Showing papers in "Nature Reviews Gastroenterology & Hepatology in 2009"
TL;DR: Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system, and may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions.
Abstract: While bidirectional brain-gut interactions are well known mechanisms for the regulation of gut function in both healthy and diseased states, a role of the enteric flora--including both commensal and pathogenic organisms--in these interactions has only been recognized in the past few years. The brain can influence commensal organisms (enteric microbiota) indirectly, via changes in gastrointestinal motility and secretion, and intestinal permeability, or directly, via signaling molecules released into the gut lumen from cells in the lamina propria (enterochromaffin cells, neurons, immune cells). Communication from enteric microbiota to the host can occur via multiple mechanisms, including epithelial-cell, receptor-mediated signaling and, when intestinal permeability is increased, through direct stimulation of host cells in the lamina propria. Enterochromaffin cells are important bidirectional transducers that regulate communication between the gut lumen and the nervous system. Vagal, afferent innervation of enterochromaffin cells provides a direct pathway for enterochromaffin-cell signaling to neuronal circuits, which may have an important role in pain and immune-response modulation, control of background emotions and other homeostatic functions. Disruption of the bidirectional interactions between the enteric microbiota and the nervous system may be involved in the pathophysiology of acute and chronic gastrointestinal disease states, including functional and inflammatory bowel disorders.
944 citations
TL;DR: Rising prevalence of smoking in developing countries, improved diagnosis and increasing population longevity are all likely to increase the global burden of pancreatic cancer in the coming decades.
Abstract: Pancreatic cancer, although infrequent, has an exceptionally high mortality rate, making it one of the four or five most common causes of cancer mortality in developed countries. The incidence of pancreatic cancer varies greatly across regions, which suggests roles for lifestyle factors, such as diet, or environmental factors, such as vitamin D exposure. Smoking is the most common known risk factor, and is the cause of 20-25% of all pancreatic tumors. Alcohol does not seem to be a risk factor, unless it leads to chronic pancreatitis, which is a probable risk factor. Long-standing diabetes increases the risk of pancreatic cancer, but can also be an early manifestation of pancreatic tumors. 5-10% of patients with pancreatic cancer have an underlying germline disorder, while the remaining percentage of cancer cases is thought to be caused by somatic mutations. Some individual studies suggest that mutations in various polymorphic genes can lead to small increases in the risk of pancreatic cancer, but these findings need to be replicated. Rising prevalence of smoking in developing countries, improved diagnosis and increasing population longevity are all likely to increase the global burden of pancreatic cancer in the coming decades.
640 citations
TL;DR: The main clinical applications for HVPG include diagnosis, risk stratification, identification of patients with hepatocellular carcinoma who are candidates for liver resection, monitoring of the efficacy of medical treatment, and assessment of progression of portal hypertension.
Abstract: Portal hypertension is a severe, almost unavoidable complication of chronic liver diseases and is responsible for the main clinical consequences of cirrhosis. Measurement of the hepatic venous pressure gradient (HVPG) is currently the best available method to evaluate the presence and severity of portal hypertension. Clinically significant portal hypertension is defined as an increase in HVPG to >or=10 mmHg; above this threshold, the complications of portal hypertension might begin to appear. Measurement of HVPG is increasingly used in clinical hepatology, and numerous studies have demonstrated that the parameter is a robust surrogate marker for hard clinical end points. The main clinical applications for HVPG include diagnosis, risk stratification, identification of patients with hepatocellular carcinoma who are candidates for liver resection, monitoring of the efficacy of medical treatment, and assessment of progression of portal hypertension. Patients who experience a reduction in HVPG of >or=20% or to <12 mmHg in response to drug therapy are defined as 'responders'. Responders have a markedly decreased risk of bleeding (or rebleeding), ascites, and spontaneous bacterial peritonitis, which results in improved survival.
539 citations
TL;DR: Somatostatin analogs are the most effective medical therapy for dumping syndrome, and a slow-release preparation is the treatment of choice, but the outcomes of such approaches are variable.
