Showing papers in "Best Practice & Research in Clinical Gastroenterology in 2011"
TL;DR: Uncovering the intricate mechanisms that underlie liver fibrogenesis forms the basis for efforts to develop targeted therapies to reverse the fibrotic response and improve the outcomes of patients with chronic liver disease.
Abstract: Multiple etiologies of liver disease lead to liver fibrosis through integrated signaling networks that regulate the deposition of extracellular matrix. This cascade of responses drives the activation of hepatic stellate cells (HSCs) into a myofibroblast-like phenotype that is contractile, proliferative and fibrogenic. Collagen and other extracellular matrix (ECM) components are deposited as the liver generates a wound-healing response to encapsulate injury. Sustained fibrogenesis leads to cirrhosis, characterized by a distortion of the liver parenchyma and vascular architecture. Uncovering the intricate mechanisms that underlie liver fibrogenesis forms the basis for efforts to develop targeted therapies to reverse the fibrotic response and improve the outcomes of patients with chronic liver disease.
709 citations
TL;DR: The epidemiology of constipation in children was investigated in 19 articles and prevalence rate was between 0.7% and 29.6% (median 12%).
Abstract: We aimed to review the published literature regarding the epidemiology of constipation in the general paediatric and adult population and to assess its geographic, gender and age distribution, and associated factors. A search of the Medline database was performed. Study selection criteria included: (1) studies of population-based samples; (2) containing data on the prevalence of constipation without obvious organic aetiology; (3) in paediatric, adult or elderly population; (4) published in English and full manuscript form. Sixty-eight studies met our inclusion criteria. The prevalence of constipation in the worldwide general population ranged from 0.7% to 79% (median 16%). The epidemiology of constipation in children was investigated in 19 articles and prevalence rate was between 0.7% and 29.6% (median 12%). Female gender, increasing age, socioeconomic status and educational level seemed to affect constipation prevalence.
648 citations
TL;DR: Autoimmune hepatitis is initiated by CD4 T cells that recognize self-antigen and effector cells differentiate into functional phenotypes according to cytokines in the microenvironment and the nature of the triggering antigen.
Abstract: 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 naive 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.
220 citations
TL;DR: The origin of activated myofibroblasts and different aspects of their activation, differentiation and potential inactivation during regression of liver fibrosis are discussed.
Abstract: Liver fibrosis is an outcome of many chronic diseases, and often results in cirrhosis, liver failure, and portal hypertension. Liver transplantation is the only treatment available for patients with advanced stage of fibrosis. Therefore, alternative methods are required to develop new strategies for anti-fibrotic therapy. Available treatments are designed to substitute for liver transplantation or bridge the patients, they include inhibitors of fibrogenic cytokines such as TGF-β1 and EGF, inhibitors of rennin angiotensin system, and blockers of TLR4 signalling. Development of liver fibrosis is orchestrated by many cell types. However, activated myofibroblasts remain the primary target for anti-fibrotic therapy. Hepatic stellate cells and portal fibroblasts are considered to play a major role in development of liver fibrosis. Here we discuss the origin of activated myofibroblasts and different aspects of their activation, differentiation and potential inactivation during regression of liver fibrosis.
156 citations
TL;DR: The most used as well as some newly described but potentially interesting models including models for studying biliary, immune, alcohol-induced, NASH-associated and viral fibrosis are reviewed to provide insight on underlying disease processes and practical details.
Abstract: Animal models are being used for several decades to study fibrogenesis and to evaluate the anti-fibrotic potential of therapies and strategies. Although immensely valuable for our understanding of pathophysiological processes, they remain models and none of them reproduces a human disease. Each model (meaning stimulus, design, strain and species) displays specific characteristics in the nature of the pathogenesis, the topography and the evolution of fibrosis. We review here the most used as well as some newly described but potentially interesting models including models for studying biliary, immune, alcohol-induced, NASH-associated and viral fibrosis and provide insight on underlying disease processes and practical details. We attempted to delineate the benefits, advantages, limitations and drawbacks of those models. We also report the new opportunities provided by genetically engineered mice for tracking and manipulating cells that participate to fibrosis. Finally, we emphasize the importance of adapting study design to the question addressed.
151 citations
TL;DR: Non invasive methods have been initially studied and validated in chronic hepatitis C but are now increasingly used in other chronic liver diseases, resulting in a significant decrease in the need for liver biopsy, however, they will likely not completely abolish theneed for Liver biopsy and they should rather be employed as an integrated system with liver biopsies.
