Liver diseases in pregnancy: Diseases unique to pregnancy

Pregnancy is a special clinical state with several normal physiological changes that influence body organs including the liver.Liver disease can cause significant morbidity and mortality in both pregnant women and their infants.This review summarizes liver diseases that are unique to pregnancy.We discuss clinical conditions that are seen only in pregnant women and involve the liver;from Hyperemesis Gravidarum that happens in 1out of 200 pregnancies and Intrahepatic Cholestasis of Pregnancy(0.5%-1.5%prevalence),to the more frequent condition of preeclampsia(10%prevalence)and its severe form;hemolysis,elevated liver enzymes,and a low platelet count syndrome(12%of pregnancies with preeclampsia),to the rare entity of Acute Fatty Liver of Pregnancy(incidence of 1 per 7270 to 13000deliveries).Although pathogeneses behind the development of these aliments are not fully understood,theories have been proposed.Some propose the special physiological changes that accompany pregnancy as a precipitant.Others suggest a constellation of factors including both the mother and her fetus that come together to trigger those unique conditions.Reaching a timely and accurate diagnosis of such conditions can be challenging.The timing of the condition in relation toward which trimester it starts at is a key.Accurate diagnosis can be made using specific clinical findings and blood tests.Some entities have well-defined criteria that help not only in making the diagnosis,but also in classifying the disease according to its severity.Management of these conditions range from simple medical remedies to measures such as immediate termination of the pregnancy.In specific conditions,it is prudent to have expert obstetric and medical specialists teaming up to help improve the outcomes.     

Mucosal healing and deep remission: What does it mean?

The use of specific terms under different meanings and varying definitions has always been a source of confusion in science.When we point our efforts towards an evidence based medicine for inflammatory bowel diseases(IBD)the same is true:Terms such as"mucosal healing"or"deep remission"as endpoints in clinical trials or treatment goals in daily patient care may contribute to misconceptions if meanings change over time or definitions are altered.It appears to be useful to first have a look at the development of terms and their definitions,to assess their intrinsic and context-independent problems and then to analyze the different relevance in present-day clinical studies and trials.The purpose of such an attempt would be to gain clearer insights into the true impact of the clinical findings behind the terms.It may also lead to a better defined use of those terms for future studies.The terms"mucosal healing"and"deep remission"have been introduced in recent years as new therapeutic targets in the treatment of IBD patients.Several clinical trials,cohort studies or inception cohorts provided data that the long term disease course is better,when mucosal healing is achieved.However,it is still unclear whether continued or increased therapeutic measures will aid or improve mucosal healing for patients in clinical remission.Clinical trials are under way to answer this question.Attention should be paid to clearly address what levels of IBD activity are looked at.In the present review article authors aim to summarize the current evidence available on mucosal healing and deep remission and try to highlight their value and position in the everyday decision making for gastroenterologists.     

Proteomic insights on the metabolism in inflammatory bowel disease

Inflammatory bowel diseases(IBD)are chronic and relapsing inflammatory conditions of the gut that include Crohn's disease and ulcerative colitis.The pathogenesis of IBD is not completely unraveled,IBD are multi-factorial diseases with reported alterations in the gut microbiota,activation of different immune cell types,changes in the vascular endothelium,and alterations in the tight junctions’structure of the colonic epithelial cells.Proteomics represents a useful tool to enhance our biological understanding and to discover biomarkers in blood and intestinal specimens.It is expected to provide reproducible and quantitative data that can support clinical assessments and help clinicians in the diagnosis and treatment of IBD.Sometimes a differential diagnosis of Crohn's disease and ulcerative colitis and the prediction of treatment response can be deducted by finding meaningful biomarkers.Although some non-invasive biomarkers have been described,none can be considered as the“gold standard”for IBD diagnosis,disease activity and therapy outcome.For these reason new studies have proposed an“IBD signature”,which consists in a panel of biomarkers used to assess IBD.The above described approach characterizes“omics”and in this review we will focus on proteomics.     