Abstract: Dumping syndrome is a frequent complication of esophageal, gastric or bariatric surgery. Rapid gastric emptying, with the delivery to the small intestine of a significant proportion of solid food as large particles that are difficult to digest, is a key event in the pathogenesis of this syndrome. This occurrence causes a shift of fluid from the intravascular component to the intestinal lumen, which results in cardiovascular symptoms, release of several gastrointestinal and pancreatic hormones and late postprandial hypoglycemia. Early dumping symptoms comprise both gastrointestinal and vasomotor symptoms. Late dumping symptoms are the result of reactive hypoglycemia. Besides the assessment of clinical alertness and endoscopic or radiological imaging, a modified oral glucose tolerance test might help to establish a diagnosis. The first step in treating dumping syndrome is the introduction of dietary measures. Acarbose can be added to these measures for patients with hypoglycemia, whereas several studies advocate guar gum or pectin to slow gastric emptying. Somatostatin analogs are the most effective medical therapy for dumping syndrome, and a slow-release preparation is the treatment of choice. In patients with treatment-refractory dumping syndrome, surgical reintervention or continuous enteral feeding can be considered, but the outcomes of such approaches are variable.
323 citations
TL;DR: The intent is to provide a conceptual basis for categorizing carcinogenetic molecular abnormalities in IBD, and for understanding how cancer-preventive therapies might target reversal of acquired abnormalities in specific biochemical pathways.
Abstract: In patients with IBD, chronic colonic inflammation increases the risk of colorectal cancer, perhaps because inflammation predisposes these tissues to genomic instability. Carcinogenesis in the inflamed colon seems to follow a different sequence of genetic alterations than that observed in sporadic cancers in the uninflamed colon. In this Review, we focus on the genetic alterations in colitis-associated colorectal cancer that contribute to the acquisition of the essential hallmarks of cancer, and on how those alterations differ from sporadic colorectal cancers. Our intent is to provide a conceptual basis for categorizing carcinogenetic molecular abnormalities in IBD, and for understanding how cancer-preventive therapies might target reversal of acquired abnormalities in specific biochemical pathways.
265 citations
TL;DR: In this article, a conceptual and practical framework that could achieve the specific blockade of fibrogenic pathways, allow for the estimation of risk of fibrotic complications, and permit the detection of early fibrosis changes and, eventually, enable the development of treatments customized to the type and stage of each patient's IBD.
Abstract: Intestinal fibrosis is a common and potentially serious complication of IBD that results from the reaction of intestinal tissue to the damage inflicted by chronic inflammation. The traditional view that fibrosis is inevitable or irreversible in patients with IBD is progressively changing in light of improved understanding of the cellular and molecular mechanisms that underlie the pathogenesis of fibrosis in general, and, in particular, intestinal fibrosis. These mechanisms are complex and dynamic, and involve multiple cell types, interconnected cellular events and a large number of soluble factors. In addition, owing to a breakdown of the epithelial barrier during inflammation of the gut, luminal bacterial products induce an innate immune response, which is triggered by activation of immune and nonimmune cells alike. Comprehension of the mechanisms of intestinal fibrosis will create a conceptual and practical framework that could achieve the specific blockade of fibrogenic pathways, allow for the estimation of risk of fibrotic complications, permit the detection of early fibrotic changes and, eventually, enable the development of treatments customized to the type and stage of each patient's IBD.
261 citations
TL;DR: This Review describes some of the important developments and targeted agents for pancreatic cancer that have been tested in clinical trials and suggests that a large number of genetic alterations affect only a few major signaling pathways and processes involved in pancreatic tumorigenesis.
Abstract: Patients with pancreatic cancer normally present with advanced disease that is lethal and notoriously difficult to treat. Survival has not improved dramatically despite routine use of chemotherapy and radiotherapy; this situation signifies an urgent need for novel therapeutic approaches. Over the past decade, a large number of studies have been published that aimed to target the molecular abnormalities implicated in pancreatic tumor growth, invasion, metastasis, angiogenesis and resistance to apoptosis. This research is of particular importance, as data suggest that a large number of genetic alterations affect only a few major signaling pathways and processes involved in pancreatic tumorigenesis. Although laboratory results of targeted therapies have been impressive, until now only erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated modest survival benefit in combination with gemcitabine in a phase III clinical trial. Whilst the failures of targeted therapies in the clinical setting are discouraging, lessons have been learnt and new therapeutic targets that hold promise for the future management of the disease are continuously emerging. This Review describes some of the important developments and targeted agents for pancreatic cancer that have been tested in clinical trials.
207 citations
TL;DR: Research efforts aimed at endowing the capsule with a range of functionalities are discussed, from tissue sampling for biopsy to optical biopsy and, in some cases, actual treatment (interventional CE), so that CE may ultimately replace both diagnostic and interventional flexible endoscopy.
