturnal acid secretion.5 Finally, a challenging problem remains the treatment of the approximately 10–20% of patients with proven GORD who have only a partial or no response to high doses of PPIs.6 Laparoscopic fundoplication is often proposed as an alternative and more definitive option, especially in young patients, because it is intended to cure the disorder and the laparoscopic approach makes surgery more acceptable.7,8 Despite the high success rate of surgery in resolving typical reflux symptoms, substantial morbidity and some mortality exist. Complications such as dysphagia, inability to belch, diarrhoea, and flatulence may develop in up to 30% of patients.9 Recent publications tempered the enthusiasm for antireflux surgery. Spechler et al reported …

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 …