Inflammatory Bowel Diseases 2024-2025 PDF

uplogo UNIVERSITY OF PERUGIA DEPARTMENT OF MEDICINE Master’s Degree in Medical, Veterinary and Forensic Biotechnological Science Academic Year 2024/2025 Digestive System Diseases...

uplogo UNIVERSITY OF PERUGIA DEPARTMENT OF MEDICINE Master’s Degree in Medical, Veterinary and Forensic Biotechnological Science Academic Year 2024/2025 Digestive System Diseases IBDs Inflammatory Bowel Diseases Monia Baldoni  IBD DEFINITION  Inflammatory bowel diseases (IBDs) are chronic systemic inflammatory disorders, that are typically classified in two subtypes: Crohn's Disease (CD) and Ulcerative Colitis (UC).  These conditions target primarily the gastrointestinal tract but can affect many organ systems through extraintestinal manifestations.  Crohn’s disease is characterized by the involvement of the gastrointestinal tract from mouth to anus in a discontinuous fashion, with the development of strictures, abscesses, or fistulas that penetrate neighboring organs or the perianal skin.  Unlike in Crohn's disease, gut inflammation in ulcerative colitis affects only the colon and rectum.  Each of them is a lifelong disease, characterized by recurrent episodes of diarrhea, often bloody, with abdominal pain, malaise, and weight loss. INFLAMMATORY BOWEL DISEASES  Crohn’s Disease (CD)  Ulcerative Colitis (UC)  Indeterminate colitis (IC) UC IC CD Microscopic Colitis CROHN’S DISEASE Crohn's disease, first described in 1932 by the gastroenterologist B.B. Crohn (1884-1983), is a recurrent chronic inflammatory disease of the intestine, of unknown etiology, characterized by a typically focal and segmental inflammatory process, generally transmural, which can affect any tract of the alimentary canal from the mouth to the anus  ULCERATIVE COLITIS UC was the first subtype of Ulcerative colitis is an inflammatory bowel disease (IBD) to be characterized as a distinct idiopathic inflammatory entity. Thus, the early history of IBD disease characterized by is the history of UC. But this is not to say that UC appeared before recurring episodes of a Crohn's disease (CD) — both inflammation limited to the conditions were likely afflicting patients long before modern mucosal layer of the colon. medicine was able to distinguish It commonly involves the them. Sir Samuel Wilks (1824– 1911), in a case report written in rectum and may extend in a 1859, was the first physician who proximal and continuous used the term “ulcerative colitis” to describe a condition similar to what fashion to involve other parts is understood as UC today of the colon. The Global Increase of Inflammatory Bowel Disease Samuel Wilks Gilead G. Kaplan et al, Understanding and Preventing the Global Increase of Inflammatory Bowel Disease - Gastroenterology 2017 The interplay and determinants of IBD incidence, prevalence and mortality. Incidence Ranges for IBD since 2000 – the end of the second stage - in regions in the Western world 6-11 CD 6-15 UC 12-26 collectivelly  Incidence of IBD in Europe Burish J t al, GUT, 2014 – EpiCom Study The most recent date show that the incidence of CD in Europe ranges from 0.4 to 22.8 cases per 100,000 person-years while the incidence of UC was generally higher ranging between 2.4 to 44.00 per 100,000 person-years. The highest incidence rates are observed in Northern countries (Netherlands), while the lowest rates are seen in southern and Eastern Europe, Moldova and Romania — suggesting a north-west/south-east gradient in IBD incidence. An estimated 1.3 – 2.0 million people in Europe are affected by IBD, which equals 0.2 – 0.3 % of the European population. The Burden of Inflammatory Bowel Disease in Europe in 2020 Zhao et al. JCC 2021 Distribution of costs during the initial 5 years after diagnosis of Crohn’s disease [A] and ulcerative colitis [B] in a pan-European inception-cohort Summary of the burden of inflammatory bowel diseases in Europe  Prevalence of IBD in Italy Estimated 150,000 - 200,000 patient with IBDs Prevalence 0.2-0.5 % of the population 200/100 000 1014 microorganisms in the GUT making us 90% bugs and 10% “us”! Microbiota=the collective microorganisms Microbiome=the collective gene content of those microorganisms “Dysbiosis”= dysregulated (abnormal) microbiota. Common to many diseases including diabetes, colon cancer, and IBD The best-defined contribution of the microbiota of the GI tract is a metabolic one: these microorganisms have a combined metabolic capacity equivalent to that of the liver, justifying their description as an additional human organ INTESTINAL MICROBIOTA  INTESTINAL MICROBIOTA The composition of the gut microbiota and its functional relationship with the host is an important determinant of health and disease. With the advent of the Human Microbiota Project (HMP), defining the composition and function of the microbiota in healthy subjects, we are beginning to understand the nature of this ecological niche as it relates to the human host. The determinants of the composition of the microbiota include environmental factors such as exposure to pollution, diet, and exposure to drugs, especially antimicrobials. Lloyd-Price J, Mahurkar A, Rahnavard G et al. Strains, functions and dynamics in the expanded Human Microbiome Project. Nature. 2017  COMPOSITION AND LUMINAL CONCENTRATIONS OF DOMINANT MICROBIAL SPECIES IN VARIOUS REGIONS OF THE GASTROINTESTINAL TRACT.  