Gastroenterology

Aims & Scope/ Editorial Board

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2

Aspirin: The balance between benefits and harms

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
Angel Lanas

Efficacy and gastrointestinal risk of aspirin used for the treatment of pain and cold

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
Denis M. McCarthy
Aims To analyse major sources of evidence-based information on the efficacy and gastrointestinal tolerability of aspirin, used short-term, in over-the-counter (OTC) doses, to relieve acute pain and cold symptoms, including associated feverishness. Methods Evidence was largely collected from published meta-analyses and systematic reviews that focused on randomised, controlled, double-blind clinical trials, in which aspirin was compared to placebo and, in some cases also, to active comparators such as OTC doses of paracetamol or ibuprofen. Results Across a large number of comparisons, aspirin was superior to placebo in treating pain, cold or fever. Efficacy was essentially similar to that of comparators used in equivalent doses. There was no serious GI adverse event attributed to ASA in any study, but mild-to-moderate dyspepsia in small percentages of cases was commonly reported. Conclusion OTC aspirin is safe and effective. Safety concerns should not limit brief use to relieve acute pain, cold or fever.

Role of ASA in the primary and secondary prevention of cardiovascular events

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
Rubén Casado-Arroyo, Fatih Bayrak, Andrea Sarkozy, Gian-Battista Chierchia, Carlo de Asmundis, Pedro Brugada
Cardiovascular disease, which includes coronary heart disease, cerebrovascular disease and peripheral artery disease, is the leading cause of death in developed countries. Evidence from basic research, clinical investigations, observational epidemiologic studies and randomized clinical trials has provided strong support for the benefits of aspirin in decreasing the risk of cardiovascular events in a wide range of pathologies in secondary prevention. Data in primary prevention have far more uncertainties. An overview for the evidence supporting the efficacy of aspirin in primary and secondary prevention of cardiovascular disease is discussed, including the relative and absolute benefit and the risks of side effects. Finally, future developments in the field directed towards individualized treatment strategies and novel antiplatelet agents are examined.

Risk factors for gastrointestinal bleeding associated with low-dose aspirin

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
Vera E. Valkhoff, Miriam C.J.M. Sturkenboom, Ernst J. Kuipers
Low-dose aspirin use is associated with an increased risk for gastrointestinal ulceration and bleeding. At-risk low-dose aspirin users are therefore recommended to take proton-pump inhibitors. However, it is poorly understood which aspirin users are at risk to develop such complications. It is assumed that the known risk factors for NSAID-induced upper gastrointestinal events also apply to low-dose aspirin users. The conventional risk factors for upper gastrointestinal complications associated with aspirin therapy include: (1) a history of peptic ulcer disease or gastrointestinal bleeding, (2) older age, (3) concomitant use of NSAIDs, including coxibs, (4) concomitant use of anticoagulants or other platelet aggregation inhibitors, (5) the presence of severe co-morbidities, and (6) high aspirin dose. In patients with a history of peptic ulcer disease, Helicobacter pylori infection should be assessed and treated. This review focuses on the evidence for upper gastrointestinal risk factors in aspirin users.

Gastrointestinal lesions and complications of low-dose aspirin in the gastrointestinal tract

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
Carlos Sostres, Carla J. Gargallo
Low dose aspirin (ASA) use has been associated with a wide range of adverse side effects in the upper gastrointestinal (GI) tract, which range from troublesome symptoms without mucosal lesions to more serious toxicity, including ulcers, GI bleeding, perforation and even death. Upper GI symptoms in low dose ASA users are common but often careless or misinterpreted and they are not always related to the presence of mucosal injury. Usually, low dose ASA related ulcers are reasonably small and asymptomatic, and probably heal over a period of weeks to a few months. But, the real clinical problem occurs when the ulcer results in a GI complication (mostly bleeding). The estimated average excess risk of symptomatic or complicated ulcer related to low dose ASA is five cases per 1000 ASA users per year. Death is the worst outcome of GI complications in low dose ASA users, but data about this aspect are scarce. Current evidence indicates that low dose ASA can damage the lower GI tract also, but the real size of the problem is still unknown.

Prevention of damage induced by aspirin in the GI tract

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
James M. Scheiman
Low-dose aspirin (325 mg or less) alone and in combination with other antiplatelet agents is widely used for the management of cardiovascular disease. Although the risk with low-dose aspirin alone is less than Nonsteroidal anti-inflammatory drugs (NSAIDs), given widespread use, aspirin related toxicity has become a substantial health care problem due to acute and chronic GI bleeding. A variety of strategies are currently available to minimize the risk of developing upper GI side effects of aspirin. Agents that have efficacy include oral prostaglandin analogues, H2 receptor antagonists and proton pump inhibitors. PPIs appear to be the most effective strategy, with the least side effects and the convenience of once daily dosing. The substitution of another antiplatelet agent such as clopidogrel for aspirin alone does not appear to provide a safer alternative to low-dose aspirin for patients at GI risk. Small bowel injury can occur with aspirin and can be assessed with capsule endoscopy; however, no strategy is known to reduce this potential toxicity in clinical practice.

Interaction of Helicobacter pylori infection and low-dose aspirin in the upper gastrointestinal tract: Implications for clinical practice

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
En-ling Leung Ki, Francis K.L. Chan
Low-dose aspirin has been shown to increase the risk of upper gastrointestinal tract injury. Risk factors in upper gastrointestinal complications in low-dose aspirin users are less well defined than in other NSAID users, and there are enough intrinsic differences in the two agents to discuss them separately. In particularly, the role of Helicobacter pylori and the benefit of its eradication in decreasing the risk of upper gastrointestinal tract injury in low-dose ASA users remains controversial. Various consensus groups have recommended H. pylori testing and eradication in low-dose ASA users with a prior history of peptic ulcer or ulcer bleeding. The basis of this recommendation is derived from a limited, albeit expanding evidence on the role of H. pylori in upper gastrointestinal tract injury in low-dose ASA users and on the effectiveness of H. pylori eradication in reducing the risk of complications such as rebleeding in high-risk patients.

Balancing the risk and benefits of low-dose aspirin in clinical practice

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
Rubén Casado-Arroyo, Carla Gargallo, Ángel Lanas Arbeloa
Antiplatelet agents are widely used in primary and secondary prevention of cardiovascular events. The scientific evidence has provided strong support for the benefits of aspirin in decreasing the risk of cardiovascular events in a wide range of pathologies. The relatively rare occurrence of major bleeding complications should not be underestimated, mainly due to its high morbi-mortality. The assessment of both gastrointestinal risk and cardiovascular benefits of low-dose aspirin for any individual patient may be difficult in clinical practice. In this review, we summarize the evidence supporting the efficacy of aspirin and the risks of side effects due to hemorrhagic complications. This article proposes a unifying framework for application to help the clinician in the decision making process of individuals who have different risk of cardiovascular and bleeding events with different examples. Finally, new developments in the field directed towards individualized risk assessment strategies are described.

Aspirin and the prevention of colorectal cancer

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
Ángel Ferrández, Elena Piazuelo, Antoni Castells
A large body of evidence from basic science, epidemiologic observations and population-based studies demonstrates that aspirin, as well as other non-steroidal anti-inflammatory drugs, has a chemopreventive effect on several cancer types and, more specifically, in CRC. This protective effect includes prevention of adenoma recurrence and reduction of CRC incidence and mortality. Although the protective effect appears to depend on the dose and the drug, the most important factor is the duration of exposure. However, the lowest effective dose, treatment duration, specific target populations, and effects on survival have not been defined yet. More important, data on the risk–benefit profile for cancer prevention are insufficient and, accordingly, no definitive recommendation can be made at present. In this article, besides reviewing current knowledge of the mechanisms involved in aspirin-based CRC chemoprevention, we will be focused on randomized controlled studies assessing its efficacy in high-, moderate- and average-risk populations.

Aspirin and NSAIDs; benefits and harms for the gut

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 2
Prarthana Thiagarajan, Janusz A. Jankowski
Despite modern advances in cancer research, screening and treatment options, gastrointestinal tumours remain a leading cause of death worldwide. Both oesophageal and colorectal malignancies carry high rates of morbidity and mortality, presenting a challenge to clinicians in search of effective management strategies. In recent years, the increasing burden of disease has led to a paradigm shift in our approach from treatment to prevention. Among several agents postulated as having a chemopreventive effect on the gastrointestinal tract, aspirin has been most widely studied and has gained universal acknowledgement. There is an expanding evidence base for aspirin as a key mediator in the prevention of dysplastic change in Barrett’s oesophagus and colorectal adenomas. Its cardioprotective effects also impact positively on the patient population in question, many of whom have ischaemic vascular disease. The major side effects of aspirin have been well-characterised and may cause significant morbidity and mortality in their own right. Complications such as peptic ulceration, upper gastrointestinal bleeding and haemorrhagic stroke pose serious threats to the routine administration of aspirin and hence a balance between the risks and benefits must be struck if chemoprevention is to be effective on a large scale. In this review, we address the current evidence base for aspirin use in gastrointestinal oncology, as well as several key questions surrounding its safety, cost effectiveness and optimal dose.

Aims & Scope/ Editorial Board

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1

Liver failure and liver transplantation

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1
Herold Metselaar

Recent developments in acute liver failure

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1
William M. Lee
Acute liver failure is a remarkably rare syndrome, the result of rapid hepatocyte injury occurring over days or a few weeks, and encompassing multiple etiologies, but all with a remarkably similar clinical picture. The clinical features of coagulopathy and encephalopathy characterize this severe and often fatal condition. To date, transplantation has been the only reliable form of rescue for many patients. Recent developments have included a clearer understanding of the different contributing etiologies, how to build a diagnosis and prognosis based on initial laboratory findings, a more aggressive approach to intensive care management and more detailed understanding of the role of transplantation in this setting. This review will provide an overview of standard practices and new research initiatives and findings for this interesting but vexing orphan disease. Particular attention will be paid to practical matters for clinicians to consider in approaching the ALF patient. Few controlled clinical trials have been possible because of the condition’s rarity. Critical care of these rare patients is key to their survival and decisions must be made decisively, sometimes with inadequate information. Experience is helpful but experienced clinician managers are even rarer than the disease: few hepatologists or intensivists have in-depth experience with ALF patients.

Artificial liver support devices as treatment option for liver failure

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1
Frederik Nevens, Wim Laleman
Non-biological artificial liver support (ALS) devices aim to remove albumin-bound and water-soluble toxins arising as a result of liver failure. They do not directly improve the liver synthetic capacity. The currently most used devices combine haemodialysis with albumin dialysis (MARS) or plasma separation and filtration (Prometheus). These devices have been used as a treatment for different types of liver failure: acute liver failure, acute-on-chronic liver failure and primary non- or poor-function after liver transplantation. Overall these devices are found to be safe. The following beneficial effects have been documented: improvement of jaundice, amelioration of haemodynamic instability, reduction of portal hypertension, lowering of intracranial pressure and improvement of hepatic encephalopathy. However, recently multicentre controlled trials failed to show a beneficial effect on transplant-free survival. Therefore the use of these devices at present seems only justified as a bridge to liver transplantation.

Liver transplantation for acute liver failure

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1
John O’Grady
Liver transplantation is now an integral part of the management of acute liver failure. The challenge for clinicians is to select the appropriate candidates with a combination of need and high likelihood of benefiting from the transplant. This is achieved through a combination of prognostic modelling and ongoing clinical evaluation. Although the outcomes after liver transplantation are good the survival rates do not quite match those achieved after elective transplantation.

Stem cells in liver failure

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1
Francesco P. Russo, Maurizio Parola
Orthotopic liver transplantation (OLT) represents the only reliable therapeutic approach for acute liver failure (ALF), liver failure associated to end-stage chronic liver diseases (CLD) and non-metastatic liver cancer. The clinical impact of liver failure is relevant because of the still high ALF mortality and the increasing worldwide prevalence of cirrhosis that, in turn, is the main predisposing cause for hepatocellular carcinoma (HCC). Moreover, in the next decade because an increased number of patients reaching end-stage disease and requiring OLT may face a shortage of donor livers. This clinical scenario led several laboratories to explore the feasibility and efficiency of alternative approaches, involving cellular therapy, to counteract liver failure. The present chapter overviews results and concepts emerged from recent experimental and clinical studies in which adult or embryonic hepatocytes, hepatic stem/progenitor cells, induced pluripotent stem (iPS) cells as well as extrahepatic stem cells have been used as putative transplantable cell sources.