Abstract: Capsule endoscopy (CE) enables remote diagnostic inspection of the gastrointestinal tract without sedation and with minimal discomfort. Initially intended for small-bowel endoscopy, modifications to the original capsule have since been introduced for imaging of the esophagus and the colon. This review presents a research update on CE. Emphasis is placed on PillCam SB, PillCam ESO, and PillCam COLON (Given Imaging, Yoqneam, Israel) since the majority of published studies have investigated these devices. Discussion of initial reports on competing devices, such as EndoCapsule (Olympus, Tokyo, Japan) and MiroCam (IntroMedic Co., Seoul, Republic of Korea) are also included. The last section of this review outlines ongoing research and development directed at the identification of capsule location, control of capsule movement and expansion of the capability of microcameras to enhance the diagnostic power of CE. Research efforts aimed at endowing the capsule with a range of functionalities are also discussed, from tissue sampling for biopsy to optical biopsy and, in some cases, actual treatment (interventional CE), so that CE may ultimately replace both diagnostic and interventional flexible endoscopy.
167 citations
TL;DR: Advances in the intensive care management of patients with ALF are highlighted that have contributed to a marked improvement in their overall survival over the past 20 years, including therapies that limit the extent of liver injury and maximize the likelihood of spontaneous recovery.
Abstract: Acute liver failure (ALF) is a syndrome of diverse etiology, in which patients without previously recognized liver disease sustain a liver injury that results in rapid loss of hepatic function. Depending on the etiology and severity of the insult, some patients undergo rapid hepatic regeneration and spontaneously recover. However, nearly 60% of patients with ALF in the US require and undergo orthotopic liver transplantation or die. Management decisions made by clinicians who initially assess individuals with ALF can drastically affect these patients' outcomes. Even with optimal early management, however, many patients with ALF develop a cascade of complications often presaged by the systemic inflammatory response syndrome, which involves failure of nearly every organ system. We highlight advances in the intensive care management of patients with ALF that have contributed to a marked improvement in their overall survival over the past 20 years. These advances include therapies that limit the extent of liver injury and maximize the likelihood of spontaneous recovery and approaches to enable prevention, recognition and early treatment of complications that lead to multi-organ-system failure, the most common cause of death. Finally, we summarize the role of orthotopic liver transplantation in salvage of the most severely affected patients.
156 citations
TL;DR: Lower gastrointestinal bleeding (LGIB) can present as an acute and life-threatening event or as chronic bleeding, which might manifest as iron-deficiency anemia, fecal occult blood or intermittent scant hematochezia.
Abstract: Lower gastrointestinal bleeding (LGIB) can present as an acute and life-threatening event or as chronic bleeding, which might manifest as iron-deficiency anemia, fecal occult blood or intermittent scant hematochezia. Bleeding from the small bowel has been shown to be a distinct entity, and LGIB is defined as bleeding from a colonic source. Acute bleeding from the colon is usually less dramatic than upper gastrointestinal hemorrhage and is self-limiting in most cases. Several factors might contribute to increased mortality, a severe course of bleeding and recurrent bleeding, including advanced age, comorbidity, intestinal ischemia, bleeding as a result of a separate process, and hemodynamic instability. Diverticula, angiodysplasias, neoplasms, colitis, ischemia, anorectal disorders and postpolypectomy bleeding are the most common causes of LGIB. Volume resuscitation should take place concurrently upon initial patient assessment. Colonoscopy is the diagnostic and therapeutic procedure of choice, for acute and chronic bleeding. Angiography is used if colonoscopy fails or cannot be performed. The use of radioisotope scans is reserved for cases of unexplained intermittent bleeding, when other methods have failed to detect the source. Embolization or modern endoscopy techniques, such as injection therapy, thermocoagulation and mechanical devices, effectively promote hemostasis. Surgery is the final approach for severe bleeding.
152 citations
TL;DR: The endoscopic characteristics, histopathology, pathogenesis, and management recommendations of polyps and common polypoid lesions in the stomach are discussed in this Review.
Abstract: 1-4% of patients who undergo gastric biopsy have gastric polyps. These lesions may be true epithelial polyps, heterotopias, lymphoid tissue, or stromal lesions. Hyperplastic polyps, which arise in patients with underlying gastritis, and fundic-gland polyps, which are associated with PPI therapy, are the most common gastric polyps; however, prevalence varies widely relative to the local prevalence of Helicobacter pylori infection and use of PPI therapy. Some polyps have characteristic topography, size, and endoscopic appearance. Approximately 20% of biopsy specimens identified endoscopically as polyps have no definite pathological diagnosis. Evaluation of the phenotype of the gastric mucosa that surrounds a lesion will provide significant information crucial to the evaluation, diagnosis and management of a patient. The presence of a gastric adenoma should prompt the search for a coexistent carcinoma. The endoscopic characteristics, histopathology, pathogenesis, and management recommendations of polyps and common polypoid lesions in the stomach are discussed in this Review.