Diet therapy for inflammatory bowel diseases: The established and the new

Although patients with inflammatory bowel diseases(IBD) have a strong interest in dietary modifications as part of their therapeutic management, dietary advice plays only a minor part in published guidelines. The scientific literature shows that dietary factors might influence the risk of developing IBD, that dysbiosis induced by nutrition contributes to the pathogenesis of IBD, and that diet may serve as a symptomatic treatment for irritable bowel syndrome-like symptoms in IBD. The role of nutrition in IBD is underscored by the effect of various dietary therapies. In paediatric patients with Crohn’s disease(CD) enteral nutrition(EN) reaches remission rates similar to steroids. In adult patients, however, EN is inferior to corticosteroids. EN is not effective in ulcerative colitis(UC). Total parenteral nutrition in IBD is not superior to steroids or EN. The use of specific probiotics in patients with IBD can be recommended only in special clinical situations. There is no evidence for efficacy of probiotics in CD. By contrast, studies in UC have shown a beneficial effect in selected patients. For patients with pouchitis, antibiotic treatment followed by probiotics, like VSL#3 or Lactobacillus GG, is effective. When probiotics are used, the risk of bacterial translocation and subsequent bacteremia has to be considered. More understanding of the normal intestinal microflora, and better characterization of probiotic strains at the phenotypic and genomic levels is needed as well as clarification of the mechanisms of action in different clinical settings. A FODMAP reduced diet may improve symptoms in IBD.     

Enteric bacterial proteases in inflammatory bowel diseasepathophysiology and clinical implications

Numerous reports have identified a dysbiosis in the intestinal microbiota in patients suffering from inflammatory bowel diseases(IBD),yet the mechanism(s)in which this complex microbial community initiates or perpetuates inflammation remains unclear.The purpose of this review is to present evidence for one such mechanism that implicates enteric microbial derived proteases in the pathogenesis of IBD.We highlight and discuss studies demonstrating that proteases and protease receptors are abundant in the digestive system.Additionally,we investigate studies demonstrating an association between increased luminal protease activity and activation of protease receptors,ultimately resulting in increased intestinal permeability and exacerbation of colitis in animal models as well as in human IBD.Proteases are essential for the normal functioning of bacteria and in some cases can serve as virulence factors for pathogenic bacteria.Although not classified as traditional virulence factors,proteases originating from commensal enteric bacteria also have a potential association with intestinal inflammation via increased enteric permeability.Reports of increased protease activity in stools from IBD patients support a possible mechanism for a dysbiotic enteric microbiota in IBD.A better understanding of these pathways and characterization of the enteric bacteria involved,their proteases,and protease receptors may pave the way for new therapeutic approaches for these diseases.     

Role of genetics in prediction of disease course and response to therapy

The clinical course of Crohn's disease and ulcerative colitis is highly variable between patients,and this has therapeutic implications.A number of clinical features have been identified,which predict a mild or more severe outcome.However,several of these are subjective and/or not persistent over time.With the progress in genetics research in inflammatory bowel disease(IBD),genetic markers are increasingly being proposed to improve stratification of patients.Genetics have the major advantage of being stable...     

Transumbilical endoscopic surgery: History, present situation and perspectives

Transumbilical endoscopic surgery or laparo-endoscopic single site(LESS)surgery has become an exciting area of surgical development as innovation continues to move in the 21st century to minimally invasive surgery.The history,present situation and perspectives are reviewed and the nomenclature of this technique is discussed in this article.The range of this technique has been applied in almost all abdominal diseases,surgeries for morbid obesity,hernia and so on,in recent years.It is estimated that 50%-80%of traditional laparoscopic surgery could be performed transumbilically in the next five years according to the LESSCAR consensus.Although the concept of transumbilical laparoscopic surgery is gaining traction rapidly and the instruments have been improved greatly, we should not advocate for slightly improved cosmetic value over safety.Multicenter,randomized and clinical trials are necessary to further elucidate the safety and efficiency of this new technique.Research that examines the efficacy of the new instruments on the market may be helpful to simplify the confusing landscape of new and novel products designed for this purpose.     