Morbidity and mortality related to non-hepatic surgery in patients with liver cirrhosis; A systematic review

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1
B. de Goede, P.J. Klitsie, J.F. Lange, H.J. Metselaar, G. Kazemier
Background The aim of this study is to review systematically morbidity and mortality after non-hepatic surgery in patients with liver cirrhosis. Methods Comprehensive searches were conducted in PubMed, Embase and the Cochrane Library for articles using the words: liver failure, hepatic insufficiency, liver cirrhosis, cirrhosis, cirrhotic, surgical procedures, operative complications, operative mortality, postoperative complications, surgical complication, surgical risk, hernia. Results Forty-six articles were selected from 5247 included after the initial search. Level of evidence provided in the articles varied greatly. Non-hepatic surgery of patients with cirrhosis resulted in increased postoperative morbidity and mortality compared to similar surgery for non-cirrhotic patients. Cholecystectomy and umbilical and inguinal hernia correction were associated with the lowest increased morbidity and mortality while pancreatic surgery, cardiovascular, and trauma surgery correlated with the highest. The preoperative model for end stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) scores appeared to be predictive of postoperative risks. Portal hypertension and surgery in the emergency setting were associated with extra increased mortality and morbidity rates. Conclusion This systematic review of the literature showed that in patients with liver cirrhosis who undergo non-hepatic surgery, postoperative morbidity and mortality rates varied greatly depending on severity of the cirrhosis and the surgical procedure. However, the majority of procedures can be safely performed in patients with low MELD scores or CTP A cirrhosis without portal hypertension.

Risk factors for infection after liver transplantation

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1
Bart van Hoek, Bert-Jan de Rooij, Hein W. Verspaget
Infection is a common cause of morbidity and mortality after liver transplantation. Risk factors relate to transplantation factors, donor and recipient factors. Transplant factors include ischaemia-reperfusion damage, amount of intra-operative blood transfusion, level and type of immunosuppression, rejection, and complications, prolonged intensive care stay with dialysis or ventilation, type of biliary drainage, repeat operations, re-transplantation, antibiotics, antiviral regimen, and environment. Donor risk factors include infection, prolonged intensive care stay, quality of the donor liver (e.g. steatosis), and viral status. For the recipient the most important are MELD score >30, malnutrition, renal failure, acute liver failure, presence of infection or colonisation, and immune status for viruses like cytomegalovirus. In recent years it has become clear that genetic polymorphisms in innate immunity, especially the lectin pathway of complement activation and in Toll-like receptors importantly contribute to the infection risk after liver transplantation. Therefore, the risk for infections after liver transplantation is a multifactorial problem and all factors need attention to reduce this risk.

Tolerance in liver transplantation

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1
G. Alex Bishop, Patrick D. Bertolino, David G. Bowen, Geoffrey W. McCaughan
Operational tolerance (OT) in liver transplant patients occurs much more frequently than OT of other transplanted organs; however the rate of OT varies considerably with the centre and patient population. Rates of OT range from 15% of the total liver transplant (LTX) patient population down to less than 5%. This review examines the reports of liver OT and compares the factors that could contribute to this variation. Multiple factors were examined, including the time from transplantation when weaning of immunosuppression (IS) was commenced, the rapidity of weaning, the contribution of maintenance and induction IS and the patient population transplanted. The approaches that might be used to increase the likelihood of OT are discussed and the approaches to monitoring OT in LTX patients are reviewed.

Optimization of the use of Calcineurin inhibitors in liver transplantation

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2012
Source:Best Practice & Research Clinical Gastroenterology, Volume 26, Issue 1
E.L.D. de Mare-Bredemeijer, H.J. Metselaar
Calcineurin inhibitors (CNIs), such as cyclosporin A and tacrolimus, are the cornerstone of maintenance immunosuppressive regimens in liver transplantation. CNIs prevent rejection by inhibition of calcineurin, via which lymphocyte proliferation and interleukin (IL)-2 production is prevented. Tacrolimus is now the first-choice immunosuppressant after liver transplantation, since it is associated with fewer episodes of rejection than cyclosporin A. In this review we will discuss interindividual differences, which influence tacrolimus metabolism. Because of these factors and the narrow therapeutic index of tacrolimus, monitoring of drug trough levels is necessary. Furthermore, we will discuss studies concerning conversion from the tacrolimus twice daily to tacrolimus once daily formulation in stable LT patients. Due to adverse effects of CNIs, such as chronic renal failure, hypertension, de novo malignancy and new-onset diabetes mellitus, CNI minimization strategies have been developed, which will be discussed too.

Aims & Scope/ Editorial Board

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6

Autoimmune liver disease

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Michael P. Manns

The benefit of animal models for autoimmune hepatitis

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Elmar Jaeckel, Matthias Hardtke-Wolenski, Katja Fischer
Autoimmune hepatitis (AIH) is a chronic liver disease which is normally recognized during late stage of the disease. Due to limited knowledge about the onset and course of disease and need for chronic immunosuppression with significant side-effects there is a requirement for a good preclinical animal model, mirroring main characteristics of AIH. In addition to the exclusion of other liver diseases, AIH is characterized by elevated serum transaminases, specific autoantibodies and elevated gammaglobulins as well as a specific liver histopathology. A good preclinical model should mirror most of these criteria. In the last decades several models have been published using different approaches to break hepatic tolerance and induce liver damage. The induction of a chronic hepatitis similar to the human disease remained a difficult challenge. Nevertheless, these models helped to get more information about the aspects of AIH induction and liver immunology.

Pathogenesis of autoimmune hepatitis

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Rodrigo Liberal, Maria Serena Longhi, Giorgina Mieli-Vergani, Diego Vergani
The mechanisms underlying the pathogenesis of autoimmune hepatitis are not fully understood, though there is growing evidence that genetic predisposition, molecular mimicry and/or impairment of regulatory T-cells are involved in the initiation and perpetuation of the autoimmune liver attack. The histological picture of interface hepatitis, characterized by a dense portal mononuclear cell infiltrate, was the first to suggest an autoaggressive cellular immune attack in the pathogenesis of this condition. Liver damage is likely to be orchestrated by CD4^pos T-cells recognizing an autoantigenic liver peptide. For autoimmunity to arise, the peptide must be presented by antigen-presenting cells to naïve CD4^pos T-helper (Th0) cells. Once activated, Th0-cells can differentiate into Th1-, Th2-, or Th17-cells, initiating a cascade of immune reactions that are determined by the cytokines they produce. Autoantigen recognition and the above effector mechanisms are opposed by regulatory T-cells, a cell subset numerically and functionally impaired in autoimmune hepatitis.

Diagnostic criteria for autoimmune hepatitis

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Ansgar W. Lohse, Christiane Wiegard
The clinical spectrum of autoimmune hepatitis is very wide. In addition, autoimmune hepatitis can present in any age group. Diagnosis is usually made by a combination of clinical, laboratory and histological features. Diagnostic scores can help both in the daily diagnostic work-up of patients, and in allowing comparability of clinical scientific studies. However, all diagnostic scores have limitations in individual cases, which are discussed in this review.

Therapy of autoimmune hepatitis

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Christian P. Strassburg, Michael P. Manns
Autoimmune hepatitis was the first chronic liver disease with a favourable response to drug therapy and a dismal prognosis when left untreated. Since its original description in 1950 and first treatment studies the basic therapeutic strategy of inducing remission with steroids and azathioprine has not been modified in principle. A timely diagnosis before cirrhosis develops, the avoidance of immunosuppressant side effect, non-responders to standard induction therapy, and adherence to therapy are the greatest challenges. Alternative immunosuppressive drugs have been tested in small series and include transplant immunosuppressants. A recent large multicenter prospective treatment trial suggests that budesonide may offer an alternative in non-cirrhotic AIH patients capable of minimizing unwanted steroid effects. The ultimate treatment approach upon drug treatment failure is liver transplantation. Only four precent of transplant candidates are transplanted for AIH but the risk for graft loss because of recurrence has to be considered and recurrent AIH treated after transplantation.

Autoimmune hepatitis in special patient populations

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Albert J. Czaja
Autoimmune hepatitis has diverse clinical phenotypes that challenge conventional diagnostic criteria and treatment strategies. The goals of this review are to characterize these special populations and provide guidelines for their management. Patients with acute or acute severe (fulminant) presentations may have centrilobular zone 3 hepatic necrosis, but they can respond to conventional corticosteroid therapy. Asymptomatic mild disease warrants corticosteroid treatment because spontaneous resolution is uncertain and 10-year survival is less than expected. Male gender or the absence of conventional autoantibodies does not preclude the diagnosis or need for treatment, and patients with cholestatic changes warrant cholangiography and possible combination therapy with ursodeoxycholic acid. Different ethnic groups commonly have advanced hepatic fibrosis, rapidly progressive disease, or cholestatic features, and elderly patients typically respond well to corticosteroid therapy. Pregnancy is usually well-tolerated by mother and foetus but requires protection against postpartum exacerbation. Special populations must be recognized and treated with tailored regimens.

Diagnosis of primary biliary cirrhosis

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Gideon M. Hirschfield
Primary biliary cirrhosis is the archetypal autoimmune liver disease, with the disease label describing a chronic granulomatous lymphocytic small bile duct cholangitis, which now most commonly presents asymptomatically and at an early pre-cirrhotic stage. Disease is more common than thought, with 1 in 1000 women over the age of 40 affected. Characteristic immunologic features of the disease assist clinicians in ready non-invasive diagnosis of patients, even if asymptomatic with only anicteric/cholestatic liver biochemical profiles. Over 90% of patients are anti-mitochondrial antibody positive, and for those negative, a significant proportion have highly specific anti-nuclear antibody profiles. Liver biopsy remains useful in certain settings where clarity is needed to confirm diagnosis, exclude alternative disease, and assess the relative contribution of PBC to other co-existent liver injury, and seeks to demonstrate in particular the classic bile duct lesions, as well as the degree of interface activity.

Genetics in primary sclerosing cholangitis

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Trine Folseraas, Espen Melum, Andre Franke, Tom H. Karlsen
Primary sclerosing cholangitis (PSC) is a chronic and severe inflammatory disease leading to fibrotic bile duct destruction and in most cases liver cirrhosis. As in other complex genetic diseases, the sibling risk of PSC is more than ten times that of the general population. Recent genome-wide association studies have consistently identified several genetic susceptibility loci. The overlap of these loci with susceptibility loci in other chronic inflammatory diseases is considerable, and offers intriguing opportunities for transfer of pathogenetic knowledge and potentially treatment options. In the present article we summarise the present knowledge on PSC genetics with a particular emphasis on the major histocompatibility complex (MHC). We discuss the clinical relevance of the risk loci and elaborate on the insight that may be obtained from associated inflammatory conditions and existing murine knock-out models.

Pathogenesis of primary sclerosing cholangitis

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Marion J. Pollheimer, Emina Halilbasic, Peter Fickert, Michael Trauner
Primary sclerosing cholangitis (PSC) represents a chronic cholestatic liver disease with fibroobliterative sclerosis of intra- and/or extrahepatic bile ducts, eventually leading to biliary cirrhosis. The association with human leukocyte antigen (HLA) and non-HLA haplotypes and the presence of autoantibodies in sera of PSC patients support a crucial role for immune-mediated mechanisms in the initiation and progression of PSC. The strong clinical association between PSC and inflammatory bowel diseases led to intriguing pathogenetic concepts, in which the inflamed gut with translocation of bacterial products and homing of gut-primed memory T lymphocytes via aberrantly expressed adhesion molecules plays a fundamental role. Genetically or chemically modified bile composition was shown to induce sclerosing cholangitis and liver fibrosis in a number of animal models ("toxic bile concept"). The potential role of vascular injury with ischemia of bile duct epithelium cells in the development of sclerosing cholangitis is supported by animal models of endothelial cell injury showing close morphological similarities with human PSC.

Medical and endoscopic therapy of primary sclerosing cholangitis

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Tobias J. Weismüller, Tim O. Lankisch
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease mainly affecting young male patients. PSC is characterised by chronic inflammation and fibrotic strictures of the intra- and extrahepatic biliary system, which eventually lead to cholestasis and biliary cirrhosis. However, the clinical course remains very variable. As the aetiology remains unknown, the development of a causative treatment is challenging and today no specific medical therapy is available. Ursodeoxycholic acid has been widely used for the treatment of PSC, but improved only biochemistry and/or symptoms in low- or medium dosages and is probably harmful in higher dosages. Other drugs such as immunosuppressive, antifibrotic or antibiotic agents have not been proven to be effective in large clinical trials. The endoscopic therapy encompasses balloon-dilatation and/or stenting of strictures, relieves clinical symptoms and improves a cholestatic enzyme profile. However, endoscopic therapy is limited to patients in advanced stages of PSC with biliary obstruction.