INTESTINAL MICROBIOTA The inoculum delivered to the newborn infant during childbirth seems to dictate the microbiota composition during the critical period of development in early life, during which the immune system and gut microbes develop a bidirectional relationship The colonization of the infant GI tract begins at birth and initiates with facultatively anaerobic Proteobacteria, due to the initially oxidizing environment; anaerobic Bacteroidetes, Actinobacteria, and Firmicutes colonize later, and the microbiome composition stabilizes and begins to resemble that of the adult between 1 and 2 years of age. A stable gut microbial composition is achieved between 1 and 3 years of age, and it remains stable unless there is a major perturbation such as an illness, use of antibiotics, or major changes in diet Yassour M, Vatanen T, Siljander H et al. ; DIABIMMUNE Study Group Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci Transl Med. 2016 THE GUT MICROBIOTA DURING THE HUMAN LIFESPAN  Diet shapes the microbioma Batteroides Prevotella Diet and lifestyle are the main determinants of the composition of the microbiota. 1 2 3 Tilg H, Moschen AR. Food, immunity, and the microbiome. Gastroenterology. 2015  Diet shapes the microbioma Burkina Faso Europe De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, Massart S, Collini S, Pieraccini G, Lionetti P. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc Natl Acad Sci USA. 2010 Different structure of the intestinal microbial community in obese mice Kostic A D et al. Genes Dev. 2013;27:701-718  GUT MICROBIOTA DYSREGULATION AND IBD IBDs disease seems to result from an impaired interaction of the intestinal commensal microbiota that is normally in a state symbiotic mutualism with the human host (immune system). Despite enormous progress in understanding the many facets of this ancient relation, distinction between primary inciting events and secondary occurrences is challenging.  Intestinal microbiota and IBD The role of bacteria in the pathogenesis of Crohn's disease (CD) is well established: clinical presentation and lesions of the disease are localized in areas of highest bacterial exposure clinical response of patients to diversion of the fecal stream and relapse on restoration or exposure to fecal material clinical response to antibacterial treatment absence of disease in germ-free animal models susceptibility genes for CD are involved in recognition of and defense against microorganisms Andoh A, et al. Faecal microbiota profile of Crohn's disease determined by terminal restriction fragment length polymorphism analysis. Aliment Pharmacol Ther 2009;29:75–82.  Intestinal microbiota and IBD In an attempt to define the microbiota in patients with IBD, most studies have compared IBD cases with healthy controls. IBD patients tend to have reduced abundance of bacteria belonging to the phyla of Firmicutes and Bacteroidetes, while being enriched for bacteria from the phyla of Proteobacteria and Actinobacteria The family of Enterobacteriaceae is increased in IBD. Two members of this family, Enterococcus and Escherichia coli (e.g. association between adherent-invasive Escherichia coli (AIEC) and development of CD), are increased in CD and UC. Other changes that are often reported include a decrease in the genera Bifidobacterium, Prevotella, and Coprococcus, as compared with healthy controls. A decrease in the relative abundance of Faecalibacterium prausnitzii has also been described in CD and UC. How these described alterations relate to the underlying nature of IBD, either CD or UC, remains to be determined. Sokol H, Seksik P, Furet JP et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm Bowel Dis. 2009 Etiologic theories of Inflammatory Bowel Disease: Defective mucosal barrier function Defective microbial clearance Persistent specific infection Dysbiosis (abnormal ratio of beneficial and detrimental commensal microbial agents) Aberrant immune-regulation  ADAPTIVE IMMUNITY IN IBD Chronic inappropriate activation of the adaptive immune system against commensal microorganism has been thought to be the main pathogenesis of IBD. Increased production of IFN-γ from Th1 cells and cytokines related with Th17 cell, such as IL-17A/F, IL-21, IL-22, and IL- 23, are observed in the intestine of CD patients, while T cells from the lamina propria of UC patients highly produce Th2 cell- related cytokines, such as IL-5 and IL-13 Cader MZ, Kaser A. Recent advances in inflammatory bowel disease: mucosal immune cells in intestinal inflammation. Gut. 2013  ADAPTIVE IMMUNITY IN IBD IL-17 Ulcerative Crohn’s IL-23 Colitis Disease Naive CD4+ T cells interacting with dendritic cells bearing their cognate antigen can undergo differentiation into distinct effector subsets of helper T [Th1, Th2, Th9, Th17, and Th22] cells, each producing a characteristic set of cytokines. Differentiation into an effector subset is controlled by the cytokine microenvironment in which the naive CD8+ T cell is activated and results in up-regulation of lineage-determining transcription factors (e.g., T-bet for Th1 and RORγt [retinoic acid–related orphan receptor gamma t] for Th17). Innate lymphoid cells can be divided into ILC1, ILC2, and ILC3 subsets, analogous to CD4+ Th1, Th2, and Th17 T-cell subsets. Treg cells have substantial heterogeneity, with thymic Treg (tTreg) subsets that mature in the thymus and peripheral (pTreg) cells that differentiate from naive CD4+ T cells interacting with antigen-bearing dendritic cells in the periphery in concert with factors such as TGF-β, retinoic acid, and short-chain fatty acids (SCFA). Some evidence suggests that tTreg cells recognize self-antigens, whereas pTreg cells may preferentially recognize microbe-derived antigens. Treg cells have additional heterogeneity according to their activation status and can be further subdivided into activated effector Treg (eTreg) and resting central (cTreg) cells.  