TL;DR: In this paper, the precore and core promoter regions that abolish or reduce the production of hepatitis B e antigen occur most commonly and are associated with an increased risk of hepatocellular carcinoma.
Abstract: HBV replicates through reverse transcription of an RNA intermediate; the inherent lack of proofreading causes a high mutation frequency. Mutations in the precore and core promoter regions that abolish or reduce the production of hepatitis B e antigen occur most commonly. Patients with these HBV variants remain viremic and can develop progressive liver disease. Mutations in the core promoter region are associated with an increased risk of hepatocellular carcinoma. Exogenous selection pressure might favor certain mutations. Mutations in the HBV polymerase that confer resistance to nucleoside and nucleotide analog treatments are a major barrier to the success of therapy for hepatitis B. The development of antiviral drug resistance negates the initial treatment response and can lead to hepatitis flares and hepatic decompensation. Prompt addition of another drug to which the virus is not cross-resistant is required. Mutations in the HBV surface protein that facilitate escape from host immunity are responsible for the failure of immune prophylaxis in infants who received HBV vaccine and in liver transplant recipients who received hepatitis B immune globulin.
TL;DR: Clinicians should be aware of the potential role of endocrine disorders in patients with cryptogenic liver disease and of the effects of liver function on the endocrine system, as evidence that causally links hormonal disorders with hepatobiliary disease is reviewed.
Abstract: This article reviews evidence that causally links hormonal disorders with hepatobiliary disease, and gives particular focus to nonalcoholic steatohepatitis (NASH). The downstream mechanisms by which endocrine disturbances cause liver disease might be similar to those involved in the development of primary liver disease. Hypothyroidism, for example, might lead to NASH, cirrhosis and potentially liver cancer via the development of hyperlipidemia and obesity. Patients with growth hormone deficiency have a metabolic-syndrome-like phenotype that is also associated with the development of NASH. Polycystic ovary syndrome is a common endocrine disorder that is often associated with insulin resistance, the metabolic syndrome, altered levels of liver enzymes and the development of NASH. Recent findings support a role of dehydroepiandrosterone sulfate deficiency in the development of advanced NASH. In addition, adrenal failure is increasingly reported in patients with end stage liver disease and in patients who have received a liver transplant, which suggests a bidirectional relationship between liver and endocrine functions. Clinicians should, therefore, be aware of the potential role of endocrine disorders in patients with cryptogenic liver disease and of the effects of liver function on the endocrine system.
TL;DR: Recommendations from an international consensus meeting in Tokyo produced the most comprehensive recommendations for the diagnosis and management of acute cholangitis, enabling a more accurate diagnosis than do earlier methods and facilitating the classification of disease as mild, moderate or severe.
Abstract: Bacterial infection that occurs in the setting of biliary obstruction can lead to acute cholangitis, a condition characterized by fever, abdominal pain and jaundice. Choledocholithiasis is the most common cause of acute cholangitis and is often associated with bacterial infection and colonization in addition to biliary obstruction. Iatrogenic introduction of bacteria into the biliary system most commonly occurs during endoscopic retrograde cholangiopancreatography in patients with biliary obstruction. The majority of patients with acute cholangitis respond to antibiotic therapy, but endoscopic biliary drainage is ultimately required to treat the underlying obstruction. Acute cholangitis is often diagnosed using the clinical Charcot triad criteria; however, recommendations from an international consensus meeting in Tokyo produced the most comprehensive recommendations for the diagnosis and management of acute cholangitis. These guidelines enable a more accurate diagnosis of acute cholangitis than do earlier methods, and they facilitate the classification of disease as mild, moderate or severe. Although these guidelines represent a notable advance toward defining a universally accepted consensus for the definition of acute cholangitis, they have several limitations. This Review discusses current recommendations for the diagnosis of acute cholangitis and addresses the advantages and disadvantages of different modalities for the treatment of this disease.
TL;DR: There is now reason for optimism that the modern anticytokine therapeutic agents available for treating children and adolescents with Crohn's disease will reduce the prevalence of this otherwise common complication.