Primary sclerosing cholangitis and malignancy

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Kirsten Muri Boberg, Guro E. Lind
Cholangiocarcinoma complicates primary sclerosing cholangitis (PSC) in approximately 10% of cases, but no risk factor that can identify this subgroup of patients is known. No imaging modalities or serum tumour markers that can diagnose early cholangiocarcinoma are available, but endoscopic retrograde cholangiography with brush cytology is recommended when clinically indicated. Liver transplantation with neoadjuvant therapy is carried out in specialist centres in cases of limited stage cancer. Transplantation should also be considered in patients with biliary dysplasia without evident tumour. Gallbladder polyps in PSC are often malignant, and liberal indication for cholecystectomy is recommended. Hepatocellular carcinoma develops in 2%–4% of patients with end-stage liver disease. Patients with inflammatory bowel disease are at risk of colorectal neoplasia. Surveillance colonoscopies are recommended, also after liver transplantation. Epigenetic markers represent one among several classes of potential biomarkers for early diagnosis of malignancies in PSC that should be further explored.

Liver transplantation in autoimmune liver diseases

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Jawad A. Ilyas, Christine A. O’Mahony, John M. Vierling
Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.

Autoimmune liver diseases in children – What is different from adulthood?

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issue 6
Giorgina Mieli-Vergani, Diego Vergani
Autoimmune liver disorders in childhood include autoimmune hepatitis, autoimmune sclerosing cholangitis and de novo autoimmune hepatitis after liver transplant. These inflammatory liver disorders are characterised histologically by interface hepatitis, biochemically by elevated transaminase levels and serologically by autoantibodies and increased levels of immunoglobulin G. Autoimmune hepatitis is particularly aggressive in children and progresses rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. Autoimmune sclerosing cholangitis responds to the same treatment used for autoimmune hepatitis in regards to parenchymal inflammation, but bile duct disease progresses in about 50% of cases, leading to a worse prognosis and higher transplantation requirement; it has a high recurrence rate post-liver transplant. De novo autoimmune hepatitis after liver transplant affects children transplanted for non-autoimmune conditions and responds well to the same treatment schedule used for autoimmune hepatitis, but not to the schedule used for acute rejection.

Aims & Scope/ Editorial Board

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5

Chemoprevention in gastroenterology

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Mark Hull, Richard F.A. Logan

Chemoprevention – History and general principles

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Xiangwei Wu, Sherri Patterson, Ernest Hawk
Our current understanding of tumourigenesis suggests that cancer develops as a series of cumulative genetic and epigenetic derangements across time culminating in a clone of cells differing from its population of origin in terms of cellular identity, growth control, and its contextual relationship to its environment. Our increasing knowledge of the timing, sequence, frequency, and specific implications of these changes provides unique opportunities for earlier identification of aberrations and preventive interventions. Here we discuss the fundamentals of cancer prevention including the targets, cohorts, agents, endpoints, mechanistic biomarkers, designs, and strategies employed in preventive drug development. There have been many notable successes in this field such as the identification and development of tamoxifen and raloxifene for breast cancer risk reduction, instillational BCG and valrubicin for treatment of preinvasive bladder cancer, and a variety of topical and systemic agents that effectively treat preinvasive neoplastic lesions of the skin. A variety of null or negative developmental endeavours have occurred as well, including trials of beta-carotene for lung cancer prevention, nutritional modifications for colorectal adenoma prevention, and most recently, selenium and alpha-tocopherol for prostate cancer prevention. A third category of prevention trials can be summarized as investigationally successful, but not achieving regulatory success. The development of finasteride and dutasteride for prostate cancer prevention, and celecoxib for colorectal neoplasia prevention fall into this category. In less than four decades, cancer chemoprevention has transformed from a concept to an achievable reality.

Aspirin for the prevention of colorectal cancer

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
X. Garcia-Albeniz, A.T. Chan
Over 600,000 people worldwide die of colorectal cancer (CRC) annually, highlighting the importance of developing effective prevention strategies. Among proposed chemopreventive interventions, aspirin is perhaps the agent with the strongest body of evidence that supports wider spread use to significantly reduce the population burden of CRC. Several epidemiological studies, four randomized controlled trials (RCTs) of colorectal polyp recurrence, and RCTs in patients with hereditary colorectal cancer syndromes, have shown that aspirin reduces incidence of colorectal neoplasia. Recently, in a pooled analysis of five cardiovascular-prevention RCTs linked to cancer outcomes, daily aspirin use at any dose reduced the risk of CRC by 24% and of CRC-associated mortality by 35% after a delay of 8–10 years. In an expanded meta-analysis of 8 cardiovascular-prevention RCTs, daily aspirin use at any dose was associated with a 21% lower risk of all cancer death, including CRC, with benefit only apparent after 5 years. In this review, we will summarize human studies of aspirin in CRC prevention as well as discuss the safety profile and mechanism of aspirin in CRC prevention.

Pharmacology and cellular/molecular mechanisms of action of aspirin and Non-aspirin NSAIDs in colorectal cancer

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Karsten Schrör
Colorectal cancer (CRC) and colorectal adenomas have in common a dysfunctional adenomatous polyposis coli suppressor gene ( APC ). This allows for activation of the oncogenic Wnt/β-catenin pathway, resulting in cytosolic accumulation of β-catenin, its translocation to the nucleus and action as a cofactor for stimulation of gene transcription. Pharmacological approaches of CRC-chemoprevention are focused to prevention of this β-catenin-mediated oncogenic signalling. Among upregulated genes in tumour tissue is COX-2 which synthesises large amounts of PGE 2 . PGE 2 inhibits apoptosis, acts proinflammatory and immunosuppressive and stimulates tumour angiogenesis and proliferation. In addition, COX-2 causes oxidation (activation) of cocarcinogens. Aspirin and non-aspirin NSAIDs inhibit COX-2, subsequent PGE 2 formation and action by transcriptional and non-transcriptional mechanisms. These also include inhibition of generation of sphingosine-1-phosphate, an amplifier of these reactions and stimulation of NSAID-induced gene (NAG-1) which acts as an inhibitor. Aspirin additionally acetylates COX-2, resulting in generation of ‘aspirin-triggered’ lipoxins (ATL), a new class of anti-inflammatory/antitumour compounds. COX-1 inhibition might also contribute to antitumour effects of aspirin, for example at low-dose aspirin. Experimental evidence suggests additional COX independent actions of aspirin and non-aspirin NSAIDs on oncogenic signalling. This includes modifications of transcription factors (NFκB), induction of apoptosis and DNA stabilization. In comparison to non-aspirin NSAIDs (sulindac, indomethacin) and coxibs (celecoxib), aspirin has the advantage of concomitant antiplatelet effects while NSAIDs rather have a thrombogenic potential. Though these actions of aspirin have to be balanced against an increased bleeding tendency, aspirin is currently the most attractive candidate for clinical CRC chemoprevention. Open questions, such as dose, (minimum) duration of treatment and the individual risk/benefit ratio are subjects of prospective randomized trials which are underway.

Calcium, vitamin D and colorectal cancer chemoprevention

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Xuehong Zhang, Edward Giovannucci
Identifying modifiable risk factors, particularly dietary factors, which have been hypothesized to play an important role in colorectal carcinogenesis, remains crucial in developing primary prevention strategies. Calcium and vitamin D have been shown consistently in experimental studies to have anti-cancerous properties including but not limited to stimulating differentiation, reducing proliferation, and inducing apoptosis. The majority of epidemiologic studies consistently support an approximately 20–30% reduction in risk of colorectal cancer and adenomas comparing high to low intake categories of both calcium and vitamin D, although independent effects may not be adequately separated. Less consistency exists on the dose–response relation for both nutrients. Intake of calcium of not more than 1000 mg/d and intake of vitamin D of 1000–2000 IU/d, achieving a level of at least 30 ng/mL, appear important for colorectal cancer prevention. More study is warranted to determine the optimal intake levels and duration to reduce the colorectal cancer risk.

DFMO: Targeted risk reduction therapy for colorectal neoplasia

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Christina M. Laukaitis, Eugene W. Gerner
Strategies to decrease intracellular polyamine levels have been studied for their efficacy in reducing colorectal cancer (CRC) risk. A successful strategy combined agents that decreased polyamine synthesis by inhibiting ornithine decarboxylase with difluoromethylornithine (DFMO), and increased cellular export of polyamines by activating the spermidine/spermine acetyl transferase with non-steroidal anti-inflammatory drugs (NSAIDs). A Phase III trial treating resected adenoma patients with DFMO plus sulindac demonstrated marked reduction of metachronous adenomas, advanced adenomas and multiple adenomas compared to placebo. This combination regimen was well-tolerated, however there was a non-significant excess of cardiovascular events in the treatment arm compared to placebo as well as modest ototoxicity. Targeting this therapy to people at elevated risk of CRC, and employing clinical and genetic predictors, should improve patient benefit and reduce the risk of side effects to improve the acceptability of this strategy.

Selenium and other antioxidants for chemoprevention of gastrointestinal cancers

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Vijayvel Jayaprakash, James R. Marshall
Antioxidants such as selenium, vitamin E and C and carotenoids have been hypothesized as chemopreventive agents for several cancers. In the current review, we evaluate the results of epidemiological and interventional studies and summarize current knowledge of the prevention potential of the antioxidants, specific to gastrointestinal cancers. While early studies based on animal models and cell lines showed promise for antioxidants as chemopreventive agents for several gastrointestinal cancers, results from epidemiological studies and randomized trials do not support this promise. One large randomized trial, conducted in a region with widespread nutritional deficiency, showed that antioxidant use may confer protection against gastrointestinal cancers. However, this result has not been replicated in other epidemiological studies or the 10 other randomized trials conducted in developed Western countries. Overall, currently there is no evidence that antioxidants are protective against gastrointestinal cancers in populations whose members are replete in antioxidant intake.

Curcumin: The potential for efficacy in gastrointestinal diseases

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Glen R.B. Irving, Ankur Karmokar, David P. Berry, Karen Brown, William P. Steward
Curcumin is a naturally occurring phytochemical and an extract of Turmeric. Extensive in vitro and in vivo data have paved the way for curcumin to become the subject of clinical trials. Curcumin modulates key signalling pathways important in cellular processes. Numerous mechanisms of action have been elucidated. The potential for clinical efficacy is apparent from benign and malignant disease models. Curcumin has potent anti-inflammatory and anti-neoplastic properties used alone and in combination with standard therapies. Early-phase trials have ascertained pharmacological properties and consistently demonstrate it to be safe and well tolerated. However, bioavailability is limited and efficacious doses have not yet been determined. Evidence of efficacy has been derived from animal models or small clinical trials. There is only finite data supporting the use of curcumin in phase III trials with specific diseases (e.g. ulcerative colitis). However, for the vast majority of conditions additional early-phase studies are required to justify larger trials determining efficacy.

Aminosalicylates

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Christoph Campregher, Christoph Gasche
Aminosalicylates are the most common drugs for the primary treatment of inflammatory bowel disease. Various pro-drugs and formulations were developed in order to improve pharmacological profiles, optimize bioavailability and to gain highest efficacy in the treatment of ulcerative colitis (UC) and Crohn’s disease. In vitro studies have greatly contributed to the understanding of the molecular actions in vivo and clinical studies have proven aminosalicylates to be effective and safe. This review summarizes the current knowledge on the molecular, pharmacological and clinical properties of aminosalicylates with respect to chemoprevention for UC-associated colorectal cancer.

Chemoprevention of colorectal cancer: A role for ursodeoxycholic acid, folate and hormone replacement treatment?

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Riccardo Solimando, Franco Bazzoli, Luigi Ricciardiello
Chemoprevention of colorectal cancer has been an intense focus of research for many years. Among the possible candidate agents, ursodeoxycholic acid, folate, and hormone replacement therapy have been recently investigated with conflicting data. Experimental evidence shows that UDCA, folate and HRT target critical molecular events important for colon carcinogenesis. In animal models of sporadic, familial and inflammatory-associated cancers, they have shown to reduce colonic neoplasms. Observational studies have shown compelling evidence of possible protective effects of all three agents. However, randomised-controlled studies have yielded disappointing results, raising the issues of possible harm rather than protective effect for some of them. In this review experimental and clinical data on UDCA, folate and HRT as potential chemopreventive agents are discussed.