MODULTION OF ANTI-INFLAMMATORY CYTOKINES ❖ The era of biologic therapy began with an anti-TNF agent, infliximab, in patients with CD. ❖ TNF-α is a proinflammatory cytokine that is produced by activated macrophages, monocytes, and T lymphocytes. ❖ TNF-α has been thought to play a pivotal role in the development of IBD. ❖ TNF-α has two forms in the human intestine: transmembrane TNF (mTNF) and soluble TNF (sTNF). mTNF is generally expressed on the surface of CD14+ macrophages and targets TNF- R2 of T cells, whereas sTNF is secreted by several immune cells as a signaling molecule and targets TNF-R1 of effector cells. ❖ Recent studies have shown that interaction between mTNF and TNF-R2 is more important for IBD pathogenesis than that of sTNF and TNF-R1 MODULTION OF ANTI-INFLAMMATORY CYTOKINES TNFΑ IS A THERAPEUTIC TARGET IN IBDS  ADAPTIVE IMMUNITY IN IBD ❖ Other important cytokines in the treatment of IBD are related to Th17 cells (IL-17A, IL21, IL-22, and IL-23) The inflamed intestinal tissue of IBD patients was shown to contain higher levels of Th17 cells and its cytokines Monteleone I, Pallone F, Monteleone G. Th17-related cytokines: new players in the control of chronic intestinal inflammation. BMC Med. 2011  MODULTION OF ANTI-INFLAMMATORY CYTOKINES ❖ IL-23 has been shown to promote the survival of Th17 cells ❖ IL-23 is a cytokine made up of two subunits ❖ P40 subunit shared with IL-12 ❖ Unique p19 subunit ❖ In IBD, especially in Crohn’s Disease, the role of IL-12 has been focused on ❖ IL-12 promotes the survival of Th1 cells ❖ Ustekinumab, a human monoclonal antibody against the p40 subunit that is a component of both IL-12 and IL-23, is a new relevant biologic therapy for the treatment of CD involving both Th1 and Th17 aspects of CD, nowadays used also for the treatment of UC. ❖ Therapies have begun to emerge targeting IL-23 for treatment of IBD ENVIRONMENTAL DETERMINANTS OF RISK FOR IBD Environmental factors and demographic factors, such as smoking and exposure to second-hand smoke, urban vs rural life, air pollution, and cultural influences on diet, all represent shared exposures that may constitute familial risk for IBD Ananthakrishnan AN, Bernstein CN, Iliopoulos D et al. Environmental triggers in IBD: a review of progress and evidence. Nat Rev Gastroenterol Hepatol. 2018 Many of these factors may explain the apparent association between “Westernisation” and the risk of IBD development, as has been described in China and offspring of South Asian immigrants to North America Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol. 2015 ENVIRONMENTAL DETERMINANTS OF RISK FOR IBD Smoking has been associated with IBD risk, specifically with the risk of CD, increased carbon monoxide from cigarette smoke may cause impairment in vasodilation capacity in chronically inflamed micro vessels, resulting in ischemia, and perpetuating ulceration and fibrosis. It remains unclear whether second-hand smoke exposure can increase risk of IBD onset. In contrast to CD, current smoking is protective against UC, however the mechanism by which smoking exerts its protective effect in UC has not been clearly defined, whereas smoking cessation increased the risk of UC Bernstein CN. Review article: changes in the epidemiology of inflammatory bowel disease-clues for aetiology. Aliment Pharmacol Ther. 2017 ENVIRONMENTAL DETERMINANTS OF RISK FOR IBD ENVIRONMENTAL DETERMINANTS OF RISK FOR IBD Environment, sanitation, industrialization and socio-economic status Public health strategies such as vaccination and environmental sanitation as well as the increasing use of antibiotics has led to changes in the interaction between humans and microbes in the environment. Consequently, improvements in hygiene and health care can alter the composition of the gut microbiota and lead to a state of disequilibrium between protective and pathogenic bacteria (dysbiosis) Benchimol EI, Mack DR, Guttmann A, Nguyen GC, To T, Mojaverian N, Quach P, Manuel DG. Inflammatory bowel disease in immigrants to Canada and their children: a population-based cohort study. Am J Gastroenterol. 2015 ENVIRONMENTAL DETERMINANTS OF RISK FOR IBD Air pollution Air pollution has dramatically increased in recent years, particularly in developing countries (such as Asia) that are experiencing rapid industrialization and the highest increase in IBD incidence. Exposure of the gut to air pollutants can occur via inhalation of gaseous pollutants, mucociliary clearance of particulate matter (PM) from the lungs and contamination of food and water sources Kaplan GG, Hubbard J, Korzenik J, Sands BE, Panaccione R, Ghosh S, Wheeler AJ, Villeneuve PJ. The inflammatory bowel diseases and ambient air pollution: a novel association. Am J Gastroenterol. 2010 ENVIRONMENTAL DETERMINANTS OF RISK FOR IBD Infection Pathobionts are symbiotic organisms within the gut that typically do not elicit an inflammatory response, however, under specific environmental conditions, pathobionts have the potential to cause inflammation leading to disease. This has led to the notion that the etiologic agents for dysbiosis in IBD patients are not necessarily pathogens, but rather disproportionate populations of pathobionts. ❖ Clostridium difficile infection (CDI) in patients with IBD is associated with significant morbidity ❖ Enteric infections such as adherent-invasive Escherichia- coli, Salmonella and Campylobacter, Mycobacterium avium species have been hypothesized to increase the risk of development of CDI and IBD ❖ CMV, EBV and HSV have been implicated in exacerbations of IBD or superimposed infection in IBD ❖ Parasites such as helminthes are thought to play an immunomodulatory role in IBD and loss of helminthes infections has been proposed as a possible explanation for the increase in incidence and prevalence of IBD in developing countries; the “IBD hygiene hypothesis ENVIRONMENTAL DETERMINANTS OF RISK FOR IBD Diet Diet is a major factor capable of modifying gut microbiota composition. Evidence from animal, and epidemiologic studies - IBD European Prospective Cohort Study (IBD-EPIC study) - suggests that dietary factors play an important role in gut inflammation and the risk of developing IBD: ❖ Increased risk of developing UC and CD with consumption of high- fat diet. ❖ The association between high meat intake and IBD is unclear, majority of studies show a positive association of total protein intake and IBD ❖ Fibers intake don’t increase the risk of developed IBD ❖ Food additives such as Aluminum, titanium dioxide (TiO2), and Microparticles/nanoparticles have been implicated in murine models of colitis Andersen V, Chan SS, Luben R et al. Fibre intake and the development of inflammatory bowel disease – a European prospective multi-centre cohort study (EPIC-IBD). J Crohn’s Colitis. 