The liver is a complex immunological organ. It has both immunogenic and tolerogenic capacity. Tolerogenic potential of human liver with its protective firewalls is required to guard the body against the continuous influx of microbial product from the gut via the sinusoids and biliary tree. Immunotolerance and anergic state is maintained by a combined effort of both immune cells, parenchyma cells, epithelial and endothelial cells. Despite this, an unknown trigger can ignite the pathway towards breakdown in hepatic tolerance leading to autoimmune liver diseases. Understanding the initial stimulus which causes the hepatic immune system to switch from the regulatory arm towards self-reactive effector arm remains challenging. Dissecting this pathology using the current technological advances is crucial to develop curative immune based therapy in autoimmune liver diseases. We discuss the hepatic immune cells and non-immune cells which maintain liver tolerance and the evidence of immune system barrier breach which leads to autoimmune hepatitis, primary biliary cholangitis and primary sclerosing cholangitis.

Technologic advancements in the field of therapeutic endoscopy have led to the development of minimally invasive techniques to create gastrointestinal anastomosis instead of surgical interventions. Examples of the potential clinical applications include bypassing malignant and benign gastric outlet obstruction, providing access to the pancreato-biliary tree in those who have undergone Roux-en-Y gastric bypass, and relieving pancreato-biliary symptoms in afferent loop syndrome. Starting from the available literature, aim of this narrative review is to summarize indications and techniques of endoscopic ultrasonography-guided visceral anastomoses. A critical review of literature on the new EUS-guided anastomoses. Increasing evidence is accumulating demonstrating advantages of EUS guided visceral anastomoses. These new procedures represent a novel, minimally invasive alternative for managing different type of intestinal obstruction.

Eosinophilic esophagitis is a chronic disease whose incidence and prevalence are increasing, based on a genetic-driven interaction between environment and immune system. Several gene loci involved in the development of the disease have been identified. A two-step mechanism has been hypothesized: a thymic stromal lymphopoietin-induced allergic sensitization followed by upregulation of CAPN14-related esophageal-specific pathways. Environment seems to have a larger effect than genetic variants. Factors that could play a role are allergens, drugs, colonizing bacteria and possibly Helicobacter Pylori infection. Acting on these modifiable risk factors may be a tool to prevent the disease. EoE is characterized by a typical eosinophilic infiltrate limited to the esophageal epithelium, supported by a Th2-mediated immune response, found in other atopic conditions. The key of the pathogenesis is the disfunction of the epithelial barrier which allow the interaction between allergens and inflammatory cells. Eosinophilic-predominant inflammation leads to the typical wall remodeling, histologically characterized by epithelial and smooth muscle hyperplasia, lamina propria fibrosis and neo-angiogenesis. These alterations find their clinical expression in the pattern of symptoms: dysphagia, food impaction, chest pain, heartburn.

The early detection of pancreatic ductal adenocarcinoma (PDAC) dramatically improves outcome. All available state-of-the-art imaging methods allow early detection with EUS being the best technique for exclusion of PDAC and detection of very early PDAC. Etiological differentiation of small SPL is important to guide individually tailored patients' management including radical surgery in resectable PDAC, medical (neoadjuvant or palliative intended) treatment in patients with non-resectable malignancy, pancreatic parenchyma saving strategies in some non-PDAC, and follow-up in particular in low-grade PanNEN or other small benign lesions. Multimodality EUS imaging including B-Mode assessment, elastography, contrast-enhancement and EUS-guided sampling is the most appropriate technique for diagnosis and risk assessment of small SPL. We present a review discussing modern (endoscopic) ultrasound imaging techniques including contrast enhanced ultrasound and elastography for the early detection and characterization of solid pancreatic lesions.

Primary sclerosing cholangitis (PSC) is a chronic liver disorder commonly affecting young patients and associated with uncertain prognosis and elevated risk of end-stage liver disease and hepatobiliary cancer. Rate of progression in PSC is heterogeneous and accurately predicting the disease course is of paramount importance to clinical practice and interventional trial design. So far, efforts have brought to the development of models looking at short-to-middle-term outcome using composite models including clinical, laboratory, radiological and histological parameters with limited performance. In the era of whole genome sequencing and digital innovation, the time is ripe for the development of stratified medicine in PSC. Efforts should be directed toward developing well-phenotyped cohorts of patients with longitudinal follow-up across sustained periods of time, application of novel image-processing technology, and biomarker discovery using multiomics platforms.