Chemoprevention in Barrett’s oesophagus

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Victoria Gordon, Janusz Jankowski
Barrett’s oesophagus normally affects the distal oesophagus when metaplastic columnar lined epithelium replaces stratified squamous epithelium which predisposes to cancer development. This develops as a consequence of chronic gastroesophageal reflux (GORD). Those with Barrett’s have a 40 fold increased risk of oesophageal adenocarcinoma [1] . There are is still a lack of understanding of the natural history of the cell of origin. This does hamper research into this area. We accept that there is a limitation in testing of the pathogenesis of Barrett’s oesophagus due to a lack of a universally accepted animal model. The major questions surrounding Barrett’s oesophagus include validity of surveillance strategies, the optimal treatment and more importantly an agent that can prevent progression to cancer without unacceptable side effects. The main chemopreventative agents that show promise are aspirin and proton pump inhibitors (PPIs). There are other agents such as green tea, berries and antioxidants and diet that have been suggested; we discuss the evidence available for these strategies. We hope for continued improvement in the clinical trial infrastructure to facilitate testing of new pharmacological and endoscopic interventions for Barrett’s oesophagus.

Chemoprevention for gastric cancer

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Alexander C. Ford
Gastric cancer remains the fourth commonest cancer, and the second commonest cause of cancer death, globally. Chemopreventive strategies to reduce the incidence of gastric cancer are required, particularly as the number of deaths per year is likely to rise for the foreseeable future. There is some evidence that population screening and treatment for Helicobacter pylori in high-risk populations may reduce incidence of gastric cancer. Trials studying the effect of anti-oxidants and selenium are conflicting. A recent meta-analysis demonstrated that aspirin use led to a reduced risk of gastric cancer after 10–20 years of follow-up. There is little convincing evidence that statins have any effect on risk of gastric cancer. More trials on chemoprevention for gastric cancer are therefore urgently required.

Chemoprevention of colorectal cancer in inflammatory bowel disease

Thu, 31 May 2012 00:34:55 +0000

Publication year: 2011
Source:Best Practice & Research Clinical Gastroenterology, Volume 25, Issues 4–5
Venkataraman Subramanian, Richard F. Logan
The risk of developing colorectal cancer is increased in patients with inflammatory bowel disease (IBD). Surveillance colonoscopy has not been shown to prolong survival and rates of interval cancer are reported to be high. Various chemopreventive agents have been clearly shown to reduce the risk of colorectal adenoma and cancer in the general population and the problems associated with colonoscopic surveillance have led to increasing interest in utilising chemopreventive strategies to reduce the risk of colorectal cancer in patients with inflammatory bowel disease as well. Continuing colonic inflammation has been shown to be important in the development of colorectal cancer and therefore anti-inflammatory agents have been considered potential chemopreventive agents. As present no agents have been shown to have indisputable chemopreventive activity in IBD but 5-ASAs and thiopurine analogues by reducing inflammation are likely to have some chemopreventive activity and will often be indicated for disease control. More studies are needed using agents such as aspirin and calcium which have been shown to be chemopreventive in sporadic colorectal neoplasia.

Conference abstract: Lubiprostone effective for opioid-induced bowel dysfunction?

Tue, 29 May 2012 00:00:00 +0000

Source: BioSpace.com
Area: News
Research presented at the Digestive Disease Week has shown that lubiprostone improves treatment response in opioid-induced bowel dysfunction (OBD) patients with chronic, non-cancer pain. The following results from the phase III randomised trial were reported: . The proportion of patients with a first spontaneous bowel movement (SBM), at 4, 8, 12, 24 and 48 hours post-dose was found to be statistically significant over placebo (p=0.002, p=0.017, p=0.021, p=0.016 and p=0.022, respectively) with the median time to first SBM being 24.25 hours for those on lubiprostone versus 38.5 hours on placebo (p=0.019). . Greater proportions of lubiprostone patients experienced improvement in their OBD symptoms over the 12 week period than did placebo subjects, including: straining associated with SBMs (p=0.002), stool consistency of SBMs (p<0.001), constipation severity (p=0.007), abdominal bloating (p=0.208, not statistically significant) and abdominal ...

Hormone replacement therapy is associated with gastro-oesophageal reflux disease: a retrospective cohort study

Tue, 29 May 2012 00:00:00 +0000

Background: Oestrogen and progestogen have the potential to influence gastro-intestinal motility; both arekey components of hormone replacement therapy (HRT). Results of observational studies inwomen taking HRT rely on self-reporting of gastro-oesophageal symptoms and the aetiologyof gastro-oesophageal reflux disease (GORD) remains unclear. This study investigated theassociation between HRT and GORD in menopausal women using validated general practicerecords. Methods: 51,182 menopausal women were identified using the UK General Practice Research Databasebetween 1995-2004. Of these, 8,831 were matched with and without hormone use. Oddsratios (ORs) were calculated for GORD and proton-pump inhibitor (PPI) use in hormone andnon-hormone users, adjusting for age, co-morbidities, and co-pharmacy. Results: In unadjusted analysis, all forms of hormone use (oestrogen-only, tibolone, combined HRTand progestogen) were statistically significantly associated with GORD. In adjusted models,this association remained statistically significant for oestrogen-only treatment (OR 1.49;1.18-1.89). Unadjusted analysis showed a statistically significant association between PPIuse and oestrogen-only and combined HRT treatment. When adjusted for covariates,oestrogen-only treatment was significant (OR 1.34; 95% CI 1.03-1.74). Findings from theadjusted model demonstrated the greater use of PPI by progestogen users (OR 1.50; 1.01-2.22). Conclusions: This first large cohort study of the association between GORD and HRT found a statisticallysignificant association between oestrogen-only hormone and GORD and PPI use. This shouldbe further investigated using prospective follow-up to validate the strength of association anddescribe its clinical significance.

Risk of inflammatory bowel disease following a diagnosis of irritable bowel syndrome

Mon, 28 May 2012 00:00:00 +0000

Background: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) symptoms oftenoverlap. In some IBS cases there are subtle inflammatory changes similar to the immunemediatedpathophysiology of IBD, and the risk of both increases after infectiousgastroenteritis (IGE). Methods: To evaluate the effect of IBS and IGE on IBD risk utilizing US Department of Defensemedical encounter data, active duty personnel with IBS were matched to subjects withoutIBS. Medical encounter history was analyzed to assess for incident IBD. IGE was identifiedfrom documented medical encounters and by self-report. Relative risks were calculated usingPoisson regression models. Results: We identified 9,341 incident IBS cases and18,678 matched non-IBS subjects and found an8.6-fold higher incidence (p < 0.0001) of IBD among those with IBS (238.1 per 100,000person-years) compared to our referent population (27.8 per 100,000 person-years). In asubset (n = 2,205) of well-defined IBS cases, IBD risk was 15 times that of subjects withoutIBS. The median time between IBS and IBD diagnoses was 2.1 years. IGE also increasedIBD risk approximately 2-fold (p < 0.05) after controlling for IBS. Conclusions: These data reflect a complex interaction between illness presentation and diagnosis of IBSand IBD and suggest intercurrent IGE may increase IBD risk in IBS patients. Additionalstudies are needed to determine whether IBS lies on the causal pathway for IBD or whetherthe two are on a pathophysiological spectrum of the same clinical illness. These data suggestconsideration of risk reduction interventions for IGE among IBS patients at high disease risk.

The balance between two isoforms of LEF-1 regulates colon carcinoma growth

Mon, 28 May 2012 00:00:00 +0000

Background: Colon cancer is one of the most aggressive human malignancies, with a very poor prognosis.Although it has been suggested that different isoforms of the lymphoid enhancer factor (LEF-1) have opposing biological activities, the biological outcome of aberrant LEF-1 activation incolon cancer is still unclear. The aim of this study was to evaluate the effect of the differentLEF-1 phenotypes on the growth of colon carcinoma cell lines. A deeper understanding ofthese processes might improve the targeted therapies for colon cancer by regulating theexpression of LEF-1. Methods: The role of different isoforms of LEF-1 on the growth of human colon carcinoma cell lines(SW480 and HT-29) was studied using various in vitro and in vivo assays. In vivoproliferation, migration, adhesion and apoptosis of the cells stably transfected of differentisoforms of LEF-1 were monitored by MTT assay, carboxyfluorescein diacetate-succinimidyl ester staining, annexin V staining, ECM adhesion assay and transwell assay,respectively. In nude mice, the formation of neovasculature in the tumors formed by ourconstructed cells was measured by immunohistochemistry. All the data were analyzed using at test, and data were treated as significant when p < 0.05. Results: Overexpression of truncated LEF-1 (LEF-1-DeltaL) in the colon cell lines, SW480 and HT29,inhibited their growth significantly in vitro and in vivo, but the full-length LEF-1 (LEF-1-FL)promoted the proliferation of HT29. Inactivation of Wnt signaling by LEF-1-DeltaL reduced theexpression of CXCR4 in colon cell lines, which may lead to a decrease in activities such asmigration, adhesion and survival. In nude mice, the formation of neovasculature as well as anincrease in tumor volume were inhibited by the short isoform of LEF-1. LEF-1-FL, however,caused an increase in all these parameters compared with controls. Conclusions: These findings suggest that LEF-1 might play an important role in colon carcinogenesis byacting as a regulator. Enhanced expression of LEF-1-FL, which occurs frequently in coloncancer, may be a new target for clinical therapy.

Cyclic Vomiting Syndrome (CVS): is there a difference based on onset of symptoms - pediatric versus adult?

Mon, 28 May 2012 00:00:00 +0000

Background: Cyclic Vomiting Syndrome (CVS) is a well-recognized functional gastrointestinal disorder in children but its presentation is poorly understood in adults. Genetic differences in pediatric-onset (presentation before age 18) and adult-onset CVS have been reported recently but their clinical features and possible differences in response to therapy have not been well studied. Methods: This was a retrospective review of 101 CVS patients seen at the Medical College of Wisconsin between 2006 and 2008. Rome III criteria were utilized to make the diagnosis of CVS. Results: Our study population comprised of 29(29%) pediatric-onset and 72 (71%) adult-onset CVS patients. Pediatric-onset CVS patients were more likely to be female (86% vs. 57%, p = 0.005) and had a higher prevalence of CVS plus (CVS + neurocognitive disorders) as compared to adult-onset CVS patients (14% vs. 3%, p = 0.05). There was a longer delay in diagnosis (10 +/- 7 years) in the pediatric-onset group when compared to (5 +/- 7 years) adult-onset CVS group (p = 0.001). Chronic opiate use was less frequent in the pediatric-onset group compared to adult-onset patients (0% vs. 23%, p = 0.004). Aside from these differences, the two groups were similar with regards to their clinical features and the time of onset of symptoms did not predict response to standard treatment. The majority of patients (86%) responded to treatment with tricyclic antidepressants, anticonvulsants (topiramate), coenzyme Q-10, and L-carnitine. Non-response to therapy was associated with coalescence of symptoms, chronic opiate use and more severe disease as characterized by longer episodes, greater number of emergency department visits in the year prior to presentation, presence of disability and non-compliance on univariate analysis. On multivariate analysis, only compliance to therapy was associated with a response. (88% vs. 38%, Odds Ratio, OR 9.6; 95% Confidence Interval [CI], 1.18-77.05). Conclusion: Despite reported genetic differences, the clinical features and response to standard therapy in pediatric- and adult-onset CVS were mostly similar. Most patients (86%) responded to therapy and compliance was the only factor associated with a response.

The relationship between urban environment and the inflammatory bowel diseases: a systematic review and meta-analysis

Thu, 24 May 2012 00:00:00 +0000

Background: The objective of this study was to conduct a systematic review with meta-analysis of studiesassessing the association between living in an urban environment and the development of theCrohn's disease (CD) or ulcerative colitis (UC). Methods: A systematic literature search of MEDLINE (1950-Oct. 2009) and EMBASE (1980-Oct.2009) was conducted to identify studies investigating the relationship between urbanenvironment and IBD. Cohort and case-control studies were analyzed using incidence rateratio (IRR) or odds ratio (OR) with 95 % confidence intervals (CIs), respectively. Stratifiedand sensitivity analyses were performed to explore heterogeneity between studies and assesseffects of study quality. Results: The search strategy retrieved 6940 unique citations and 40 studies were selected forinclusion. Of these, 25 investigated the relationship between urban environment and UC and30 investigated this relationship with CD. Included in our analysis were 7 case-control UCstudies, 9 case-control CD studies, 18 cohort UC studies and 21 cohort CD studies. Based ona random effects model, the pooled IRRs for urban compared to rural environment for UCand CD studies were 1.17 (1.03, 1.32) and 1.42 (1.26, 1.60), respectively. These associationspersisted across multiple stratified and sensitivity analyses exploring clinical and studyquality factors. Heterogeneity was observed in the cohort studies for both UC and CD,whereas statistically significant heterogeneity was not observed for the case-control studies. Conclusions: A positive association between urban environment and both CD and UC was found.Heterogeneity may be explained by differences in study design and quality factors.