2018 ENVIRONMENTAL DETERMINANTS OF RISK FOR IBD Drugs No causal relationship between NSAID use and incident IBD has been established. Antibiotic use can induce selection pressure and alter the gut microbiome. A recent meta-analysis showed that exposure to antibiotics was significantly associated with newly diagnosed CD, but not UC. Oral contraceptive pills (OCPs) were positively associated with UC and CD in a meta-analysis of 14 case control studies. Estrogen enhances inflammation and progesterone suppresses inflammation in patients with IBD. Ungaro R, Bernstein CN, Gearry R, Hviid A, Kolho KL, Kronman MP, Shaw S, Van Kruiningen H, Colombel JF, Atreja A. Antibiotics associated with increased risk of new-onset Crohn’s disease but not ulcerative colitis: a meta-analysis. Am J Gastroenterol. 2014 ENVIRONMENTAL DETERMINANTS OF RISK FOR IBD Stress A few studies have shown that stress is associated with increased relapse in patients with UC and CD. However, there is no evidence that stress is associated with increased risk of incident IBD. Stress is defined as a state of disharmony or threatened homeostasis. The hypothalamo-pituitary-adrenal (HPA) axis and the immune system work closely together when the body is confronted with a stressful response. When stimulated by a stress event, the immune system activates the HPA axis by producing cytokines that ultimately result in the production of powerful anti-inflammatory agents such as glucocorticoids. Disruptions of the HPA axis and immune system loop could potentially lead to diseases with an inflammatory and behavioral component due to abnormal responses to stressful stimuli. The loop that connects the immune system to the HPA is complex and disruptions at different levels could lead to different manifestations of disease. Gerbarg PL, Jacob VE, Stevens L, Bosworth BP, Chabouni F, DeFilippis EM, Warren R, Trivellas M, Patel PV, Webb CD, et al. The Effect of Breathing, Movement, and Meditation on Psychological and Physical Symptoms and Inflammatory Biomarkers in Inflammatory Bowel Disease: A Randomized Controlled Trial. Inflamm Bowel Dis. 2015  IBD PATHOLOGY: MACROSCOPIC FEATURES Risultati immagini per crohn disease and intestinal wall CD: relapsing, UC: diffuse discontinuous, inflammatory disease transmural limited to the colon, granulomatous rectal involvement disease from oral with continuous cavity to anus, proximal usually involves involvement; almost small intestine and always rectal colon. involvement at disease Small bowel only onset but may develop (particularly terminal rectal sparing and ileum) in 40%, colon patchiness after only in 30% The treatment or chronic rectum is often disease. spared in CD Moderate to Also called terminal markedly active ileitis regional chronic cecal enteritis, involvement is granulomatous associated with colitis backwash ileitis  IBD PATHOLOGY: MACROSCOPIC FEATURES Crohn’s Ulcerative Disease Colitis Inflamed ileum in > 80% of cases Rectal involvement with continuous proximal involvement Transmural granulomatous disease CROHN’S DISEASE PATHOLOGY: ANATOMICAL INVOLVEMENT mouth 0,6-0,9% gastroduodenal 0,5-5% Ileitis 30-40% Jejunoileitis Ileocolitis 45-55% Colon (20-30%)  CROHN’S DISEASE PATHOLOGY: MACROSCOPIC FEATURES  Aphthous or small superficial ulcerations characterize mild disease;  Ulcerations, in more active disease, fuse longitudinally (serpentine linear ulcers along bowel axis) and transversely to demarcate islands of mucosa that frequently are histologically normal. This "cobblestone" appearance is characteristic of CD, (endoscopic diagnosis). As in UC, pseudopolyps can form in CD.  Fissurations (serpentine ulcers more extensive in depth than on the surface) that lead to the formation of Fistulas  CROHN’S DISEASE PATHOLOGY: MACROSCOPIC FEATURES http://www.pharmaceutical-journal.com/Pictures/580xAny/7/1/6/1067716_crohns-disease-specimen-inflammatory-bowel-disease-14.jpg  Active CD is characterized by focal transmural inflammation and formation of fistula tracts, which resolve by fibrosis and stricturing of the bowel.  The bowel wall thickens and becomes narrowed and fibrotic, leading to chronic, recurrent bowel obstructions. Projections of thickened mesentery encase the bowel ("creeping fat"), and serosal and mesenteric inflammation promotes adhesions and fistula formation.  