Abstract: Chronic liver diseases represent a major public health problem, accounting for significant morbidity and mortality worldwide. Their prognosis and management greatly depend on the amount and progression of liver fibrosis with the risk of developing cirrhosis. Liver biopsy, traditionally considered as the reference standard for staging of fibrosis, has been challenged over the past decade by the development of novel non invasive methodologies. These methods rely on two distinct but complementary approaches: i) a 'biological' approach based on the dosage of serum biomarkers of fibrosis; ii) a 'physical' approach based on the measurement of liver stiffness using transient elastography (TE). Non invasive methods have been initially studied and validated in chronic hepatitis C but are now increasingly used in other chronic liver diseases, resulting in a significant decrease in the need for liver biopsy. However, they will likely not completely abolish the need for liver biopsy and they should rather be employed as an integrated system with liver biopsy. This review is aimed at discussing the advantages and inconveniences of non invasive methods in comparison with liver biopsy for the management of patients with chronic liver diseases.
138 citations
TL;DR: Liver fibrogenic cells are a heterogenous population of cells that include α-smooth muscle actin positive myofibroblasts that promote the progression of chronic liver diseases towards cirrhosis by means of their multiple phenotypic responses to injury.
Abstract: Liver fibrogenic cells are a heterogenous population of cells that include α-smooth muscle actin positive myofibroblasts (MFs). MFs promote the progression of chronic liver diseases (CLDs) towards cirrhosis. MFs are highly proliferative and contractile and promote fibrogenesis by means of their multiple phenotypic responses to injury. These include: excess deposition and altered remodelling of extracellular matrix; the synthesis and release of growth factor which sustain and perpetuate fibrogenesis; chronic inflammatory response and neo-angiogenesis. MFs mainly originate from hepatic stellate cells or portal fibroblasts through activation and transdifferentiation. MFs may also potentially differentiate from bone marrow-derived stem cells. It has been suggested that MFs can be derived from hepatocytes or cholangiocytes through a process of epithelial to mesenchymal transition in the liver, however this is controversial. Hepatic MFs may also modulate the immune responses to hepatocellular carcinomas and metastatic cancers through cross talk with hepatic progenitor and tumour cells.
111 citations
TL;DR: The recent advances in diagnostic testing with a particular emphasis on when and why to test are summarized, and the utility of diagnostic tests for chronic constipation are discussed.
Abstract: Constipation is a common ailment with multiple symptoms and diverse etiology. Understanding the pathophysiology is important to guide optimal management. During the past few years, there have been remarkable developments in the diagnosis of constipation and defecation disorders. Several innovative manometric, neurophysiologic, and radiologic techniques have been discovered, which have improved the accuracy of identifying the neuromuscular mechanisms of chronic constipation. These include use of digital rectal examination, Bristol stool scale, colonic scintigraphy, wireless motility capsule for assessment of colonic and whole gut transit, high resolution anorectal manometry, and colonic manometry. These tests provide a better definition of the underlying mechanism(s), which in turn can lead to improved management of this condition. In this review, we summarize the recent advances in diagnostic testing with a particular emphasis on when and why to test, and discuss the utility of diagnostic tests for chronic constipation.
110 citations
TL;DR: 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.
Abstract: 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.
107 citations
TL;DR: EPA has now been demonstrated to reduce rectal polyp number and size in patients with familial adenomatous polyposis and a randomized polyp prevention trial of EPA is underway in order to test chemopreventative efficacy against 'sporadic' colorectal neoplasia.
Abstract: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are naturally occurring omega (ω)-3 long-chain polyunsaturated fatty acids (PUFAs), which are found in highest quantities in oily fish such as sardines and mackerel. Epidemiological studies of the association between fish intake, ω-3 PUFA intake or blood ω-3 PUFA levels and colorectal cancer (CRC) risk have not consistently suggested beneficial effects of ω-3 PUFAs on CRC (and other gastrointestinal cancer) risk. However, dietary administration of one or both of the main ω-3 PUFAs in rodent models of colorectal carcinogenesis has been demonstrated to reduce colorectal tumour size and multiplicity, compatible with CRC chemopreventative activity. EPA has now been demonstrated to reduce rectal polyp number and size in patients with familial adenomatous polyposis. A randomized polyp prevention trial of EPA is underway in order to test chemopreventative efficacy against ‘sporadic’ colorectal neoplasia.
106 citations
TL;DR: Human studies of aspirin in CRC prevention are summarized as well as the safety profile and mechanism of aspirinIn CRC prevention, aspirin is perhaps the agent with the strongest body of evidence that supports wider spread use to significantly reduce the population burden of CRC.