Interval colon cancer in a Lynch syndrome patient under annual colonoscopic surveillance: a case for advanced imaging techniques?

Thu, 24 May 2012 00:00:00 +0000

Background: Lynch syndrome confers increased risk for various malignancies, including colorectal cancer.Colonoscopic surveillance programs have led to reduced incidence of colorectal cancer andreduced mortality from colorectal cancer. Colonoscopy every 1-2 years beginning at age 20-25, or 10 years earlier than the first diagnosis of colorectal cancer in a family, with annualcolonoscopy after age 40, is the recommended management for mutation carriers. Screeningprograms have reduced colon cancer mortality, but interval cancers may occur.Case presentationWe describe a 48-year-old woman with Lynch syndrome who was found to have an adenomawith invasive colorectal cancer within one year after a normal colonoscopy. Conclusion: Our patient illustrates two current concepts about Lynch syndrome: 1) adenomas are thecancer precursor and 2) such adenomas may be "aggressive," in the sense that the adenomaprogresses more readily and more rapidly to carcinoma in this setting compared to usualcolorectal adenomas. Our patient's resected tumor invaded only into submucosa and alllymph nodes were negative; in that sense, she represents a success for annual colonoscopicsurveillance. Still, this case does raise the question of whether advanced imaging techniquesare advisable for surveillance colonoscopy in these high-risk patients.

MHRA Drug Safety Update: Domperidone: small risk of serious ventricular arrhythmia and sudden cardiac death

Wed, 23 May 2012 00:00:00 +0000

Source: MHRA Drug Safety Update
Area: Evidence > Medication Safety
The Medicines Healthcare and products Regulatory Agency (MHRA) has issued a warning about the risks of developing serious ventricular arrhythmia or sudden cardiac death with domperidone. The warning is based on epidemiological studies which have reported on the relation between domperidone and either sudden cardiac death alone, or on serious ventricular arrhythmia and sudden cardiac death as a combined endpoint. The warning, featured in the May 2012 edition of the "Drug Safety Update", makes the following recommendations for healthcare professionals (taken directly from source): . Domperidone should be used at the lowest effective dose . Non-prescription domperidone products are not recommended for use in patients with underlying cardiac disease, without medical supervision . Prescribers should exercise caution for patients who have: existing prolongation of cardiac conduction intervals (particularly QTc); significant electrolyte ...

Highlights from this issue

Thu, 17 May 2012 18:15:30 +0000

Luminal gastroenterology What is the incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's?

The most widely cited annual incidence of oesophageal adenocarcinoma (OAC) in Barrett's oesophagus (BO) is 0.5% but this estimate did not account for the presence of baseline dysplasia. In this issue of Gut, Desai et al report an updated meta-analysis of observational studies and provide an accurate estimate of the risk of OAC in patients with BO who were free of dysplasia at baseline. The 57 included studies comprised 11 434 patients and 58 547 patient-years of follow-up. The pooled annual incidence of OAC was 0.33% (95% CI 0.28% to 0.38%). During surveillance, patients with non-dysplastic BO may be at least 10 times more likely to die from an unrelated cause than to develop OAC. Among 16 studies that provided information on patients with short-segment BO, the annual incidence of OAC was only 0.19%. The incidence of OAC in non-dysplastic...

A major advance in ex vivo intestinal organ culture

Thu, 17 May 2012 18:15:30 +0000

Important advances are being made in our understanding of the composition and function of the large amount of commensal bacteria that the human intestine has long been known to contain. Metagenomic sequencing has shown that the microbiome of healthy individuals is different from that of patients with inflammatory bowel disease (IBD) and that the microbial composition of patients with Crohn's disease is distinct from ulcerative colitis. 1 Whether such microbial alterations in patients with IBD are the cause or consequence of the disease remains to be determined.

Attempts to modulate intestinal disease with bacteria started with the treatment of acute gastrointestinal infections by Alfred Nissle with a strain of Escherichia coli in 1917. Bacterial treatments have been attempted for a large variety of indications, mainly with different Lactococcal and Bifidobacterial species. In general, the better designed trials have shown modest if any clinical effects for most diseases in...

The multiple effects of tumour necrosis factor inhibitors on immune cells: new insights on inhibition of activation and cycling

Thu, 17 May 2012 18:15:30 +0000

Together with immunosuppressants, anti-tumour necrosis factor (TNF) monoclonal antibodies represent a major class of treatment for the inflammatory bowel diseases (IBD) therapeutic arsenal. Almost 20 years after the first report of infliximab in Crohn's disease, 1 we do not know exactly how these TNF inhibitors control the inflammatory response, and their mechanism of action is still a matter of investigation.

Werner et al 2 show that infliximab and adalimumab not only induce T-cell apoptosis but also inhibit T-cell function, activation and cycling (see page 1016 ). They demonstrate that while T-cell apoptosis is mediated by TNF signalling, the inhibition of T-cell activation and cycling is not dependent on TNF signalling but on Notch-1 signalling. They thereby provide new insights on the mechanisms of action of TNF inhibitors, and more specifically on T cells.

Anti-TNF monoclonal antibodies bind and neutralise TNF, and downregulate the inflammatory response, through suppression...

Role of Helicobacter pylori CagL in modulating gastrin expression

Thu, 17 May 2012 18:15:30 +0000

Helicobacter pylori is a Gram-negative bacterium that is highly adapted for persistent colonisation of the human stomach. Although most H pylori-infected people remain asymptomatic, the presence of this organism is a risk factor for gastric adenocarcinoma, peptic ulcer disease and gastric lymphoma. There is a high level of genetic heterogeneity among H pylori strains and the risk of gastric disease is determined, in part, by characteristics of the H pylori strain(s) with which a person is infected. 1 One of the most extensively studied genetic features of disease-associated H pylori strains is the cag pathogenicity island (PAI). This 40 kb region of chromosomal DNA, comprising about 27 genes, may be present, incomplete or absent in H pylori strains.

CagA, the first cag PAI-encoded protein to be studied in detail, is a highly antigenic protein that is translocated into gastric epithelial cells. Within gastric epithelial cells, CagA undergoes phosphorylation by...

The window hypothesis: haemodynamic and non-haemodynamic effects of {beta}-blockers improve survival of patients with cirrhosis during a window in the disease

Thu, 17 May 2012 18:15:30 +0000

Background

Cirrhosis is one of the most frequent and severe chronic diseases worldwide. In the initial stages it has few or no symptoms, but advanced stages of cirrhosis are characterised by reduced liver function, complications due to portal hypertension and neuroendocrine abnormalities with increased activity of the sympathetic nervous system (SNS) and renin-aldosterone axis. The prognosis is severe, with an increasing frequency of complications including variceal bleeding, ascites and spontaneous infections with subsequent development of hepatic encephalopathy and hepatorenal syndrome. More than one-third of patients diagnosed with cirrhosis develop oesophageal varices within 3 years after the diagnosis is made. Varices develop and later bleed when the portal pressure is increased and the hepatic vein pressure gradient (HVPG) is more than 10–12 mm Hg. Life-threatening spontaneous bacterial infections are another common complication of advanced cirrhosis. The infections are mainly triggered by gut bacterial translocation, which is the migration of microorganisms from the intestinal...

The incidence of oesophageal adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-analysis

Thu, 17 May 2012 18:15:30 +0000

Introduction

The risk of oesophageal adenocarcinoma (OAC) in non-dysplastic Barrett's oesophagus (BO) may have been overestimated. The objective was to estimate the incidence of OAC in patients with BO without dysplasia.

Methods

The authors searched MEDLINE and EMBASE from 1966 to 2011 and performed a bibliographic review of previous publications, excluding abstracts, non-peer-reviewed publications and those not published in English, for prospective or retrospective studies of the incidence of OAC in patients with BO. They excluded patients with any degree of dysplasia at baseline and those without documented intestinal metaplasia. Studies were independently reviewed by two individuals. 57 of 3450 studies were included. The authors extracted information on number of patients with BO, length of follow-up, incident cases of OAC, mean age of patients, country of origin, whether prospective or retrospective, mean length of BO segments and mortality from causes other than OAC. Study quality was assessed by the Ottawa Newcastle criteria.

Results

The 57 included studies comprised 11 434 patients and 58 547 patient-years of follow-up. The pooled annual incidence of OAC was 0.33% (95% CI 0.28% to 0.38%). Among 16 studies that provided appropriate information on mortality, there were 56 incident cases of OAC but 684 deaths from apparently unrelated causes. Among 16 studies that provided information on patients with short-segment BO, the annual incidence of OAC was only 0.19%.

Conclusions

The incidence of OAC in non-dysplastic BO is around 1 per 300 patients per year. The incidence of OAC in short-segment BO is under 1 per 500 patients per year.

Epigenetic inactivation of BCL6B, a novel functional tumour suppressor for gastric cancer, is associated with poor survival

Thu, 17 May 2012 18:15:30 +0000

Objective

Using genome-wide promoter methylation assay, B cell CLL/lymphoma 6 member B (BCL6B) was found to be preferentially methylated in cancer. A study was undertaken to examine the epigenetic regulation, biological function and clinical significance of BCL6B in gastric cancer (GC).

Methods

BCL6B promoter methylation was evaluated by combined bisulfite restriction analysis and sequencing. The biological functions of BCL6B were determined by cell viability, colony formation, flow cytometry and in vivo tumorigenicity assays. The molecular targets of BCL6B were identified by cDNA expression array.

Results

BCL6B was silenced or downregulated in all nine GC cell lines and readily expressed in normal gastric tissues. Loss of BCL6B expression was regulated by promoter hypermethylation. Re-expression of BCL6B in GC cell lines inhibited colony formation, suppressed cell viability, induced apoptosis and restrained the tumorigenecity in nude mice. These effects were associated with upregulation of the pro-apoptosis genes tumour necrosis factor receptor superfamily member 1A, caspase-8, caspase-9, caspase-3 and caspase-7 and nuclear enzyme poly (ADP-ribose) polymerase, downregulation of the pro-proliferation genes S100 calcium binding protein A4 and vascular endothelial growth factor A, and induction of the tumour suppressor genes ataxia telangiectasia mutated homologue and p53. BCL6B hypermethylation was detected in 49.0% (102/208) and 66.3% (67/101) of two independent cohorts of patients with GC, respectively. BCL6B methylation was an independent factor for the survival of patients with GC (p=0.001 for cohort I, p=0.02 for cohort II).

Conclusions

BCL6B plays a pivotal role as a potential tumour suppressor in GC. Detection of methylated BCL6B may serve as an independent biomarker for the prognosis of GC.

Helicobacter pylori CagL dependent induction of gastrin expression via a novel {alpha}v{beta}5-integrin-integrin linked kinase signalling complex

Thu, 17 May 2012 18:15:30 +0000

Objective

One of the most important hormones in the human stomach is the peptide gastrin. It is mainly required for the regulation of gastric pH but is also involved in growth and differentiation of gastric epithelial cells. In Helicobacter pylori infected patients, gastrin secretion can be upregulated by the pathogen, resulting in hypergastrinaemia. H pylori induced hypergastrinaemia is described as being a major risk factor for the development of gastric adenocarcinoma.

Design

In this study, the upstream receptor complex and bacterial factors involved in H pylori induced gastrin gene expression were investigated, utilising gastric epithelial cells which were stably transfected with a human gastrin promoter luciferase reporter construct.

Results

Integrin linked kinase (ILK) and integrin β5, but not integrin β1, played an important role in gastrin promoter activation. Interestingly, a novel CagL/integrin β5/ILK signalling complex was characterised as being important for H pylori induced gastrin expression. On interaction of H pylori with αvβ₅-integrin and ILK, the epidermal growth factor receptor (EGFR) ->Raf->mitogen activated protein kinase kinase (MEK)->extracellular signal regulated kinase (Erk) downstream signalling cascade was identified which plays a central role in H pylori gastrin induction.

Conclusion

The newly discovered recognition receptor complex could be a useful target in treating precancerous conditions triggered by H pylori induced hypergastrinaemia.