Effect of probiotic administration on the intestinal microbiota,current knowledge and potential applications

Although it is now known that the human body is colonized by a wide variety of microbial populations in different parts(such as the mouth, pharynx and respiratory system, the skin, the gastro- and urogenital tracts), many effects of the complex interactions between the human host and microbial symbionts are still not completely understood. The dysbiosis of the gastrointestinal tract microbiota is considered to be one of the most important contributing factors in the development of many gastrointestinal diseases such as inflammatory bowel disease, irritable bowel syndrome and colorectal cancer, as well as systemic diseases like obesity, diabetes, atherosclerosis and non-alcoholic fatty liver disease. Fecal microbial transplantations appear to be promising therapies for dysbiosis-associated diseases; however, probiotic microorganisms have been growing in popularity due to increasing numbers of studies proving that certain strains present health promoting properties, among them the beneficial balance of the intestinal microbiota. Inflammatory bowel diseases andobesity are the pathologies in which there are more studies showing this beneficial association using animal models and even in human clinical trials.In this review,the association of the human gut microbiota and human health will be discussed along with the benefits that probiotics can confer on this symbiotic activity and on the prevention or treatment of associated diseases.     

Contribution of genetics to a new vision in the understanding of inflammatory bowel disease

Inflammatory bowel diseases (IBD), such as Crohn' s disease (CD) and ulcerative colitis (UC), are chronic inflammatory autoimmune conditions of the gastrointestinal tract. Other organs, such as the eyes, skin and articulations, are often affected and IBD may be accompanied by other diseases of autoimmune origin. There is no single etiological factor responsible for the onset of IBD. Recent advances in genetics and in the molecular mechanisms of the proteins coded by these genes have given rise to a new vision in understanding these complex diseases. Activation of specific genes that affect antigen presentation and the handling of cells by innate immunity may lead to autoimmunity with the consequent activation of the major histocompatibility complex (MHC) and multiple cytokines involved in the regulation of acquired immunity. In this review IBD is described as a constellation of diseases that can best be classified as barrier diseases. This vision, developed by Kiel in Germany, includes the idea that changes in our environment due to the westernization of civilization have not been met with adaptation of the innate immune system, and this has given rise to autoimmune diseases. These diseases affect 1-5 of 1000 individuals and represent a major burden on the national health systems of many countries on different continents. On a world scale, a major challenge is to generate interventions to prevent the development of these diseases in Asia, Latin America and Africa.     

The role of the gut and microbes in the pathogenesis of spondyloarthritis

The intestinal microbiota is firmly implicated not only in the pathogenesis of inflammatory bowel disease (IBD) but increasingly also in the development of inflammation at extraintestinal tissue sites. Significant clinical, genetic, immunological, and microbiological overlap exists between IBD and spondyloarthritis (SpA), which indicates that pathophysiological mechanisms are shared between these diseases and may center on the intestinal microbiota. Recently, culture-independent techniques have enabled the microbiota in health and disease to be described in increasing detail. Moreover, functional studies have identified myriad host effector and regulatory pathways that shape or are shaped by this microbial community. We consider the complex relationship between SpA pathogenesis and gut microbes, with a discussion of how manipulation of the gut microbiota itself may be a promising future target for SpA therapy.     

Non-pulmonary allergic diseases and inflammatory bowel disease: A qualitative review

While the etiological underpinnings of inflammatory bowel disease(IBD) are highly complex, it has been not-ed that both clinical and pathophysiological similarities exist between IBD and both asthma and non-pulmonary allergic phenomena. In this review, several key points on common biomarkers, pathophysiology, clinical manifesta-tions and nutritional and probiotic interventions for both IBD and non-pulmonary allergic diseases are discussed.Histamine and mast cell activity show common behav-iors in both IBD and in certain allergic disorders. IgE also represents a key immunoglobulin involved in both IBD and in certain allergic pathologies, though these links require further study. Probiotics remain a critically important intervention for both IBD subtypes as well as multiple allergic phenomena. Linked clinical phenomena, especially sinonasal disease and IBD, are discussed. In addition, nutritional interventions remain an underuti-lized and promising therapy for modification of both al-lergic disorders and IBD. Recommending new mothers breastfeed their infants, and increasing the duration of breastfeeding may also help prevent both IBD and al-lergic diseases, but requires more investigation. While much remains to be discovered, it is clear that non-pulmonary allergic phenomena are connected to IBD in a myriad number of ways and that the discovery of com-mon immunological pathways may usher in an era of vastly improved treatments for patients.     