Abstract: 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.
TL;DR: The preponderance of evidence indicates that the adverse effects of chronic constipation on quality of life (QOL) in both children and adults are comparable to that seen in other chronic gastrointestinal and non-gastrointestinal disorders.
Abstract: This review summarises the literature on quality of life (QOL) assessments in both children and adults with functional constipation. Studies of adults with constipation include subjects from both tertiary care centres and population-based surveys whereas there are no population-based studies in children. The preponderance of evidence indicates that the adverse effects of chronic constipation on QOL in both children and adults are comparable to that seen in other chronic gastrointestinal and non-gastrointestinal disorders. There are no data on the effect of treatment of children with constipation with regard to QOL whereas several studies indicate that successful treatment of constipation in adults has a favourable effect on QOL. The emerging concept in the treatment of chronic constipation is to measure both objective measures such as frequency and ease of defecation and subjective parameters such as QOL.
TL;DR: The concept of chemoprevention and the current clinical literature in FAP chemop revention are reviewed to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery with colectomy and ileorectal anastamosis.
Abstract: Familial adenomatous polyposis (FAP) predictably leads to adenomas and eventual adenocarcinomas in the lower gastrointestinal tract and less frequently, the upper gastrointestinal tract. Chemopreventive strategies have been studied in FAP patients to delay the development of adenomas in the upper and lower gastrointestinal tract, as well as to prevent recurrence of adenomas in the retained rectum of patients after prophylactic surgery with colectomy and ileorectal anastamosis (IRA). The nonsteroidal anti-inflammatory drug (NSAID) sulindac and selective cyclooxygenase-2 (COX-2) inhibitor celecoxib reduce polyposis of the retained rectum after colectomy with IRA. Reports of cardiovascular risks of some NSAIDs and selective COX-2 inhibitors have led to promising studies of lower doses in combination with ursodeoxycholic acid, statin, and difluoromethylornithine. Curcumin and eicosapentaenoic acid show efficacy in small clinical trials of FAP chemoprevention. This article will review the concept of chemoprevention and the current clinical literature in FAP chemoprevention.
TL;DR: There is only finite data supporting the use of curcumin in phase III trials with specific diseases (e.g. ulcerative colitis), and for the vast majority of conditions additional early-phase studies are required to justify larger trials determining efficacy.
Abstract: 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.
TL;DR: While benefits for fiber and, perhaps, for certain prebiotic and probiotic preparations in constipation appear to be extant, there is a real need for large well-conducted clinical trials in this important area of human medicine.
Abstract: For centuries, fiber has been recommended on an empirical basis for the management of constipation; it has only been in recent decades that the mechanisms whereby fiber and related products may influence colonic function have begun to be elucidated. The interaction between fiber and the microbiota of the human colon appears to play a major role in generating the beneficial effects of fiber. The microbiota is also the target for the other therapeutic interventions discussed in this chapter: prebiotics and probiotics. While a scientific basis for a role for these approaches in the management of constipation continues to develop, evidence from high-quality clinical trials to support their use in daily practice continues to lag far behind. While benefits for fiber and, perhaps, for certain prebiotic and probiotic preparations in constipation appear to be extant there is a real need for large well-conducted clinical trials in this important area of human medicine.
TL;DR: Epigenetic markers represent one among several classes of potential biomarkers for early diagnosis of malignancies in PSC that should be further explored.
Abstract: 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.
TL;DR: Reductions in ICC appear to a consistent finding but one whose role as a primary cause of slow-transit constipation requires further evaluation, and which require further validation in respect of normative data.
Abstract: Some patients with chronic constipation may undergo colectomy yielding tissue appropriate to diagnosis of underlying neuromuscular pathology. The analysis of such tissue has, over the past 40 years, fuelled research that has explored the presence of neuropathy, myopathy and more recently changes in interstitial cells of Cajal (ICC). In this chapter, the data from these studies have been critically reviewed in the context of the significant methodological and interpretative issues that beset the field of gastrointestinal neuromuscular pathology. On this basis, reductions in ICC appear to a consistent finding but one whose role as a primary cause of slow-transit constipation requires further evaluation. Findings indicative of significant neuropathy or myopathy are variable and in many studies subject to considerable methodological bias. Methods with practical diagnostic utility in the individual patient have rarely been employed and require further validation in respect of normative data.
TL;DR: Development of user friendly approaches to biofeedback therapy and use of homeBiofeedback programs will significantly enhance the adoption of this treatment by gastroenterologists and colorectal surgeons in the future.