Probiotic and postbiotic activity in health and disease: comparison on a novel polarised ex-vivo organ culture model

Thu, 17 May 2012 18:15:30 +0000

Background and aims

Probiotics and their metabolic products, here called postbiotics, have been proposed as food supplements for a healthier intestinal homeostasis, but also as therapeutic aids in inflammatory bowel disease (IBD) with, however, very little clinical benefit. This may be due to the lack of reliable preclinical models for testing the efficacy of different strains.

Methods

The activity of three probiotic strains of Lactobacillus (or a postbiotic) was analysed and compared with a pathogenic strain of Salmonella on a novel organ culture system of human healthy and IBD intestinal mucosa developed in our laboratory. The system maintains an apical to basolateral polarity during stimulation due to the presence of a glued cave cylinder. The cylinder is detached at the end of the experiment and the tissue is processed for histology and immunohistochemistry. Cytokines released from the basolateral side are analysed.

Results

The model system provides several physiological characteristics typical of a mucosal microenvironment including the presence of an organised mucus layer and an apical to basolateral polarity. Polarised administration of bacteria is critical to control the ensuing immune response as it mimics the physiological entrance of bacteria. The authors show that probiotics are not always beneficial for the healthy host and can also be detrimental in inflamed IBD. This study shows that a potent postbiotic can protect against the inflammatory properties of invasive Salmonella on healthy tissue and also downregulate ongoing inflammatory processes in IBD tissue.

Conclusions

Probiotics can have inflammatory activities in both healthy and IBD tissue. Valid preclinical data on proper model systems should therefore be obtained before specific probiotic strains enter the clinics, especially if administered during acute inflammatory responses. Postbiotics may be a safe alternative for the treatment of patients with IBD in the acute inflammatory phase.

TNF{alpha} inhibitors restrict T cell activation and cycling via Notch-1 signalling in inflammatory bowel disease

Thu, 17 May 2012 18:15:30 +0000

Background

Tumour necrosis factor α (TNFα) inhibitors such as adalimumab and infliximab are frequently prescribed for inflammatory bowel disease (IBD). Despite the clinical success of TNFα inhibitors, their physiological mode of action is not fully understood. The aim of this study was to investigate the mode of action of anti-TNFα agents in IBD.

Methods

It was hypothesised that Notch mediates anti-TNFα action in T cells. A study was carried out to identify Notch-1 as a link by which anti-TNFα antibodies mediate their inhibitory functions.

Results

TNFα inhibitors induced T cell apoptosis, inhibited activation, reduced cytokine secretion and restricted cell cycling. TNFα blockade at several levels showed that TNFα is responsible for inducing apoptosis by anti-TNFα but not for cell cycle restriction. By linking Notch and TNFα it was shown that (1) Notch-1 mucosal expression differs in inflamed and non-inflamed mucosa and increases in response to anti-TNFα treatment; (2) Notch-1 function is regulated by TNFα inhibitors; (3) Notch-1 binds to TNFα; and (4) Notch-1 inhibition prevents anti-TNFα-induced T cell cycle arrest but not apoptosis.

Conclusions

TNFα inhibitors potently inhibit T cell function. By demonstrating for the first time that Notch-1 mediates the inhibitory effects of adalimumab and infliximab on T cell cycling, this study reveals a new mode of action and also an underlying signalling pathway by which biological agents act in IBD.

NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2

Thu, 17 May 2012 18:15:30 +0000

Objective

The NOX2 NADPH oxidase complex produces reactive oxygen species and plays a critical role in the killing of microbes by phagocytes. Genetic mutations in genes encoding components of the complex result in both X-linked and autosomal recessive forms of chronic granulomatous disease (CGD). Patients with CGD often develop intestinal inflammation that is histologically similar to Crohn's colitis, suggesting a common aetiology for both diseases. The aim of this study is to determine if polymorphisms in NOX2 NADPH oxidase complex genes that do not cause CGD are associated with the development of inflammatory bowel disease (IBD).

Methods

Direct sequencing and candidate gene approaches were used to identify susceptibility loci in NADPH oxidase complex genes. Functional studies were carried out on identified variants. Novel findings were replicated in independent cohorts.

Results

Sequence analysis identified a novel missense variant in the neutrophil cytosolic factor 2 (NCF2) gene that is associated with very early onset IBD (VEO-IBD) and subsequently found in 4% of patients with VEO-IBD compared with 0.2% of controls (p=1.3x10^–5, OR 23.8 (95% CI 3.9 to 142.5); Fisher exact test). This variant reduced binding of the NCF2 gene product p67^phox to RAC2. This study found a novel genetic association of RAC2 with Crohn's disease (CD) and replicated the previously reported association of NCF4 with ileal CD.

Conclusion

These studies suggest that the rare novel p67^phox variant results in partial inhibition of oxidase function and are associated with CD in a subgroup of patients with VEO-IBD; and suggest that components of the NADPH oxidase complex are associated with CD.

Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up

Thu, 17 May 2012 18:15:30 +0000

Background

Three large randomised trials have shown that screening for colorectal cancer (CRC) using the faecal occult blood test (FOBt) can reduce the mortality from this disease. The largest of these trials, conducted in Nottingham since 1981, randomised 152 850 individuals between the ages of 45 and 74 years to an intervention arm receiving biennial Haemoccult (FOB) test kit or to a control arm. In 2006, the National Bowel Cancer Screening Programme was launched in England using the FOBt, with the expectation that it will reduce CRC mortality.

Aims

To compare the CRC mortality and incidence in the intervention arm with the control arm after long-term follow-up.

Methods

The 152 850 randomised individuals were followed up through local health records and central flagging (Office for National Statistics).

Results

At a median follow-up of 19.5 years there was a 13% reduction in CRC mortality (95% CI 3% to 22%) in the intervention arm despite an uptake at first invitation of approximately 57%. The CRC mortality reduction in those accepting the first screening test, adjusted for the rate of non-compliers, was 18%. There was no significant difference in mortality from causes other than CRC between the intervention and control arms. Despite removing 615 adenomas >10 mm in size from the intervention arm, there was no significant difference in CRC incidence between the two arms.

Conclusions

Although the reduction in CRC mortality was sustained, further follow-up of the screened population has not shown a significant reduction in the CRC incidence. Moreover, despite the removal of many large adenomas there was no reduction in the incidence of invasive cancer which was independent of sex and site of the tumour.

Colonoscopy quality measures: experience from the NHS Bowel Cancer Screening Programme

Thu, 17 May 2012 18:15:30 +0000

Objectives

Colonoscopy is central to colorectal cancer (CRC) screening. Success of CRC screening is dependent on colonoscopy quality. The NHS Bowel Cancer Screening Programme (BCSP) offers biennial faecal occult blood (FOB) testing to 60–74 year olds and colonoscopy to those with positive FOB tests. All colonoscopists in the screening programme are required to meet predetermined standards before starting screening and are subject to ongoing quality assurance. In this study, the authors examine the quality of colonoscopy in the NHS BCSP and describe new and established measures to assess and maintain quality.

Design

The NHS BCSP database collects detailed data on all screening colonoscopies. Prospectively collected data from the first 3 years of the programme (August 2006 to August 2009) were analysed. Colonoscopy quality indicators (adenoma detection rate (ADR), polyp detection rate, colonoscopy withdrawal time, caecal intubation rate, rectal retroversion rate, polyp retrieval rate, mean sedation doses, patient comfort scores, bowel preparation quality and adverse event incidence) were calculated along with measures of total adenoma detection.

Results

2 269 983 individuals returned FOB tests leading to 36 460 colonoscopies. Mean unadjusted caecal intubation rate was 95.2%, and mean withdrawal time for normal procedures was 9.2 min. The mean ADR per colonoscopist was 46.5%. The mean number of adenomas per procedure (MAP) was 0.91; the mean number of adenomas per positive procedure (MAP+) was 1.94. Perforation occurred after 0.09% of procedures. There were no procedure-related deaths.

Conclusions

The NHS BCSP provides high-quality colonoscopy, as demonstrated by high caecal intubation rate, ADR and comfort scores, and low adverse event rates. Quality is achieved by ensuring BCSP colonoscopists meet a high standard before starting screening and through ongoing quality assurance. Measuring total adenoma detection (MAP and MAP+) as adjuncts to ADR may further enhance quality assurance.

Prospective derivation and validation of early dynamic model for predicting outcome in patients with acute liver failure

Thu, 17 May 2012 18:15:30 +0000

Objective

It is difficult to predict the outcome in patients with acute liver failure (ALF) using existing prognostic models. This study investigated whether early changes in the levels of dynamic variables can predict outcome better than models based on static baseline variables.

Design

380 patients with ALF (derivation cohort n=244, validation cohort n=136) participated in a prospective observational study. The derivation cohort was used to identify predictors of mortality. The ALF early dynamic (ALFED) model was constructed based on whether the levels of predictive variables remained persistently high or increased over 3 days above the discriminatory cut-off values identified in this study. The model had four variables: arterial ammonia, serum bilirubin, international normalised ratio and hepatic encephalopathy >grade II. The model was validated in a cohort of 136 patients with ALF.

Results

The ALFED model demonstrated excellent discrimination with an area under the receiver operator characteristic curve of 0.91 in the derivation cohort and of 0.92 in the validation cohort. The model was well calibrated in both cohorts and showed a similar increase in mortality with increasing risk scores from 0 to 6. The performance of the ALFED model was superior to the King's College Hospital criteria and the Model for End stage Liver Disease score, even when their 3-day serial values were taken into consideration. An ALFED score of ≥4 had a high positive predictive value (85%) and negative predictive value (87%) in the validation cohort.

Conclusion

The ALFED model accurately predicted outcome in patients with ALF, which may be useful in clinical decision-making.

Genetic evolution of pancreatic cancer: lessons learnt from the pancreatic cancer genome sequencing project

Thu, 17 May 2012 18:15:30 +0000

Pancreatic cancer is a disease caused by the accumulation of genetic alterations in specific genes. Elucidation of the human genome sequence, in conjunction with technical advances in the ability to perform whole exome sequencing, have provided new insight into the mutational spectra characteristic of this lethal tumour type. Most recently, exomic sequencing has been used to clarify the clonal evolution of pancreatic cancer as well as provide time estimates of pancreatic carcinogenesis, indicating that a long window of opportunity may exist for early detection of this disease while in the curative stage. Moving forward, these mutational analyses indicate potential targets for personalised diagnostic and therapeutic intervention as well as the optimal timing for intervention based on the natural history of pancreatic carcinogenesis and progression.

Linking risk conferring mutations in NCF4 to functional consequences in Crohn's disease

Thu, 17 May 2012 18:15:30 +0000

We read with interest the paper from Muise et al in which they describe a rare variant in the NCF2 gene, which demonstrates a diminished RAC2 binding capacity. 1 The NCF2 encoded protein p67^phox is one of the components of the NADPH oxidase complex which drives the production of reactive oxygen species (ROS) during the bactericidal response of innate immune cells. Output of disturbed granulocytic ROS as a result of impaired functioning of this enzyme complex has been shown in a number of diseases, including myelodysplasia (MDS) and chronic granulomatous disease. 2 3 As Muise and colleagues point out, these diseases have been linked to development of a colitis resembling that seen in Crohn's disease (CD), suggesting a potential role for impaired ROS production in CD pathology.

Genome-wide association studies (GWAS) are a promising tool to identify genetic variants of genes linked to an increased...

The Authors' reply

Thu, 17 May 2012 18:15:30 +0000

We read with interest the letter by Somasundaram et al 1 in response to our paper ‘NADPH oxidase complex and IBD candidate gene studies: identification of a rare variant in NCF2 that results in reduced binding to RAC2’ that further demonstrates the importance of the NADPH oxidase complex genes in the pathogenesis of Crohn's disease. Their letter provides interesting confirmatory data that complement our findings, which already clearly demonstrate the role of the NADPH oxidase complex in inflammatory bowel disease (IBD). 2 However, there are a number of important issues that require further clarification.

Somasundaram et al suggest that our study did not show the association between reactive oxygen species (ROS) production and IBD. 1 Our study clearly shows that ROS production is important in the pathogenesis of IBD. 2 Our index patient with the novel p67^phox R38Q variant had low ROS production in...

Prothrombin index slope is an early prognostic marker in patients with severe acute liver diseases

Thu, 17 May 2012 18:15:30 +0000

In a recent study published in Gut, Mura et al 1 followed up patients with cirrhosis until their death or liver transplantation (LT), and their results suggest that serum levels of von Willebrand factor can discriminate patients with a high probability of clinical worsening requiring LT. 1 Identifying biomarkers with a high prognostic value is a major challenge, since it can help physicians in their therapeutic decision. While chronic liver disease requires middle- or long-term prognostic biomarkers, very short-term prognostic markers are needed in acute liver disease (ALD) in order to help in deciding whether and when an LT should be performed. In patients with severe hepatic encephalopathy (HE), the outcome can be rapidly determined using validated scores (King's College and Clichy Criteria and Model for End-Stage Liver Disease); however, these scores do not apply to patients admitted with ALD or early-stage acute liver failure (ALF, HE...