CROHN’S DISEASE PATHOLOGY: MICROSCOPIC FEATURES https://upload.wikimedia.org/wikipedia/commons/3/33/Crohn's_disease_-_colon_-_intermed_mag.jpg Sharply delimited and typically transmural involvement of bowel by an inflammatory process with mucosal damage, noncaseating, nonconfluent, sarcoid-like granulomas (60%) in involved and noninvolved bowel, fissuring (30%) deep into muscularis propria with formation of fistulas and strictures Focal neutrophils in epithelium early on, particularly overlying lymphoid aggregates Also plasmacytosis, cryptitis, crypt abscesses Superficial or deep ulceration, edema, lymphatic dilation, hyperplasia / duplication of muscularis mucosa May have prominent nerve plexuses (submucosal, myenteric), fibrosis, muscularization Often serositis and thickened bowel wall CROHN’S DISEASE PATHOLOGY: MICROSCOPIC FEATURES Late: architectural distortion (villus blunting), crypt atrophy, particularly in colon, pyloric or Paneth cell metaplasia in distal colon, rarely cystically dilated glands (enteritis cystica profunda) Areas of stricture may have thick and continuous muscle layer from mucosal base to muscularis propria 1 cm or more in length, called "obliterative muscularization of submucosa" Isolated colonic Crohn's may mimic ulcerative colitis involve younger patients, only mucosal involvement and with fewer major microscopic features  ULCERATIVE COLITIS PATHOLOGY: MACROSCOPIC FEATURES In the UC the process is limited to the mucosa and superficial submucosa, with deeper layers unaffected except in fulminant disease. Early: mucosa is hemorrhagic, granular, friable; changes usually diffuse (similar intensity throughout) Late: extensive ulceration along bowel axis but usually not serpentine as in Crohn's disease; have pseudopolyps (isolated islands of regenerating mucosa) and flat mucosa; usually normal wall thickness and normal serosa; severe cases may have megacolon or fibrotic, narrow or shortened colon ULCERATIVE COLITIS PATHOLOGY: MICROSCOPIC FEATURES In UC, two major histologic features suggest chronicity and help distinguish it from infectious or acute self-limited colitis. First: the crypt architecture of the colon is distorted; crypts may be bifid and reduced in number, often with a gap between the crypt bases and the muscularis mucosae. Second: some patients have basal plasma cells and multiple basal lymphoid aggregates. Mucosal vascular congestion, with edema and focal hemorrhage, and an inflammatory cell infiltrate of neutrophils, lymphocytes, plasma cells, and macrophages may be present. The neutrophils invade the epithelium, usually in the crypts, giving rise to cryptitis and, ultimately, to crypt abscesses  IBD PATHOLOGY: MICROSCOPIC FEATURES  CROHN’S DISEASE Signs and Symptoms Although CD usually presents as acute or chronic bowel inflammation, the inflammatory process evolves toward one of three patterns of disease: 1. Inflammatory (no evidence of stricturing or fistulizing disease) 2. Fibrostenotic-obstructing 3. Penetrating-fistulous each with different treatments and prognoses. The site of disease influences the clinical manifestations. Crohn’s disease: phenotype Montreal classification  Crohn’s disease: phenotype Montreal classification The Lancet 2012 380, 1590-1605DOI: (10.1016/S0140-6736(12)60026-9)  CROHN’S DISEASE Ileocolitis (L3 B1) Because the most common site of inflammation is the terminal ileum, the usual presentation of ileocolitis is a chronic history of recurrent episodes of right lower quadrant pain and diarrhea. Sometimes the initial presentation mimics acute appendicitis with pronounced right lower quadrant pain, a palpable mass, fever, and leukocytosis. Pain is usually colicky; it precedes and is relieved by defecation. A low-grade fever is usually noted. High-spiking fever suggests intra-abdominal abscess formation. Weight loss is common — typically 10–20% of body weight—and develops as a consequence of diarrhea, anorexia, and fear of eating. An inflammatory mass may be palpated in the right lower quadrant of the abdomen. The mass is composed of inflamed bowel, adherent and indurated mesentery, and enlarged abdominal lymph nodes.  CROHN’S DISEASE Ileocolitis (L3 B2 –B3) Bowel obstruction may take several forms. In the early stages of disease, bowel wall edema and spasm produce intermittent obstructive manifestations and increasing symptoms of postprandial pain. Over several years, persistent inflammation gradually progresses to fibrostenotic narrowing and stricture. Diarrhea will decrease and be replaced by chronic bowel obstruction. Acute episodes of obstruction occur as well, precipitated by bowel inflammation and spasm or sometimes by impaction of undigested food or medication. Severe inflammation of the ileocecal region may lead to localized wall thinning, with microperforation and fistula formation to the adjacent bowel, the skin, or the urinary bladder, or to an abscess cavity in the mesentery. Enterovesical, enetrovaginal, enterocutaneous are commons.  CROHN’S DISEASE Jejunoileitis (L4-L3)  Extensive inflammatory disease is associated with a loss of digestive and absorptive surface, resulting in malabsorption and steatorrhea. Nutritional deficiencies can also result from poor intake and enteric losses of protein and other nutrients.  Diarrhea is characteristic of active disease; its causes include (1) bacterial overgrowth in obstructive stasis or fistulization, (2) bile-acid malabsorption due to a diseased or resected terminal ileum, and (3) intestinal inflammation with decreased water absorption and increased secretion of electrolytes.  CROHN’S DISEASE Colitis (L2)  Patients with colitis present with low-grade fevers, malaise, diarrhea, crampy abdominal pain, and sometimes hematochezia.  Gross bleeding is not as common as in UC and appears in about half of patients with exclusively colonic disease. Only 1–2% bleed massively. Pain is caused by passage of fecal material through narrowed and inflamed segments of large bowel. Decreased rectal compliance is another cause for diarrhea in Crohn's colitis patients.  CROHN’S DISEASE Colitis (L2) and Perianal Disease (B3p)  Stricturing can occur in the colon in 4–16% of patients and produce symptoms of bowel obstruction.  Colonic disease may fistulize into the stomach or duodenum, causing feculent vomiting, or to the proximal or mid small bowel, causing malabsorption by "short circuiting" and bacterial overgrowth. Ten percent of women with Crohn's colitis will develop a rectovaginal fistula.  