Abstract: Dyssynergic defecation is common and affects up to one half of patients with chronic constipation. This acquired behavioural problem is due to the inability to coordinate the abdominal and pelvic floor muscles to evacuate stools. Today, it is possible to diagnose this problem and treat this effectively with biofeedback therapy, history, prospective stool diaries, and anorectal physiological tests. Several randomised controlled trails have demonstrated that biofeedback therapy using neuromuscular training and visual and verbal feedback is not only efficacious but superior to other modalities such as laxative or sham training. Also the symptom improvement is due a change in the underlying pathophysiology. Development of user friendly approaches to biofeedback therapy and use of home biofeedback programs will significantly enhance the adoption of this treatment by gastroenterologists and colorectal surgeons in the future. Improved reimbursement for this proven and relatively inexpensive treatment will carry a significant impact on the problem.
TL;DR: The scope of this review encompasses the latest findings that improve the understanding of the motility disorders associated with colonic dysfunction in both the paediatric and adult population suffering from constipation.
Abstract: Constipation is a common and distressing condition with major morbidity, health care burden, and impact on quality of life. Colonic motor dysfunction remains the leading hypothesis to explain symptom generation in the most severe cases of chronic constipation and physiological testing plays a role in identifying the colonic dysmotility and the subsequent patient management. Measurement of colonic motor patterns and transit has enhanced our knowledge of normal and abnormal colonic motor physiology. The scope of this review encompasses the latest findings that improve our understanding of the motility disorders associated with colonic dysfunction in both the paediatric and adult population suffering from constipation.
TL;DR: This review broadly addresses the epidemiology and pathophysiology of coexistent constipation and incontinence in both children and adults, and also reviews clinical presentation and treatment response in pediatrics.
Abstract: The coexistence of constipation and fecal incontinence has long been recognised in paediatric and geriatric populations, but is grossly underappreciated in the rest of the adult population. In children, functional fecal incontinence is usually associated with constipation, stool retention and incomplete evacuation, and is frequently allied to urinary incontinence. Pathophysiology of the incontinence is incompletely understood, although both in children and adults, it is thought to be secondary to overflow, while in adults it may also be related to pelvic floor dysfunction and denervation. Incontinence has an important impact on quality of life and daily functioning, and in children may be associated with behaviour problems. The treatment of underlying constipation usually results in improvement in incontinence. This review broadly addresses the epidemiology and pathophysiology of coexistent constipation and incontinence in both children and adults, and also reviews clinical presentation and treatment response in pediatrics.
TL;DR: The present review discusses the current concepts and ideas with regards to myofibroblastic cell populations, mechanisms of fibrosis, characteristic histological findings and currently employed animal models of autoimmune and cholestatic liver disease.
Abstract: Autoimmune and cholestatic liver disease account for a significant part of end-stage liver disease and are leading indications for liver transplantation. Especially cholestatic liver diseases (primary biliary cirrhosis and primary sclerosing cholangitis) appear to be different from other chronic liver diseases with regards to pathogenesis. Portal fibroblasts located in the connective tissue surrounding bile ducts appear to be different from hepatic stellate cells with regards to expression of marker proteins and response the profibrogenic and mitogenic stimuli. In addition there is increasing evidence for a cross talk between activated cholangiocytes and portal myofibroblasts. Several animal models have improved our understanding of the mechanisms underlying these chronic liver diseases. In the present review, we discuss the current concepts and ideas with regards to myofibroblastic cell populations, mechanisms of fibrosis, summarize characteristic histological findings and currently employed animal models of autoimmune and cholestatic liver disease.
TL;DR: Autoimmune liver disorders in childhood include autoimmune hepatitis, autoimmune sclerosing cholangitis and de novo autoimmune hepatitis after liver transplant, which affects children transplanted for non-autoimmune conditions and responds well to the same treatment schedule used for autoimmune hepatitis.
Abstract: 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.
TL;DR: Experimental evidence suggests additional COX independent actions of aspirin and non-aspirin NSAIDs on oncogenic signalling, which includes modifications of transcription factors, induction of apoptosis and DNA stabilization, makes aspirin the most attractive candidate for clinical CRC chemoprevention.
Abstract: 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.
TL;DR: 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 and better understanding of the pathogenesis of recurrent autoimmune liver disease is needed.
Abstract: 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.
TL;DR: The characteristics of fibrosis in alcoholic and nonalcoholic steatohepatitis are discussed, focussing on the diagnostic issues and predictive factors, and the pathogenetic mechanisms responsible for appearance and progression of Fibrosis in the two conditions are discussed.