Percutaneous cooled-tip microwave ablation under ultrasound guidance for primary liver cancer: a multicentre analysis of 1363 treatment-naive lesions in 1007 patients in China

Thu, 17 May 2012 18:15:30 +0000

We read with interest the article by Auernhammer and Göke 1 on therapeutic strategies for liver metastasis in neuroendocrine carcinomas. Local tumour progress following radiofrequency ablation (RFA) occurred in only 6% of neuroendocrine carcinomas, but no data on overall survival and prognostic factors following RFA were available. As another thermal ablative technique for liver cancer, microwave ablation (MWA), which uses electromagnetic energy to rapidly rotate adjacent polar water molecules to achieve primarily active heating, shows the following advantages: higher intratumorous temperatures, larger ablation volumes, shorter ablation time and simultaneously multiple probe deployment. 2 3 We wish to report an incidence of MWA treatment for primary liver cancer and to examine additional factors that affect survival.

A large database with 1007 patients (1363 nodules) was generated in seven Chinese centres between January 2005 and July 2010. Criteria for radical treatment were as follows: a single lesion...

Cognitive impairment in non-cirrhotic chronic liver disease is unrelated to liver disease severity but associated with ineffective baroreflex function

Thu, 17 May 2012 18:15:30 +0000

Research letter

We read with interest the commentary by Bercik 1 emphasising the influence that gut intestinal microflora may have on cognitive function—a model with clear therapeutic implications. We would like to propose, however, that a third party—the presence of autonomic nervous system dysfunction—complicates the relationship between cognitive impairment and gut microflora.

In a number of diseases, autonomic dysfunction has been associated with cognitive impairment, 2 3 and its presence is associated with impaired gastrointestinal motility, a risk factor for changes in bacterial colonisation. Autonomic dysfunction is a common problem in patients with chronic liver disease (CLD) 4 —the group of patients highlighted in the commentary as having obvious cognitive problems, as benefiting from treatment aimed at modifying the gut flora and where abnormal gut permeability has been recognised. 5 Cognitive problems are increasingly being recognised in patients with non-cirrhotic CLD, where hepatic encephalopathy...

Familial fundic gland polyposis with gastric cancer

Thu, 17 May 2012 18:15:30 +0000

We read with interest the article by Worthley et al 1 regarding a new autosomal dominant syndrome characterised by fundic gland polyposis (FGP) and gastric cancer, which was not associated with familial adenomatous polyposis (FAP). We have experienced two similar cases of gastric adenocarcinoma occurring in pedigrees with familial FGP without FAP.

Case 1

A 56-year-old woman was referred to our institution for further investigation of her multiple gastric polyps. On admission, serology and ¹³C urea breath test yielded negative results for Helicobacter pylori. Upper gastrointestinal endoscopy revealed numerous fundic gland polyps covering the gastric fundus and corpus ( figure 1A ). In the fundus, there was also a flat and discoloured area circumscribed by polyps ( figure 1B ). A biopsy from the area revealed well-differentiated adenocarcinoma. No other polyps or adenomas were found in the duodenum. The colonoscopy did not show any colorectal lesions and the...

Absence of Helicobacter pylori high tetracycline resistant 16S rDNA AGA926-928TTC genotype in gastric biopsy specimens from dyspeptic patients of a city in the interior of Sao Paulo, Brazil

Thu, 17 May 2012 00:00:00 +0000

Background: Treatment effectiveness of Helicobacter pylori varies regionally and is decreasingworldwide, principally as a result of antibiotic resistant bacterium. Tetracycline is generallyincluded in second line H. pylori eradication regimens. In Brazil, a high level of tetracyclineresistance (TetR) is mainly associated with AGA926-928TTC 16 S rDNA nucleotidesubstitutions. As H. pylori culture is fastidious, we investigated the primary occurrence of H.pylori 16 S rDNA high level TetR genotype using a molecular approach directly on gastricbiopsies of dyspeptic patients attending consecutively at Hospital das Clinicas of Marilia, SaoPaulo, Brazil. Methods: Gastric biopsy specimens of 68 peptic ulcer disease (PUD) and 327 chronic gastritis (CG)patients with a positive histological diagnosis of H. pylori were investigated for TetR 16 SrDNA genotype through a molecular assay based on amplification of a 16 S rDNA 545 bpfragment by polymerase chain reaction and HinfI restriction fragment length polymorphism(PCR/RFLP). Through this assay, AGA926-928TTC 16 S rDNA TetR genotype resulted in athree DNA fragment restriction pattern (281, 227 and 37 bp) and its absence originated twoDNA fragments (264 and 281 bp) due to a 16 S rDNA conserved Hinf I restriction site. Results: The 545 bp 16 S rDNA PCR fragment was amplified from 90% of gastric biopsies fromhistological H. pylori positive patients. HinfI RFLP revealed absence of the AGA926-928TTC H. pylori genotype and PCR products of two patients showed absence of theconserved 16 S rDNA HinfI restriction site. BLASTN sequence analysis of four amplicons(two conserved and two with an unpredicted HinfI restriction pattern) revealed a 99%homology to H. pylori 16 S rDNA from African, North and South American bacterialisolates. A nucleotide substitution abolished the conserved HinfI restriction site in the twoPCR fragments with unpredicted HinfI RFLP, resulting in an EcoRI restriction site. Conclusions: H. pylori AGA926-928TTC 16 S rDNA gene substitutions were not found in our population.More research is required to investigate if H. pylori TetR has a different genetic backgroundin our region and if the nucleotide substitutions of the uncultured H. pylori 16 S rRNA partialsequences have biological significance.

Vertebral fractures in patients with inflammatory bowel disease COMPARED with a healthy population: a prospective case-control study

Mon, 14 May 2012 00:00:00 +0000

Background: A prospective study was performed to compare the prevalence of morphometric vertebralfractures (MVF) between patients with inflammatory bowel disease (IBD) and healthysubjects and to identify predictive factors of fracture. Methods: A total of 107 patients with IBD (53 with Crohn's disease and 54 with ulcerative colitis) and51 healthy subjects participated in the study. Information about anthropometric parameters,toxins, previous fractures, and parameters related to this disease were evaluated. The index ofvertebral deformity, bone mass density (BMD), and biochemical parameters were calculated. Results: A total of 72 fractures were detected in 38.32% of patients with IBD, and 10 fractures weredetected in 13.73% of healthy subjects; the risk of fracture in patients with IBD was higherthan that in control subjects (OR, 4.03; 95% CI, 1.652-9.847; p < 0.002). We found nocorrelation between fracture and BMD in patients with IBD (lumbar spine, r = 0.103, p =0.17 and femoral neck, r = 0.138, p = 0.07). Corticosteroid treatment was not associatedwith prevalent vertebral fractures nor with taking corticosteroids (r = 0.135, p = 0.14) or theduration for which they were taken (r = 0.08, p = 0.38), whereas this relationship was presentin the controls (r = 0.365, p = 0.01). In the multivariate analysis, none of the measuredparameters were significantly predictive of fracture, only to manifested IBD.Hypovitaminosis D was observed in 55.14% of patients with IBD. Conclusions: The prevalence of morphometric vertebral fractures is higher in patients with IBD than in thehealthy population, without association with BMD or corticoid treatment. Simply having IBDwas proven to be a predictive factor of fracture. We observed a high incidence ofhypovitaminosis D in patients with IBD.

Cover 1

Tue, 01 May 2012 00:00:00 +0000

Viral Hepatitis at a Crossroad

Tue, 01 May 2012 00:00:00 +0000

Every May, Gastroenterology publishes a supplementary issue, the “13th Issue”, that is devoted to a specific topic or theme. When the 2012 theme was discussed by the new Board of Editors (each member of which desperately tried to avoid having his or her favorite topic be chosen, as this would undoubtedly mean a considerable amount of additional work), the topic of viral hepatitis emerged unanimously. It must be acknowledged that no other field in Hepatology and Gastroenterology has grown more rapidly than viral hepatitis during the past 15 years, thanks to the considerable interest of the scientific community for diseases that involve over 500 million patients worldwide, active support for research from governments in the United States, Europe, Japan, and Australia, among other regions, and major drug industry investment for what promises to be an incredibly rewarding market for antiviral drugs. Viral hepatitis care and research are now at a crossroad. After many years of investigation aimed at understanding the life cycle of hepatitis viruses, the immunology of acute and chronic infection and the pathophysiology of related liver and extra-hepatic disorders, the field is poised with powerful therapeutic and preventive strategies that will efficiently control these infections. With entecavir and tenofovir now approved in most areas of the world, hepatitis B virus (HBV) replication can be controlled in the long-term in the vast majority of chronically infected patients. In addition, the universal HBV vaccination of newborns in high endemic areas has proven to reduce not only HBV infection but also HBV-related hepatocellular carcinoma (HCC). After some false starts, the search for antiviral drugs targeting hepatitis C virus (HCV) is now moving at an incredible pace with more than 100 compounds currently at the preclinical, or early-to-late clinical developmental stages. After 10 years of stagnation with pegylated interferon alfa and ribavirin therapy, 2 specific inhibitors of the HCV NS3/4A protease, telaprevir and boceprevir, were approved in 2011 in the United States and Europe for the treatment of patients infected with HCV genotype 1. Many other compounds are likely to be approved within the next 5 years. Most importantly, the hope that very high rates of viral eradication will be achieved soon with all-oral, interferon-free regimens is no longer a fantasy. Reasonably, one can now foresee that most chronic HCV infections will be cured, at least in countries that will be able to afford the high price of the new drug combinations.

Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma

Tue, 01 May 2012 00:00:00 +0000

Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States.

Is Hepatitis C Virus Carcinogenic?

Tue, 01 May 2012 00:00:00 +0000

No one would argue with the notion that chronic infection with hepatitis C virus (HCV) causes hepatocellular carcinoma (HCC). Early observations of the association between post-transfusion non-A, non-B hepatitis and HCC in Japan from the 1980s have, unfortunately, proved to be all too true, and in many industrialized countries (including the United States and Japan), HCV infection is now the leading risk factor for HCC. The age-adjusted incidence rate of HCC has tripled in the United States over the past 30 years, reflecting the spread of HCV among Americans decades earlier. Most cases occur in patients with well-established cirrhosis, by itself a very strong risk factor for liver cancer. However, this is not always the case. Eight percent of patients developing HCC in the prospective Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study lacked any evidence of cirrhosis, although all had an Ishak fibrosis score of at least 3 when enrolled in the study. Adjusting for other risk factors, such as alcohol intake, active HCV infection increases the risk of HCC about 18-fold. Thus, the question is not whether HCV infection causes liver cancer, but rather how it does this. Is HCV directly carcinogenic? Or does infection simply set in motion a brisk inflammatory and profibrotic response that causes cancer?

Animal Models for the Study of Hepatitis C Virus Infection and Related Liver Disease

Tue, 01 May 2012 00:00:00 +0000

Hepatitis C virus (HCV) causes liver-related death in more than 300,000 people annually. Treatments for patients with chronic HCV are suboptimal, despite the introduction of directly acting antiviral agents. There is no vaccine that prevents HCV infection. Relevant animal models are important for HCV research and development of drugs and vaccines. Chimpanzees are the best model for studies of HCV infection and related innate and adaptive host immune responses. They can be used in immunogenicity and efficacy studies of HCV vaccines. The only small animal models of robust HCV infection are T- and B- cell deficient mice with human chimeric livers. Although these mice cannot be used in studies of adaptive immunity, they have provided new insights into HCV neutralization, interactions between virus and receptors, innate host responses, and therapeutic approaches. Recent progress in developing genetically humanized mice is exciting, but these models only permit studies of specific steps in the HCV life cycle and have limited or no viral replication.

HCV Infection and Metabolic Syndrome: Which Is the Chicken and Which Is the Egg?

Tue, 01 May 2012 00:00:00 +0000

Hepatitis C virus (HCV) causes chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The World Health Organization estimates that approximately 2.35% of the world population (∼160 million individuals) is infected with HCV. Another widespread disorder, metabolic syndrome, comprises a group of correlated clinical features that have insulin resistance as a common pathogenic determinant; it can lead to type 2 diabetes mellitus, nonalcoholic fatty liver disease, cardiovascular disorders, and many types of cancer, including hepatocellular carcinoma. Metabolic syndrome is pandemic; its estimated prevalence in the United States is ∼25%. It is important to determine the relationship between HCV infection and metabolic syndrome.