Perianal disease affects about one-third of patients with Crohn's colitis and is manifested by incontinence, large hemorrhoidal tags, anal strictures, anorectal fistulae, and perirectal abscesses. CROHN’S DISEASE  Perianal Crohn’s Disease The incidence of perianal Crohn’s disease (pCD) ranges from 17% to 43% of CD cases. pCD is associated with more distal CD. Perianal Crohn disease (PCD) is defined as inflammation at or near the anus, including tags, fissures, fistulae, abscesses, or stenosis. The symptoms of PCD include pain, itching, bleeding, purulent discharge, and incontinence of stool. Perianal Crohn’s Disease Perianal Crohn’s Disease Simple fistulae: – Are located in the lower anal canal. – Present a unique external orifice. – Are not associated with pain or fluctuation. – Are generally superficial and, therefore, less dangerous. Complex fistulae: – Are located in the upper or middle anal canal. – Can present multiple external orifices. – Can be associated with pain or fluctuation and anal stenosis, and is at a high risk for bringing about septic complications and anal incontinence. – Include rectovaginal fistulae. Extraintestinal manifestations Extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) are common in both ulcerative colitis (UC) and Crohn's disease (CD). These manifestations can involve nearly any organ system — including the musculoskeletal, dermatologic, hepato-pancreatobiliary, ocular, renal, and pulmonary systems — and can cause a significant challenge to physicians managing IBD patients. Most IBD patients with EIMs have colonic inflammation, although some patients develop EIMs prior to the onset of colonic symptoms. Extraintestinal manifestations EIMs are seen in 25–40% of IBD patients. Inflammatory manifestations of the skin, eyes, liver, and joints are considered primary manifestations. Twenty-five percent of IBD patients have more than 1 EIM. CD UC Tot CD UC Tot Vavricka, Am J Gastroenterol 2011 Major extraintestinal immune- related manifestations of IBD Arthritis Erythema nodosum Pyoderma gangrenosum Aphthous stomatitis Iritis/uveitis Autoimmune disorders associated to IBDs Alopecia areata Ankylosing spondylitis Bronchiolitis obliterans Cold urticaria Hemolytic anemia Henoch-Schoenlein purpura Insulin-dependent diabetes mellitus Pancreatitis Primary biliary cirrhosis Primary sclerosing cholangitis Polymyositis Raynaud phenomenon Seropositive rheumatoid arthritis Sjogren syndrome Thyroid disease Vitiligo Wegener’s granulomatosis Takayasu’s arteritis  Pathogenesis of immune-related extraintestinal manifestation in IBD Extraintestinal immune-related manifestations in IBD are directly dependent on intestinal disease, often coexist in the same patients and have probably the same, even if not completely clarified, pathogenesis. Evidence coming from many studies in genetically susceptible animal models of colitis suggests the crucial role of enteric flora in activating the immune system against bacterial antigens and contemporary against colonic mucosa on the basis of an antigenic cross-reactivity (“antigen mimicry”). The sharing of these colonic antigens by extraintestinal organs, associated with a genetic susceptibility, would finally lead to an immune attack to these organs.  Pathogenesis of immune-related extraintestinal manifestation in IBD Antigen mimicry Extraintestinal complications in IBD and principal pathogenetic mechanisms Extraintestinal complications in IBD Principal pathogenetic mechanisms Anaemia Iron deficiency, inflammation Thromboembolic events Hypercoagulopathies, platelet activation Osteopathy Steroid therapy, vitamin D deficiency inflammation Growth failure Malnutrition Nephrolithiasis Dehydration, hyperoxaluria, low urinary PH Cholelithiasis Intestinal loss of bile acids Amyloidosis Acute phase reaction, chronic inflammation Fatty liver Malnutrition  Joint involvement in IBD Articular and musculoskeletal manifestations are included in the spondyloarthropathies (SpAs) that are a group of seronegative autoimmune related disorders with common characteristics including: ankylosing spondylitis, reactive arthritis, psoriatic arthritis, inflammatory bowel disease, some forms of juvenile arthritis and acute anterior uveitis Inflammatory arthropathies are the most common extraintestinal manifestations in IBD patients with a prevalence ranging between 7% and 25%  Spondyloarthropathies Ankylosing spondylitis Sacroiliitis  Osteoporosis Beyond age-related risk factors that are present in the general population, IBD-specific risk factors include corticosteroid therapy, reduced physical activity, inflammatory-mediated bone resorption (increased levels of interleukin [IL]-1, IL-6, TNF-α), calcium and magnesium dietary malabsorption, vitamin D deficiency, poor dietary calcium intake (related to lactose intolerance), decreased serum albumin levels, and ileal resorption. The overall risk of fracture in IBD patients is 1 per 100 patient-years — 40% higher than in the general population—and this risk increases with age Cutaneous manifestation in IBD Erythema nodosum (EN) appears as erythematous painful rounded lumps, usually 1-6 cm in diameter. Erythema nodosum is almost always located symmetrically on the anterior surface of the lower extremities, but can also spread to the thighs, arms and neck. These lesions do not have a tendency to necrosis and resolve spontaneously within 2–8 weeks without leaving scars. Pyoderma gangrenosum is a very debilitating ulcerating chronic skin disorder occurring in about 1-2% of IBD patients. It occurs often on the extensor surface of the legs, particularly in coincidence with exacerbation of intestinal disease and in association with other extraintestinal manifestations (arthritis and erythema nodosum) Cutaneous manifestation in IBD Metastatic CD is a rare complication defined as the occurrence of