Abstract: Crohn's disease manifests during childhood or adolescence in up to 25% of patients. The potential for linear growth impairment as a complication of chronic intestinal inflammation is unique to pediatric patient populations. Insulin-like growth factor I (IGF-I), produced by the liver in response to growth hormone (GH) stimulation, is the key mediator of GH effects at the growth plate of bones. An association between impaired growth in children with Crohn's disease and low IGF-I levels is well recognized. Early studies emphasized the role of malnutrition in suppression of IGF-I production. However, a simple nutritional hypothesis fails to explain all the observations related to growth in children with Crohn's disease. The direct, growth-inhibitory effects of proinflammatory cytokines are increasingly recognized and explored. The potential role of noncytokine factors, such as lipopolysaccharides, and their potential to negatively influence the growth axis have recently been investigated with intriguing results. There is now reason for optimism that the modern anticytokine therapeutic agents available for treating children and adolescents with Crohn's disease will reduce the prevalence of this otherwise common complication. As our understanding of the mechanisms that underlie growth impairment advance, so too should the opportunity for developing further novel and targeted therapies.
TL;DR: Therapeutic options for most forms of SSC are limited, and patients with SSC who do not undergo transplantation have significantly reduced survival compared with patients with primary sclerosing cholangitis.
Abstract: Secondary sclerosing cholangitis (SSC) is a chronic cholestatic biliary disease, characterized by inflammation, obliterative fibrosis of the bile ducts, stricture formation and progressive destruction of the biliary tree that leads to biliary cirrhosis. SSC is thought to develop as a consequence of known injuries or secondary to pathological processes of the biliary tree. The most frequently described causes of SSC are longstanding biliary obstruction, surgical trauma to the bile duct and ischemic injury to the biliary tree in liver allografts. SSC may also follow intra-arterial chemotherapy. Sclerosing cholangitis in critically ill patients is a largely unrecognized new form of SSC, and is associated with rapid progression to liver cirrhosis. The mechanisms leading to cholangiopathy in critically ill patients are widely unknown; however, the available clinical data indicate that ischemic injury to the intrahepatic biliary tree may be one of the earliest events in the development of this severe form of sclerosing cholangitis. Therapeutic options for most forms of SSC are limited, and patients with SSC who do not undergo transplantation have significantly reduced survival compared with patients with primary sclerosing cholangitis. Sclerosing cholangitis in critically ill patients, in particular, is associated with rapid disease progression and poor outcome.
TL;DR: An overview of the different types of stem cell is provided, focusing on tissue-restricted adult stem cells in the fields of gastroenterology and hepatology and summarizing the potential benefits and risks of using stems cells to treat gastroenterological and liver disorders.
Abstract: Cellular and tissue regeneration in the gastrointestinal tract and liver depends on stem cells with properties of longevity, self-renewal and multipotency. Progress in stem cell research and the identification of potential esophageal, gastric, intestinal, colonic, hepatic and pancreatic stem cells provides hope for the use of stem cells in regenerative medicine and treatments for disease. Embryonic stem cells and induced pluripotent stem cells have the potential to give rise to any cell type in the human body, but their therapeutic application remains challenging. The use of adult or tissue-restricted stem cells is emerging as another possible approach for the treatment of gastrointestinal diseases. The same self-renewal properties that allow stem cells to remain immortal and generate any tissue can occasionally make their proliferation difficult to control and make them susceptible to malignant transformation. This Review provides an overview of the different types of stem cell, focusing on tissue-restricted adult stem cells in the fields of gastroenterology and hepatology and summarizing the potential benefits and risks of using stems cells to treat gastroenterological and liver disorders.
TL;DR: The majority of localized GISTs are managed via surgical resection, although a select few may be observed using serial endoscopic ultrasound examinations, and the management of incidentally discovered Gists.
Abstract: Gastrointestinal stromal cell tumors (GISTs) are the most common mesenchymal neoplasm of the gastrointestinal tract and are frequently detected on routine endoscopy. Although only approximately 10-30% of GISTs are clinically malignant, all may have some degree of malignant potential. Preoperative determination of malignancy risk can be estimated from tumor size and location, but reliable histopathologic criteria are not currently available. Given such biological uncertainty, accurate diagnosis is essential to differentiate these lesions from other truly benign, subepithelial tumors. Endoscopic ultrasound-guided fine-needle aspiration has emerged as an important procedure to secure a tissue diagnosis of a GIST. When encountering GISTs, gastroenterologists are faced with challenging management decisions, especially in the face of small, incidentally discovered lesions. The majority of localized GISTs are managed via surgical resection, although a select few may be observed using serial endoscopic ultrasound examinations. This Review provides a general overview of GISTs, with an emphasis on their endoscopic diagnosis, the management of localized disease, and the management of incidentally discovered GISTs.