Noninvasive Methods to Assess Liver Disease in Patients With Hepatitis B or C

Tue, 01 May 2012 00:00:00 +0000

The prognosis and management of patients with chronic viral hepatitis B and C depend on the amount and progression of liver fibrosis and the risk for cirrhosis. Liver biopsy, traditionally considered to be the reference standard for staging of fibrosis, has been challenged over the past decade by the development of noninvasive methodologies. These methods rely on distinct but complementary approaches: a biologic approach, which quantifies serum levels of biomarkers of fibrosis, and a physical approach, which measures liver stiffness by ultrasound or magnetic resonance elastography. Noninvasive methods were initially studied and validated in patients with chronic hepatitis C but are now used increasingly for patients with hepatitis B, reducing the need for liver biopsy analysis. We review the advantages and limitations of the noninvasive methods used to manage patients with chronic viral hepatitis B or C infection.

New Virologic Tools for Management of Chronic Hepatitis B and C

Tue, 01 May 2012 00:00:00 +0000

Molecular biology techniques are routinely used to diagnose and monitor treatment of patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. These tools can detect and quantify viral genomes and analyze their sequence to determine their genotype or subtype and to identify nucleotide or amino acid substitutions associated with resistance to antiviral drugs. They include real-time target amplification methods, which have been standardized and are widely used in clinical practice to diagnose and monitor HBV and HCV infections, and next-generation sequencing techniques, which are still restricted to research laboratories. In addition, new enzyme immunoassays can quantify hepatitis B surface and hepatitis C core antigens, and point-of-care tests and alternatives to biologic tests that require whole-blood samples obtained by venipuncture have been developed. We review these new virologic methods and their clinical and research applications to HBV and HCV infections.

Maximizing Opportunities and Avoiding Mistakes in Triple Therapy for Hepatitis C Virus

Tue, 01 May 2012 00:00:00 +0000

Recently developed drugs and innovative strategies for the treatment of chronic infection with genotype 1 hepatitis C virus (HCV) have become the standard of care. The protease inhibitors telaprevir (Incivek) and boceprevir (Victrelis) are the first direct-acting antiviral (DAA) agents approved, and many more are being developed. These drugs substantially increased rates of sustained virologic response in treatment-naïve and -experienced patients, in conjunction with peginterferon and ribavirin (triple therapy), in phase 3 trials. The efficacy of triple therapy depends on appropriate selection of patients, although the population of patients that receive triple therapy could be expanded as the risk/benefit ratio improves. Attention to details that reflect the standard of care, such as appropriate dosing, anticipation of adverse effects, and strict adherence to stopping rules, will insure the success of these drugs and lead the way for new combination therapies.

Management of Patients Coinfected With HCV and HIV: A Close Look at the Role for Direct-Acting Antivirals

Tue, 01 May 2012 00:00:00 +0000

With the development of effective therapies against human immunodeficiency virus (HIV), hepatitis C virus (HCV) infection has become a major cause of morbidity and mortality among patients with both infections (coinfection). In addition to the high prevalence of chronic HCV, particularly among HIV-infected injection drug users, the rate of incident HIV infections is increasing among HIV-infected men who have sex with men, leading to recommendations for education and screening for HCV in this population. Liver disease is the second leading and, in some cases, a preventable cause of death among coinfected patients. Those at risk for liver disease progression are usually treated with a combination of interferon (IFN) and ribavirin (RBV), which is not highly effective; it has low rates of sustained virologic response (SVR), especially for coinfected patients with HCV genotype 1 and those of African descent. Direct-acting antivirals might overcome factors such as immunodeficiency that can reduce the efficacy of IFN. However, for now it remains challenging to treat coinfected patients due to interactions among drugs, additive drug toxicities, and the continued need for combination therapies that include pegylated IFN. Recently developed HCV protease inhibitors such as telaprevir and boceprevir, given in combination with pegylated IFN and RBV, could increase the rate of SVR with manageable toxicity and drug interactions. We review the latest developments and obstacles to treating coinfected patients.

Genetic Factors and Hepatitis C Virus Infection

Tue, 01 May 2012 00:00:00 +0000

It is now possible to comprehensively screen the human genome for genetic variation that influences the outcomes of human disease and pharmacotherapy. The most popular approach remains the genome-wide association study (GWAS), in which many hundreds of thousands of genetic markers, representing common variation across the genome, are tested for association with disease. Two success stories of the GWAS era are reviewed here: the discoveries of the association between interleukin-28B (IL28B) polymorphism and peginterferon-α (pegIFN) and ribavirin (RBV) treatment response for genotype 1 HCV, as well as spontaneous clearance of acute HCV infection, and the association between inosine triphosphatase (ITPA) variation and RBV-induced hemolytic anemia.

Anti−Hepatitis C Virus Drugs in Development

Tue, 01 May 2012 00:00:00 +0000

Development of robust cell culture models for hepatitis C viral infection has greatly increased our understanding of this virus and its life cycle. This knowledge has led to the development of many drugs that target specific elements of viral replication, including viral proteins and host factors required for replication. The NS3/4A serine protease inhibitors were the first of these to be used in the clinic, and reagents that target other elements of the viral lifecycle are in advanced stages of clinical development. These include new NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase inhibitors, NS5A inhibitors, and host-directed antivirals, such as cyclophilin inhibitors. Alternative interferons with possibly improved tolerability, specifically interferon-λ1 (interleukin-29), are also under development. These new reagents against hepatitis C virus should lead to highly effective, well-tolerated, and likely interferon-sparing therapies in the next several years.

Will Interferon-Free Regimens Prevail?

Tue, 01 May 2012 00:00:00 +0000

Many promising small molecule inhibitors directed against hepatitis C virus (HCV) proteins (direct-acting antiviral [DAA] agents) and compounds targeting host cell factors (host-targeting agents [HTAs]) are currently in the drug development and clinical trial pipeline, whereas contraindications and adverse effects limit the clinical applicability of peginterferon (Peg-IFN)-based therapies. The increasing number of alternative treatment options is driving the investigation of interferon-sparing regimens and paving the way for the question on the future place for interferon in HCV therapy. The recent approval of 2 DAAs by the US Food and Drug Administration and European Medicines Agency has opened a new era in the treatment of chronic HCV infection (CHC). The new standard of care is a triple therapy, combining the previous standard, Peg-IFN-α plus ribavirin (RBV), with a ketoamide protease inhibitor. The new standard of care is licensed for patients infected with genotype 1 HCV, the most prevalent genotype in Europe and North America. Ketoamide compounds, boceprevir (Victrelis, Merck & Co, Whitehouse Station, NJ) and telaprevir (Incivek, Vertex Pharmaceuticals, Cambridge, MA), are designed to mimic the natural NS3/4A protease substrate in genotype 1 HCV. Their addition to Peg-IFN/RBV significantly improves the sustained virologic response (SVR) rate.

Is There a Role for Ribavirin in the Era of Hepatitis C Virus Direct-Acting Antivirals?

Tue, 01 May 2012 00:00:00 +0000

The Protease Inhibition for Viral Evaluation (PROVE) 2 and PROVE 3 trials tested the efficacy of various regimens of telaprevir-combination therapy in treatment-naïve and treatment-experienced patients. Both studies included a ribavirin-free arm in which patients received telaprevir with peginterferon alone. The results were striking. In the PROVE 2 study, patients who received only peginterferon and telaprevir had a sustained virologic response (SVR) rate of only 36%, significantly lower than in those treated with standard peginterferon and ribavirin (SVR, 46%; P = .003). In treatment-experienced patients, replacement of ribavirin with telaprevir led to a very modest increase in SVR from 14% in the control group to only 24% in those treated with peginterferon plus telaprevir alone (P = .02). The serine protease inhibitor therapy 1 (SPRINT 1) trial evaluated boceprevir combination therapy and included an arm with low-dose ribavirin. Similar to the telaprevir studies, ribavirin proved to be very important. Only 36% of patients randomized to receive low-dose ribavirin achieved an SVR, a markedly worse outcome than in those treated with either the standard of care or with boceprevir with peginterferon and full-dose ribavirin. These trials clearly demonstrated that ribavirin will not disappear quite as quickly as some might have anticipated.

Effectiveness of Hepatitis B Treatment in Clinical Practice

Tue, 01 May 2012 00:00:00 +0000

It is important to examine the effectiveness of current therapies for chronic hepatitis B in clinical practice, given the therapeutic advances over the past 15 years. A 2010 Institute of Medicine report on hepatitis and liver cancer stated that the public and health care providers have a lack of knowledge and awareness about viral hepatitis, and that there is a gap between medical innovation and community care. We review the efficacy of hepatitis B treatment, based on results from clinical trials, and discuss the effectiveness of these treatments in clinical practice. We also discuss why having efficacious treatments alone would have a small impact on the global health burden of hepatitis B, and highlight the importance of educating the public and the medical community and coordination of care.

Is Hepatitis Virus Resistance to Antiviral Drugs a Threat?

Tue, 01 May 2012 00:00:00 +0000

The onset of the acquired immune deficiency syndrome epidemic in the early 1980s led to successful antiviral drug discovery programs, which brought to the market a large number of antiretroviral drugs with different targets and mechanisms of action. However, it soon became apparent that human immunodeficiency virus (HIV) resistance to these drugs would be a problem in long-term antiretroviral therapy. A combination of drugs with different viral targets and no cross-resistance (highly active antiretroviral therapy [HAART]) was shown to be a valuable option to prevent HIV resistance in the long-term. Nevertheless, multidrug-resistant viruses emerge in some patients on HAART therapy, generally those who have been on treatment for many years and have received a number of different drugs during their life. These viruses escape the antiviral effect of all available drugs and their outgrowth is responsible for treatment failure, disease progression, and death.

Viral Hepatitis in Liver Transplantation

Tue, 01 May 2012 00:00:00 +0000

Liver transplantation is the only alternative for patients with end-stage liver disease. Viral hepatitis B and C are among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent indication for liver transplantation. Hepatitis B virus immunoglobulin and nucleot(s)ide analogues have facilitated the management of patients with hepatitis B who have received liver transplants and resulted in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Current therapeutic approaches are far from optimal, because sustained virologic responses are only achieved in one-third of treated patients, and adverse effects are common and severe. However, the rapid development of direct-acting antivirals against hepatitis C virus will change the management of this disease and in a few years prevent graft infection with this virus.

Will There Be a Vaccine to Protect Against the Hepatitis C Virus?

Tue, 01 May 2012 00:00:00 +0000

The discovery of the hepatitis C virus (HCV) more than 20 years ago offered the promise of a vaccine to prevent life-long persistent infection and associated progressive liver diseases. To date, only a few candidate vaccines have been tested in human beings for safety and immunogenicity. None have yet been assessed for prevention of HCV infection or persistence. In the event that current vaccine candidates do not advance to efficacy trials, or fail to provide protection against HCV, the pipeline of alternatives appears to be very small. With a sharp reduction in new HCV infections because of effective screening of the blood supply, and the possibility that acute and chronic infections will be curable because of improving therapy, it is reasonable to ask if the considerable effort to develop a preventive HCV vaccine still is needed. The answer is almost certainly affirmative. Vaccines that protect against hepatitis A and B virus infections were first targeted to health care workers. The value of adding a vaccine to prevent accidental HCV infection in the workplace is clear.

Pathogenesis and Treatment of Hepatitis E Virus Infection

Tue, 01 May 2012 00:00:00 +0000

Hepatitis E has been considered to be a travel-associated, acute, self-limiting liver disease that causes fulminant hepatic failure in specific high-risk groups only. However, hepatitis E virus (HEV) infection can also be acquired in industrialized countries—HEV genotype 3 infection is a zoonosis, with pigs and rodents serving as animal reservoirs. In recent years, cases of chronic HEV infection that were associated with progressive liver disease have been described in several cohorts of immunocompromised individuals, including recipients of organ transplants. The topic of hepatitis E is therefore re-emerging and has raised the following important questions: what is the risk for HEV infection in Western countries (eg, from eating uncooked meat)? How frequently does chronic hepatitis E develop among human immunodeficiency virus–infected patients and recipients of organ transplants? What are the treatment options? What is the current status of vaccine development? What do we know about the pathogenesis of HEV infection, and why does it have a more severe course in pregnant women? This review summarizes the current knowledge on the pathogenesis and treatment of HEV infection.

Editorial Board

Tue, 01 May 2012 00:00:00 +0000