specific granulomatous cutaneous lesions remote from the intestinal disease. It manifests as subcutaneous nodules or ulcers mainly at the lower extremities with rare case of genital (testicular and vulvar) localizations. An association between autoimmune cutaneous disease and IBD has been reported. The most frequent disease is psoriasis (7- 11% of IBD population vs 1-2% of general population) than vitiligo and more rarely are polimyositis, lupus erythematosus and scleroderma  Ocular manifestations of IBD Ocular manifestations occur in about 10% of IBD patients. They can be immune- related (episcleritis, scleritis, uveitis, corneal disease) or related to drug exposure (cataract, glaucoma). Uveitis: a heterogeneous group of diseases characterized by inflammation of intraocular structures. Anterior uveitis (iritis and iridocyclitis), intermediate uveitis which affects the vitreous, and posterior uveitis which affects the retina. Patients typically present with red eyes that may have a characteristic concentration of conjunctival injection around the limbus called the perilimbal flush. One of the clinical hallmarks of the uveitis is sensitivity to light, (photophobia) which is often the presenting complaint. Patients can also have blurred vision or headaches. Episcleritis manifests as acute redness, irritation, burning, tender to palpation; if there is also an impairment of vision, the presence of a scleritis is possible.  Hepatobiliary disease Primary Sclerosing Cholangitis The most common immuno-mediated hepatobiliary disease is primary sclerosing cholangitis (PSC) that is a chronic cholestatic disorder characterized by inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. It is more frequent in male individuals, and the prevalence of IBD (mostly UC) in PSC is about 70-80% Conversely about 2-7% of UC patients and 0.7-3.4% of CD patients have a diagnosis of PSC. Suggestive symptoms of PSC are fatigue, pruritus, jaundice, and abdominal discomfort but it is not rare that the isolated finding of abnormalities in liver biochemical markers (first of all alkaline phosphatase); in fact 50-70% of PSC patients are asymptomatic. There are no specific auto-antibodies (p-ANCA, ANA, SMA) and so magnetic resonance cholangiopancreatography is necessary for the diagnosis. In patients with contraindications to MRCP, an ERCP may also be used for studying biliary ducts. Liver biopsy is not necessary to establish diagnosis. However, it may be useful for histological staging of disease and for the diagnosis of “small duct” PSC. Primary Sclerosing Cholangitis  Primary Sclerosing Cholangitis In PSC patients, IBD frequently present some specific features: pancolonic extension with rectal sparing, backwash ileitis, low intestinal activity, and high pouchitis incidence after colectomy. These distinguishing features have suggested the existence of an IBD- PSC specific clinical phenotype. It is well-known that the increased risk of colonic dysplasia/carcinoma in PSC patients compared to the general population (10-fold risk) and to other UC patients it could depend on the long-lasting and asymptomatic colitis (consequently often underestimated) and by alterations in bile salts pool or folate deficiency. Similarly it has significantly increased the risk of bile duct cancer and metabolic bone disease.  Primary Biliary Cirrhosis Association between primary biliary cirrhosis (PBC) and UC is rare but possible; similarly to the CSP it seems that colectomy does not alter the progression of the hepatic disease. Steatosis has been described in more than 30% of patients and it does not seem to be related to the kind of IBD and sex. Data about the influence of disease activity and pharmacological treatment on steatosis are contradictory. Cholelithiasis is more frequent in IBD patients (about 10%) than in the general population (7%) and mainly in CD (first of all in ileal localization); it seems to correlate with female sex, previous surgery (mainly ileal resection), and old age. Probably cholelithiasis is caused by bile salt pool alteration for malabsorption.  Thromboembolism and IBD Patients with IBD have a well-known increased risk (threefold higher than in controls) of thromboembolism (TE), which is an important cause of morbidity and mortality. The incidence ranges from 1.2% to 6.1% according to different studies and in necropsy studies it reaches 39%. Thrombosis accidents occur prevalently as deep vein thrombosis and pulmonary thromboembolism; they happen in earlier age than in non-IBD patients and are more frequent in active or complicated IBD; the type of IBD and the sex seems not to influence thromboembolic risk. Using the logistic regression model, it has been found that IBD is an independent risk factor for thrombosis that is a specific IBD feature. In fact, other inflammatory chronic condition as rheumatoid arthritis or chronic intestinal malabsorptive conditions as celiac disease do not show an increased risk of TE  Thromboembolism and IBD Hyperhomocysteinemia, a well-known risk factor for venous and arterial thrombosis, occurs more often in IBD patients than in the general population and seems to be directly dependent by folate and vitamin B12 deficiency. A recent study comparing IBD patients with thrombosis and IBD controls has revaluated the role of genetic factors finding a significant higher prevalence of factor V Leiden in the thrombosis group (20% vs 0%)  Urinary system manifestations The prevalence of nephrolithiasis in IBD varies from 2% to 6% and is more frequent in CD than in UC. Calcium-oxalate stones are the most common and are caused by hyperoxaluria due to increased intestinal absorption of oxalate. The main lithogenic risk factors are: low urinary volume, low urinary PH, increased excretion of lithogenic substances as oxalate, phosphate, uric acid, and decreased concentration of anti- lithogenic substances as citrate and magnesium. Colectomy in UC and ileo-colonic resection in CD seems to further increase the risk of lithiasis and oxalate stone formation occurs mainly in ileal CD. Urinary tract fistulas occur in about 1.7-7.7% of patients. They can cause pneumaturia, dysuria, recurrent infections, and fecaluria. Clinical relevant renal amyloidosis has been reported in about 1% of IBD patients (more frequently in ileal CD). It is probably related to acute phase reaction proteins.  