Up to 30-70% of patients may experience mild and moderate side effects during iron therapy and this is often associated with a poor adherence to therapy. Anemia is frequent in patients with active inflammatory bowel disease (IBD), due to both iron deficiency and chronic inflammation, therefore iron supplementation is frequently needed. Considering that gastrointestinal disorders are the most common side effects with oral iron, in IBD patients intravenous administration must be preferred. Although intravenous iron supplementation remains the most effective therapy of IBD-associated iron deficiency anemia, the perception of risk related to intravenous administration by clinicians could limit this successful strategy. In this narrative review we provided an up to date on the safety of the different iron formulations for intravenous administration, by reporting the most recent studies in IBD patients.

In recent years, there has been growing interest in the comprehension of the physiology of intestinal permeability and microbiota; and how these elements could influence the pathogenesis of diseases. The term intestinal permeability describes all the processes that allow the passage of molecules as water, electrolytes and nutrients through the intestinal barrier by the paracellular or the transcellular transport systems with several implications for self-tolerance and not-self immunity. An increased permeability might induce a more significant interaction of the immune system with unknown external antigens. This might favor the onset of several immune-related extra-intestinal diseases including coeliac disease, diabetes mellitus type 1, bronchial asthma and inflammatory bowel diseases. Furthermore, the intestinal permeability interacts every day with microbiota, the complex system of mutualistic inhabitants and commensal microorganisms living in the healthy gut. Microbiota is implicated in physiological functions by actively participating in digestion, absorption, synthesis of vitamins and protection from external aggressions. The critical site where these processes occur is the small intestine to which this updated review is dedicated. Understanding its anatomy, its barrier structure and permeability modulation and its microbiota composition is the essential skill to comprehend the complex pathogenesis of several - not only gastroenterological - diseases.

Autoimmune hepatitis (AIH) is a rare autoimmune disease of the liver with many open questions as regards its etiopathogenesis, natural history and clinical management. The classical picture of AIH is chronic hepatitis with fluctuating elevation of serum transaminases and Immunoglobulin G levels, the presence of circulating autoantibodies and typical histological features. However, atypical presentations do occur and are not well captured by current diagnostic scores, with important consequences in terms of missed diagnoses and delayed treatments. AIH is treated with corticosteroids and immunosuppressive drugs but up to 40% of patients do not achieve full biochemical response and are at risk of progressing to cirrhosis and liver failure. Moreover, standard therapies are associated by significant side-effects which may impair the quality of life of patients living with AIH. However, advances in the understanding of the underlying immunology of AIH is raising the prospect of novel therapies and optimization of existing therapeutic approaches to reduce side-effect burdens and potentially restore immunological tolerance. In this review we outlined the clinical characteristics, etiopathogenesis and management of AIH and current challenges in the diagnosis and management of AIH and provided evidence underlying the evolution of diagnostic and clinical management protocols.

Eosinophilic esophagitis (EoE) is a clinicopathological disease defined by symptoms of esophageal dysfunction and ≥15 eosinophils/HPF after excluding other causes of esophageal eosinophilia. Increasing attention has been paid by clinicians and researchers after its first description in 1978. Many consensuses and guidelines have been issued over the years, as gastroenterologists did not reach an agreement on EoE definition, especially regarding the controversial responsiveness to proton pump inhibitor (PPI) therapy. Of note, recent evidence suggests that the incidence and prevalence of EoE have been increasing through the years: many risk factors have been advocated as possible reasons for this, although further studies are needed. In this brief review, we will first cover the history of EoE in the literature, with a focus on its varying definition throughout the years. Then, we will discuss EoE epidemiology, emphasizing potential risk factors explaining its increasing incidence and prevalence. Last, we will deal with the quality of life of adult and pediatric patients with EoE.