TL;DR: The mechanisms of targeted therapies and clinical studies that have investigated these therapies in patients with HCC are discussed and the effectiveness of targeted therapy with monoclonal antibodies or small-molecule kinase inhibitors has now been demonstrated for the treatment of different tumors.
Abstract: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The major etiologies and risk factors for development of HCC are well defined and some steps of hepatocellular carcinogenesis have been elucidated. Despite these scientific advances and the implementation of measures for early detection of HCC in patients who are at risk of this disease, survival of patients has not improved greatly over the past three decades. This situation is partly due to the limited therapeutic options available. While surgery and percutaneous or transarterial interventions are effective for patients with limited or compensated underlying liver disease, more than 80% of patients present with multifocal HCC and/or advanced liver disease, or have comorbidities at the time of diagnosis. Treatment options for these patients have previously been limited to best supportive care. The effectiveness of targeted therapy with monoclonal antibodies or small-molecule kinase inhibitors has now been demonstrated for the treatment of different tumors. In 2007, the multitargeted kinase inhibitor, sorafenib, was found to prolong survival significantly for patients with advanced HCC. This Review discusses the mechanisms of targeted therapies and clinical studies that have investigated these therapies in patients with HCC. Perspectives for future developments are also provided.
TL;DR: No specific treatments for the gastrointestinal symptoms of systemic amyloidosis are available; however, case reports and small published series encourage nutritional support for patients with motility disorders and pharmacological agents for treatment of diarrhea.
Abstract: Systemic amyloidosis is characterized by the extracellular deposition of protein in an abnormal fibrillar form. Several different types of amyloidosis exist, each defined by the identity of their respective fibril precursor protein. Among patients with systemic amyloidosis, histological involvement of the gastrointestinal tract is very common but is often subclinical. Conversely, primary diseases of the gastrointestinal tract can cause systemic amyloidosis; for example, AA amyloidosis can occur secondary to IBD. The presence and pattern of gastrointestinal symptoms varies substantially, not only between the different types of amyloidosis but also within them. Typical clinical presentations, most of which are nonspecific, include macroglossia, hemorrhage, motility disorders, disturbance of bowel habit and malabsorption. Endoscopic and radiological features are also nonspecific, with the small intestine most commonly affected. Currently, the aim of therapy for amyloidosis is to slow amyloid formation by reducing the abundance of the fibril precursor protein. No specific treatments for the gastrointestinal symptoms of systemic amyloidosis are available; however, case reports and small published series encourage nutritional support for patients with motility disorders and pharmacological agents for treatment of diarrhea. Surgical procedures should be contemplated only in an emergency setting because of the risk of decompensation of organs affected by amyloid deposition.
TL;DR: Findings from studies in animals have revealed that small-molecule ghrelin antagonists favorably influence glucose tolerance, appetite suppression and weight loss, and strongly indicates that they should be tested in clinical trials.
Abstract: Ghrelin is a peptide hormone that possesses unique orexigenic properties. By acting on the growth-hormone secretagogue receptor 1a, ghrelin induces a short-term increase in food consumption, which ultimately induces a positive energy balance and increases fat deposition. Reduced ghrelin levels have been observed in obese patients and after bariatric surgery. In particular, bariatric procedures that involve gastric resection or bypass lead to reduced ghrelin levels. Administration of physiological doses of exogenous ghrelin to humans does not significantly alter gastric motility; however, administration of high doses stimulates gastric motility, with increased gastric tone and emptying, and increased activity of migrating motor complexes in the small bowel. The potential of ghrelin agonists to be used as prokinetics is being tested in patients with gastroparesis and postoperative ileus. Ghrelin acts directly on pancreatic islet cells to reduce insulin production. Findings from studies in animals have revealed that small-molecule ghrelin antagonists favorably influence glucose tolerance, appetite suppression and weight loss. Other studies have demonstrated that ghrelin antagonists retard gastric emptying only at very high doses, which suggests that these agents will probably not induce upper gastrointestinal symptoms. The potential of this new class of therapeutic agents to influence appetite and glycemic control strongly indicates that they should be tested in clinical trials.
TL;DR: The current understanding of osteoporosis associated with liver disease and the new advances that have been made in this field are summarized.