COMPONENTS OF IBD DIAGNOSIS  History  Physical Examination  Labs  CBC, CMP, ESR, CRP, iron studies, vitamin B12  Fecal calprotectin or lactoferrin Endoscopy  Stool sample for microbiological analysis  C difficile toxin, culture, ova & parasites Histology  Colonoscopy  EGD if CD L4 suspected Radiography  Wireless capsule endoscopy of small intestine  CT and/or MRI enterography Clinical course of  Barium small bowel follow through symptoms  Device assisted balloon enteroscopy CBC, complete blood count; CMP, comprehensive metabolic panel; CRP, C-reactive protein; EGD = esophagogastroduodenoscopy; ESR, erythrocyte sedimentation rate; CT, computed tomography; MRI, magnetic resonance imaging.  COMPONENTS OF IBD DIAGNOSIS Statement 1.1. ECCO-ESGAR Diagnostics GL A single reference standard for the diagnosis of Crohn’s disease [CD] or ulcerative colitis [UC] does not exist. The diagnosis of CD or UC is based on a combination of clinical, biochemical, stool, endoscopic, cross-sectional imaging, and histological investigations When CD is suspected, it may be necessary to visualize [radiologically] the small intestine. Infectious colitis, including Clostridium difficile, should be excluded. Faecal calprotectin [FC], a neutrophil-derived protein, appears to be the most sensitive marker of intestinal inflammation in IBD. Calprotectin values correlate well with endoscopic indices of disease activity and are thus important in various clinical settings, including initial diagnosis, diagnosis of relapse, and response to treatment.  COMPONENTS OF IBD DIAGNOSIS Statement 1.2. ECCO-ESGAR Diagnostics GL Genetic or serological testing is currently not recommended for routine diagnosis of CD or UC. Serological markers may be used to support a diagnosis, though the accuracy of the best available tests [pANCA and ASCAs] is rather limited and hence ineffective at differentiating colonic CD from UC Statement 1.6. ECCO-ESGAR Diagnostics GL For suspected IBD, ileocolonoscopy with biopsies from inflamed and uninflamed segments are required to establish diagnosis, except in the case of acute severe colitis in which sigmoidoscopy may be sufficient Statement 1.7. ECCO-ESGAR Diagnostics GL No endoscopic feature is specific for CD or UC. The most useful endoscopic features of UC are considered to be continuous and confluent colonic involvement with clear demarcation of inflammation and rectal involvement. The most useful endoscopic features in CD are discontinuous lesions, presence of strictures and fistulae, and perianal involvement  ILEOCOLONOSCOPY WITH BIOPSIES http://www.kolumbus.fi/hans/gastrolab/e1121.jpg Endoscopic diagnosis staging of Crohn’s disease Ileal: L1  Endoscopic staging of Crohn disease Ileocolic: L3 http://www.gastrolab.fi/images/a145.jpg B2 Pneumatic endoscopic dilatation of a stricture  The Simple Endoscopic Score for Crohn’s Disease (SES-CD) Score Variable 0 1 2 3 Size of ulcers Aphtous ulcers Large ulcers Very large ulcers None (cm) (0.1-0.5) (0.5-2) (>2) Ulcerated None 30% surface (%) Affected Unaffected 75% surface (%) Presence of Single, can be Multiple, can be None Cannot be passed narrowings passed passed Daperno M, et al. Gastrointest Endosc 2004; 60(4):505-12  Intestinal ultrasound Statement 1.10. ECCO-ESGAR Diagnostics GL All newly diagnosed CD patients should undergo small bowel assessment [intestinal ultrasound, MR enterography and/or capsule endoscopy] Native and (gas or shell microbubble) contrast-enhanced abdominal ultrasound is a readily available, non-invasive imaging technique with an overall sensitivity and specificity that are much the same as with MRI and CT. Prospective studies have shown utility for the initial diagnosis, assessment of disease activity, detection of fistulas, stenosis and abscesses, and significant correlation with histopathology, laboratory findings, validated disease activity indices, and endoscopy. Transrectal and endoscopic ultrasound can assist in perianal complications  Small Bowel Capsule Endoscopy Statement 1.8. ECCO-ESGAR Diagnostics GL Patients with clinical suspicion of CD and with normal endoscopy should be considered for small bowel capsule endoscopy [SBCE] evaluation or cross-sectional imaging. If stenotic disease is suspected, risk of retention should be assessed. Double balloon enteroscopy Small Bowel Follow-Through (SBFT) CT AND MR ENTEROGRAPHY Enhancement uptake after gadolinium RM is highly effective in detecting pelvis and perianal fistulas  Transrectal ultrasonography (TRUS) Castellani D, Baldoni M, et al. J Clin Gastroenterol 2009 Transrectal ultrasonography in the Perianal Crohn’s Disease Castellani D, et al. Tech Coloproctol 2008;12:207–209 Castellani D, Baldoni M, et al. J Clin Gastroenterol 2009 PROGRESSION OF DIGESTIVE DISEASE DAMAGE AND INFLAMMATORY ACTIVITY Inflammatory Activity (CDAI, CDEIS, CRP) Stricture Surgery Digestive Damage Fistula/abscess Stricture Disease Diagnosis Early onset disease Pre-clinical Clinical Pariente B et al. Inflamm Bowel Dis 2011;17(6):1415-22 CDAI: Crohn's Disease Activity Index; CDEIS : Crohn’s Disease Endoscopic Index of Severity; CRP: C-Reactive Protein RISK FACTORS FOR A MORE SEVERE DISEASE COURSE CROHN’S DISEASE ULCERATIVE COLITIS ▪ Early age at diagnosis (