From the surface to the single cell: Novel endoscopic approaches in inflammatory bowel disease

Inflammatory bowel diseases(IBD) comprise the two major entities Crohn's disease and ulcerative colitis and endoscopic imaging of the gastrointestinal tract has always been an integral and central part in the management of IBD patients. Within the recent years,mucosal healing emerged as a key treatment goal in IBD that substantially decides about the clinical outcome of IBD patients,thereby demanding for a precise,timely and detailed endoscopic assessment of the mucosal inflammation associated with IBD. Further,molecular imaging has tremendously expanded the clinical utility and applications of modern endoscopy,now encompassing not only diagnosis,surveillance,and treatment but also the prediction of individual therapy response. Within this review we describe novel endoscopic approaches and advanced endoscopic imaging methods for the diagnosis,treatment and surveillance of IBD patients. We begin by providing an overview over novel and advanced imaging techniques such as magnification endoscopy and dye-based and dye-less chromoendoscopy,endomicroscopy and endocytoscopy. We then describe how these techniques can be utilized for the precise and ultrastructural assessment of mucosal inflammation and dysplasia development associated with IBD and outline how they have enabled the endoscopist to gain insight onto the cellular level in real-time. Finally,we provide an outlook on how molecular imaging has rapidly evolved in the recent past and can be used to make individual predictions about the therapeutic response towards biological treatment.     

Combined therapeutic approach： Inflammatory bowel diseases and peripheral or axial arthritis

Inflammatory bowel diseases （IBDs）, particularly Crohn＇s disease （CD） and ulcerative colitis （UC）, are associated with a variety of extra-intestinal manifestations （EIMs）. About 36% of IBD patients have at least one EIM, which most frequently affect the joints, skin, eyes and the biliary tract. The EIMs associated with IBD have a negative impact on patients with UC and CD, and the resolution of most of them parallels that of the active IBD in terms of timing and required therapy; however, the clinical course of EIMs such as axial arthritis, pyoderma gangrenosum, uveitis, and primary sclerosing cholangitis is independent of IBD activity. The peripheral and axial arthritis associated with IBD have traditionally been treated with simple analgesics, non-steroidal anti-inflammatory drugs, steroids, sulfasalazine, methotrexate, local steroid injections and physiotherapy, but the introduction of biological response modifiers such as tumor necrosis factor-α blockers, has led to further improvements.     

Gene and cell therapy based treatment strategies for inflammatory bowel diseases

Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders most commonly affecting young adults. Currently available therapies can result in induction and maintenance of remission, but are not curative and have sometimes important side effects. Advances in basic research in IBD have provided new therapeutic opportunities to target the inflammatory process involved. Gene and cell therapy approaches are suitable to prevent inflammation in the gastrointestinal tract and show therefore potential in the treatment of IBD. In this review, we present the current progress in the field of both gene and cell therapy and future prospects in the context of IBD. Regarding gene therapy, we focus on viral vectors and their applications in preclinical models. The focus for cell therapy is on regulatory T lymphocytes and mesenchymal stromal cells, their potential for the treatment of IBD and the progress made in both preclinical models and clinical trials.     

Applications of proteomics in the study of inflammatory bowel diseases: Current status and future directions with available technologies

Inflammatory bowel diseases (IBD) are chronic, heterogeneous, and multifactorial intestinal inflammatory disorders. Major challenges in IBD research include identification of major pathogenic alterations of genes/proteins as well as effective biomarkers for early diagnosis, prognosis, and prediction of therapeutic response. Since proteins govern cellular structure and biological function, a wide selection of proteomic approaches enables effective characterization of IBD pathogenesis by investigating the dynamic nature of protein expression, cellular and subcellular distribution, posttranslational modifications, and interactions at both the cellular and subcellular levels. The aims of this review are to 1) highlight the current status of proteomic studies of IBD, and 2) introduce the available and emerging proteomic technologies that have potential applications in the study of IBD. These technologies include various mass spectrometry technologies, quantitative proteomics (2D-PAGE, ICAT, SILAC, iTRAQ), protein/antibody arrays, and multi-epitope-ligand cartography. This review also presents information and methodologies, from sample selection and enrichment to protein identification, that are not only essential but also particularly relevant to IBD research. The potential future application of these technologies is expected to have a significant impact on the discovery of novel biomarkers and key pathogenic factors for IBD.     