Abstract: Osteoporosis is a common complication of many types of liver disease. Research into the pathogenesis of osteoporosis has revealed that the mechanisms of bone loss differ between different types of liver disease. This Review summarizes our current understanding of osteoporosis associated with liver disease and the new advances that have been made in this field. The different mechanisms by which cholestatic and parenchymal liver disease can lead to reduced bone mass, the prevalence of osteopenia and osteoporosis in patients with early and advanced liver disease, and the influence of osteoporotic fractures on patient survival are discussed along with the advances in our understanding of the molecular pathways associated with bone loss. The role of the CSF1-RANKL system and that of the liver molecule, oncofetal fibronectin, a protein that has traditionally been viewed as an extracellular matrix protein are also discussed. The potential impact that these advances may have for the treatment of osteoporosis associated with liver disease is also reviewed.
TL;DR: An update on the status of acid-suppression therapy is provided and directions for future research are discussed, including potassium-competitive acid blockers, new histamine receptor 2 antagonists, and gastrin antagonists.
Abstract: The development of effective acid-suppression therapy (particularly PPIs) has revolutionized the treatment of acid-related diseases. Despite the overall effectiveness of these agents, they have some shortcomings, including a delayed onset of action, incomplete acid suppression in the majority of patients, and the need for ingestion before a meal to achieve maximal efficacy. Attempts to overcome these issues have included the development of isomeric PPIs (such as esomeprazole), alterations in drug delivery (such as delayed-release dexlansoprazole), and combined therapy with nonenterically coated PPIs and antacids (such as 'naked' omeprazole combined with sodium biocarbonate). Other acid-suppression agents in development or in late-phase trials include potassium-competitive acid blockers, new histamine receptor 2 antagonists, and gastrin antagonists. Although these agents could potentially achieve complete gastric acid suppression, risks may be associated with this level of suppression, including enteric infections and malabsorption of nutrients such as vitamin B(12), iron and calcium. This Review provides an update on the status of acid-suppression therapy and discusses directions for future research.
TL;DR: Although pegylated interferon and ribavirin are likely to remain a cornerstone of therapeutic regimens in the short term, combinations of antiviral drugs of different classes, possibly along with novel agents that target host factors and modulate viral replication or augment antiviral defenses, offer the eventual possibility of interferons-free regimens.
Abstract: Standard treatment with pegylated interferon and ribavirin only cures just over half of patients with HCV infection. Pereira and Jacobson review the evidence on the efficacy and promise of several specifically targeted antiviral therapies, which, most likely in combination with interferon and ribavirin, may improve the success rate of HCV therapy.
TL;DR: It is concluded that early endoscopy aids risk stratification of patients and reduces the need for hospitalization, however, it may also expose additional cases of active bleeding and hence increase the use of therapeuticEndoscopy.
Abstract: Early endoscopy has been advocated for the management of upper gastrointestinal bleeding, but the optimal timing for early endoscopy is still uncertain. The aim of this Review is to evaluate the optimal timing of early endoscopy by examining the findings of randomized clinical trials and retrospective cohort studies that used comparable outcome measures and have been reported in the literature. Outcome measurements included recurrent bleeding, surgery, mortality, length of hospital stay, and blood transfusion. Studies were categorized into those in which endoscopy was performed within 2-3 h, 6-8 h, 12 h or 24 h of the patient's presentation to hospital. We conclude that early endoscopy aids risk stratification of patients and reduces the need for hospitalization. However, it may also expose additional cases of active bleeding and hence increase the use of therapeutic endoscopy. No evidence exists that very early endoscopy (within a few hours of presentation) can reduce the risk of rebleeding or improve survival.
TL;DR: The ability of HCV to persist within a host is believed to be related to the numerous mechanisms by which it evades the immune response of the host.
Abstract: HCV infection is a key cause of liver disease and a worldwide health problem. The authors of this Review discuss the HCV life cycle and the mechanisms that enable the virus to evade host immune mechanisms and persist within the host. Improved understanding of HCV survival strategies should facilitate the development of effective antiviral therapies. HCV infection is an important cause of liver disease worldwide—nearly 80% of infected patients develop chronic liver disease, which leads to the development of liver cirrhosis and hepatocellular carcinoma. The ability of HCV to persist within a host is believed to be related to the numerous mechanisms by which it evades the immune response of the host. These mechanisms can be divided into defensive and offensive strategies. Examples of defensive mechanisms include replication within enclosed structures, which provides protection from the host's antiviral defenses, genetic diversity created by inaccurate replication, which yields mutants resistant to the cell's antiviral strategies, and association of the virion with protective lipoproteins. Offensive mechanisms include virally encoded proteins and other factors that disrupt the ability of the host cells to detect the virus and downregulate its ability to respond to interferon, impair innate immune defense mechanisms and alter T-cell responses, and prevent the development of an effective B-cell-mediated humoral response. Greater understanding of these viral survival strategies will ultimately translate into more effective antiviral therapies and better prognosis for patients.