Abstract: Both alcoholic and nonalcoholic steatohepatitis are relevant causes of cirrhosis and liver-related mortality. Alcohol abuse represents a major health problem in many countries, and liver disease is considered one of the most relevant causes of death related to this factor. Nonalcoholic fatty liver disease is the most common hepatic abnormality in the Western world, and progresses to cirrhosis and hepatocellular carcinoma in a significant portion of cases. Moreover, presence of NAFLD is associated with an increased risk of cardiovascular events. In this review, we discuss the characteristics of fibrosis in alcoholic and nonalcoholic steatohepatitis, focussing on the diagnostic issues and predictive factors. In addition, the pathogenetic mechanisms responsible for appearance and progression of fibrosis in the two conditions are briefly discussed.
TL;DR: In this article, the complex interaction between sensory/motor/biomechanical domains, and how best to measure these functions are addressed, and where data exist, the impact of sensorimotor dysfunction on therapeutic outcomes is highlighted.
Abstract: The pathophysiological mechanisms underlying chronic constipation in both adults and children remain to be unravelled. This is a not inconsiderable challenge, but is fundamental to improving management of such patients. Rectal sensorimotor function, which encompasses both sensation and motility, as well as biomechanical components (compliance, capacity), is now strongly implicated in the pathogenesis of constipation. Rectal hyposensitivity, rectal hypercompliance, increased rectal capacity, rectal motor dysfunction (phasic contractility and tone), and altered rectoanal reflex activity are all found in constipated patients, particularly in association with 'functional' disorders of defaecation (i.e. pelvic floor dyssynergia). This review covers contemporary understanding of how components of rectal sensorimotor function may contribute to symptom development in both adult and paediatric populations. The complex interaction between sensory/motor/biomechanical domains, and how best to measure these functions are addressed, and where data exist, the impact of sensorimotor dysfunction on therapeutic outcomes is highlighted.
TL;DR: The fundamentals of cancer prevention including the targets, cohorts, agents, endpoints, mechanistic biomarkers, designs, and strategies employed in preventive drug development are discussed.
Abstract: 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.
TL;DR: Methods of neuromodulation used to treat constipation include direct stimulation of sacral nerves and stimulation across the skin, which is the most well developed method and is presented in detail.
Abstract: Constipation is a frequently occurring digestive ailment that is usually treated conservatively. Neuromodulation is altering function of an organ by altering neural activity. This paper reviews methods of neuromodulation used to treat constipation. This includes direct stimulation of sacral nerves and stimulation across the skin. Direct stimulation of sacral nerves is the most well developed method and is presented in detail. It is generally accepted that the mechanism of action is modulation rather than stimulation so it is called sacral neuromodulation (SNM). SNM involves percutaneous placement of an electrode in the third sacral foramen and implanting a stimulating device under the skin in the buttocks. SNM is founded on the physiological principle that activity in one neural pathway modulates pre-existing activity in another through synaptic interaction. The mechanism of action in constipation may be neuromodulation of the extrinsic neural control of the large bowel or modulation of reflexes inhibiting large bowel function. Limited evidence is available to assess the outcome of SNM in constipation. Results in the medium term seem promising for selected patients with idiopathic slow and normal transit constipation not responding to optimal conservative treatment. Adverse events include electrode migration and infection. The availability of a testing phase provides a predictor of treatment outcome. In addition, transcutaneous stimulation using sticky pad electrodes over the lumbosacral region or acupuncture points has been reported to improve constipation symptoms. In general, the level of evidence is low and further studies are needed.
TL;DR: It is shown that along with functional constipation, there are numerous clinical syndromes associated with childhood constipation that appear to be the result of mutations in genes affecting all aspects of the normal physiology of human defecation.
Abstract: Constipation is a common problem in children but little is known about its exact pathophysiology. Environmental, behavioural but also genetic factors are thought to play a role in the aetiology of childhood constipation. We provide an overview of genetic studies performed in constipation. Until now, linkage studies, association studies and direct gene sequencing have failed to identify mutations in specific genes associated with constipation. We show that along with functional constipation, there are numerous clinical syndromes associated with childhood constipation. These syndromic forms of constipation appear to be the result of mutations in genes affecting all aspects of the normal physiology of human defecation. We stress that syndromic causes of childhood constipation should be considered in the evaluation of a constipated child.
TL;DR: Overall, currently there is no evidence that antioxidants are protective against gastrointestinal cancers in populations whose members are replete in antioxidant intake.
Abstract: 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.