Increased frequency of autoimmune diseases in patients with primary sclerosing cholangitis

OBJECTIVES: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin that mostly affects male patients with inflammatory bowel disease (IBD). The immune system is believed to be involved in the etiology/pathogenesis as these patients present with several immunological disturbances. Susceptibility to develop primary sclerosing cholangitis is partly determined by genes in the HLA complex. The aim of this study was to compare the prevalence of autoimmune disorders in IBD patients with and without PSC and to correlate the presence of autoimmune disorders in PSC to outcome and HLA association. METHODS: One hundred nineteen PSC patients were included in the study. Each PSC patient with IBD was matched to a IBD patient without PSC. The presence of autoimmune disorders was carefully evaluated in each group. Moreover, comparisons between PSC patients with and without autoimmune disorders were performed. RESULTS: Twenty-five percent of the PSC patients had at least one autoimmune disorder outside the liver and colon compared to 9% in the IBD group without PSC (p < 0.005). Nine of the PSC patients had two or more autoimmune diseases compared to only one patient in the IBD group (p < 0.02). The PSC patients with and without associated autoimmune disease did not differ in clinical presentation, outcome of PSC or HLA alleles. A significant overrepresentation of DRB1*03 was still present after excluding PSC patients with concomitant autoimmune diseases outside the liver and colon compared to a healthy Swedish control group. CONCLUSIONS: Autoimmune disorders are more frequent among PSC patients compared to IBD patients without liver disease. Associated autoimmune diseases in PSC patients does not influence the outcome or clinical presentation of PSC.     

Crucial steps in the natural history of inflammatory bowel disease

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.     

Challenges in animal modelling of mesenchymal stromal cell therapy for inflammatory bowel disease

Utilization of mesenchymal stromal cells(MSCs) for the treatment of Crohn's disease and ulcerative colitis is of translational interest.Safety of MSC therapy has been well demonstrated in early phase clinical trials but efficacy in randomized clinical trials needs to be demonstrated.Understanding MSC mechanisms of action to reduce gut injury and inflammation is necessary to improve current ongoing and future clinical trials.However, two major hurdles impede the direct translation of data derived from animal experiments to the clinical situation:(1) limitations of the currently available animal models of colitis that reflect human inflammatory bowel diseases(IBD).The etiology and progression of human IBD are multifactorial and hence a challenge to mimic in animal models; and(2) Species specific differences in the functionality of MSCs derived from mice versus humans.MSCs derived from mice and humans are not identical in their mechanisms of action in suppressing inflammation.Thus, preclinical animal studies with murine derived MSCs cannot be considered as an exact replica of human MSC based clinical trials.In the present review, we discuss the therapeutic properties of MSCs in preclinical and clinical studies of IBD.We also discuss the challenges and approaches of using appropriate animal models of colitis, not only to study putative MSC therapeutic efficacy and their mechanisms of action, but also the suitability of translating findings derived from such studies to the clinic.     

Prevention and management of infectious complications in IBD

In an era of increasing use of immunomodulating therapy and biologics, opportunistic infections have emerged as a pivotal safety concern for patients with IBD. Clinical studies, registries and case reports warn of the increased risk of infection, particularly opportunistic infections. The current challenge to physicians lies not only in managing IBD, but also in recognizing, preventing and treating common and uncommon infections. The European Crohn's and Colitis Organization (ECCO) guidelines on the management and prevention of opportunistic infections in patients with IBD provide clinicians with guidance on the prevention, detection and management of such infections. The proposals therein may appear radical, potentially changing current practice, but we believe that these recommendations will help optimize patient outcome by reducing the morbidity and mortality related to these infections. In this ongoing process, prevention is by far the most important step; this relies on the recognition of risk factors for infection, the use of primary or secondary chemoprophylaxis, careful monitoring (clinical and laboratory work-up) before and during use of immunomodulators and the vaccination and education of the patient. Special recommendations should also be given to patients before and after travelling. Management of infection in IBD patients is case-dependent. Severe infection should be treated according to advice from infectious-disease experts.