TL;DR: The histology of Barrett esophagus and the gastroesophageal junction is summarized, and an overview of information necessary to interpret pathology reports from patients either with or without endoscopic evidence of Barrett Esophagus is provided to appropriately guide management of patients.
Abstract: The incidence of adenocarcinoma of the esophagus and gastroesophageal junction has increased dramatically over the past 30 years. The major precursor to this type of adenocarcinoma is Barrett esophagus, which is defined as the conversion of normal squamous epithelium into metaplastic columnar epithelium. Abundant evidence suggests that adenocarcinoma in the setting of Barrett esophagus develops via a progressive sequence of histological and molecular events. Consequently, patients with Barrett esophagus routinely undergo endoscopic surveillance for early detection of neoplasia. Histological evaluation of mucosal biopsy samples from the esophagus and gastroesophageal junction for identification of goblet cells and evaluation of the presence, grade and extent of dysplasia is the mainstay of risk assessment for these patients. This Review provides physicians with a summary of the pertinent, clinically relevant histological features of Barrett esophagus and its neoplastic complications. The histology of Barrett esophagus and the gastroesophageal junction is summarized, and an overview of information necessary to interpret pathology reports from patients either with or without endoscopic evidence of Barrett esophagus is provided to appropriately guide management of patients. Close interaction between the clinician and the pathologist is essential for proper interpretation of biopsy results and to provide optimal surveillance or treatment strategies.
TL;DR: No pathognomonic features have been identified for EoE and its diagnosis must be made on both clinical and histological grounds, so effective treatments rely on steroids and dietary exclusions.
Abstract: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory disease of undetermined pathophysiology that results in dense mucosal eosinophilia and esophageal dysfunction. In childhood, vague symptoms associated with GERD and feeding difficulties are the first manifestations of EoE. Adults typically present with dysphagia and food impaction. No pathognomonic features have been identified for EoE and, therefore, its diagnosis must be made on both clinical and histological grounds. Effective treatments rely on steroids and dietary exclusions.
TL;DR: Together, the advances in enteral access have improved patients' outcomes and led to a 70–90% reduction in the demand for total parenteral nutrition.
Abstract: The advent of total parenteral nutrition in the late 1960s meant that no situation remained in which a patient could not be fed. Unfortunately, total parenteral nutrition was complicated by serious infective and metabolic side effects that undermined the beneficial effects of nutrient repletion. Consequently, creative ways of restoring upper gut function were designed, based on semielemental diets and novel feeding tube systems. The employment of specific protocols and acceptance of increased gastric residual volumes has allowed most patients in intensive care to be fed safely and early by nasogastric tube. However, nasogastric feeding is unsuitable for patients with severely compromised gastric emptying owing to partial obstruction or ileus. Such patients require postpyloric tube placement with simultaneous gastric decompression via double-lumen nasogastric decompression and jejunal feeding tubes. These tubes can be placed endoscopically 40-60 cm past the ligament of Treitz to enable feeding without pancreatic stimulation. In patients whose disorders last more than 4 weeks, tubes should be repositioned percutaneously, by endoscopic, open or laparoscopic surgery. Together, the advances in enteral access have improved patients' outcomes and led to a 70-90% reduction in the demand for total parenteral nutrition.
TL;DR: This Review focuses on data from studies that investigated the risk factors for recurrent attacks of acute pancreatitis, and discusses the late consequences of this disease.
Abstract: Research into the clinical management of acute pancreatitis has primarily focused on the immediate complications of the disease, whereas its late consequences have received less attention. These late sequelae of acute pancreatitis refer to complications that arise after the convalescence period, which lasts for 3-6 months after the initial episode. In patients who do not undergo necrosectomy that involves removal of the exocrine gland, pancreatic exocrine function usually improves rather than deteriorates during follow-up. By contrast, glucose intolerance is likely to worsen over time in all patients with acute pancreatitis. Despite the risk of late complications for patients with acute pancreatitis, their long-term quality of life is usually good. The number of pancreatitis episodes a patient has experienced is an important factor that determines the severity of late complications of acute pancreatitis. Risk factors for the recurrence of acute pancreatitis episodes have now been identified. This Review focuses on data from studies that investigated the risk factors for recurrent attacks of acute pancreatitis, and discusses the late consequences of this disease.