Dietary elimination therapy has been for a long time an option for patients with eosinophilic esophagitis (EoE) and remains the only therapy targeting the cause of the disease. Different dietary approaches have been described along the last 3 decades, and cumulative evidence has defined the effectiveness and usefulness of each approach. Elemental diets are highly effective to induce EoE remission, but unpractical in most patients. Allergy testing-directed food restrictions resulted inefficient to induce remission in a significant proportion of patients (especially adults) and show a low concordance with the dietary causes of EoE. Empiric elimination diets are currently considered the most effective drug-free treatment for patients of all ages with EoE, after widely providing reproducible results. Highly restrictive empiric six-food elimination diets have paved the way to most efficient and less restrictive step-up approaches, which now include four-food and two-food elimination diets. The potential role of milk-elimination, especially in children, should be also considered. Multiple factors including demographics, nutritional status, patient and family lifestyles, social and financial support, and acceptance of repeated endoscopies influence the results of dietary therapy. Dietary therapy in EoE should be patient centered, and the patients and/or their families together with the medical provider should participate in the decision to set up this treatment. This article updates recent knowledge on dietary therapy for EoE and provides guideline to choose the most suitable alternative for patients with EoE, as well as practical tips to achieve the best results in clinical practice.

The term IgG4-related autoimmune liver disease (AILD) refers to hepato-biliary manifestations of Immunoglobin G4-related disease (IgG4-RD) including IgG4-related sclerosing cholangitis and IgG4-related pseudotumor. The association of some forms of autoimmune hepatitis to IgG4-RD remains controversial. Although autoimmune phenomena have not been clearly observed in IgG4-AILD, perturbation of the adaptive immune system and activation of the humoral response represent established pathophysiological hallmarks and potential therapeutic targets. Clinical manifestations of IgG4-AILD are virtually indistinguishable from bile duct cancer or primary sclerosing cholangitis and are due to mass forming lesions and thickening of the biliary tract that progressively lead to biliary ducts obstruction. There are no current reliable biomarkers for IgG4-AILD and diagnosis should rely on the integration of clinical, serological, radiological, and histological findings. In analogy to most IgG4-RD manifestations, and in contrast to its major mimickers, IgG4-AILD promptly responds to glucocorticoids but frequently relapses, thus requiring long-term maintenance therapy to avoid progressive fibrosclerotic disease and liver cirrhosis. Accumulating evidence on the efficacy of B-cell depletion therapy in patients with systemic IgG4-RD is gradually changing the treatment paradigm of IgG4-AILD and biologics will be increasingly used also for gastroenterological manifestations of IgG4-RD to spare glucocorticoids and traditional immunosuppressive agents. Looking ahead, identification of reliable biomarkers and of mini-invasive strategies to obtain informative biopsies from the biliary tree represent unavoidable priorities to optimize diagnosis and management of IgG4-AILD.

Endoscopy plays an important role in the management of eosinophilic esophagitis (EoE), since it is involved in the diagnosis, follow-up and treatment of this condition. In patients presenting with food impaction, dysphagia and other symptoms of suspected EoE, esophago-gastric-duodenoscopy (EGD) with multiple esophageal biopsies should be performed to confirm or rule out the diagnosis of EoE. The EREFS system, a validated instrument for assessment of the endoscopically-identified esophageal features in EoE (edema, rings, exudates, longitudinal furrows and strictures), is currently used in the clinical practice for the evaluation of the macroscopic aspects of esophageal mucosa during EGD. Multiple esophageal biopsies are mandatory to further confirm EoE diagnosis and subsequent response to treatment, since symptoms reported by patients do not always correlate with histological activity, and considering the low sensitivity of endoscopic assessment; a cut-off of ≥15 eosinophils in at least one high power field is the density threshold considered the standard for diagnosis (sensitivity 100%, specificity 96%). Other histological features, included in the EoE histologic scoring system (EoEHSS), are supportive for the diagnosis and for the assessment of inflammatory activity during follow-up. Esophageal dilation, performed either with Savary dilators/bougie or hydrostatic balloon, is an effective and safe treatment in both adult and pediatric EoE patients with fibrostenotic features, mainly in association with other therapeutic strategies which can control eosinophilic inflammation.

Eosinophilic esophagitis (EoE) incidence and prevalence have sharply increased in the last decade; so, the management of these patients is changing rapidly. Standard regimens as elimination diet, proton pump inhibitors and topical swallowed steroids are not able to achieve remission in all patients. Moreover, loss of efficacy and safety concerns for long-term medical treatments are rising questions. As for other chronic immune-mediated diseases, biologics have been evaluated for the treatment of EoE. Several targets in the Th2-mediated inflammatory cascade with eosinophilic mucosal infiltration, have been tested with alternating results. This review provides a comprehensive discussion of the available studies evaluating biologics in EoE and the possible future options most desirable for these patients.