*4.5.1 Crohn disease*

Crohn's disease is an inflammatory bowel disease characterized by skip lesions and transmural inflammation, leading to inflammation throughout the entire gastrointestinal tract, from the mouth to the anus [178] There are three major locations of Crohn's disease, involving the terminal ileum, the colon, and the small bowel in about 55% of patients, and the colon in about 20% of cases. In 25% of patients, fissures and fistulas may develop, as well as upper gastrointestinal disease or extraintestinal manifestations. In 10% of patients, isolated perianal complaints may develop [179]. Although Crohn's etiology is not completely understood, genetics, immunology, and environment contribute to the onset and progression of this disease [180]. The annual incidence of Crohn is approximately 3 to 20 cases per 100,000 people [154]. Incidence of Crohn is highest among patients younger than 30 years of age, although it is increasing in older individuals [181]. North America and Western Europe are the most common places where individuals experience Crohn's disease, but Asia and Latin America are experiencing it in an increasingly more often manner as well [174, 182]. In general, the gender ratio of CD is almost similar with slightly higher prevalence in women. In western countries, there is no sex difference is apparent in incidence, whereas in Asian populations, Crohn is slightly more prevalent in men than in women. It was identified

that more than 200 loci were associated with Crohn's risk [183]. The coding variation in the intracellular pattern recognition receptor gene NOD2 (also known as CARD15), is selectively associated with Crohn's risk. There is considerable variance at a few loci that are associated with aggregate heritable risk, including IL23R, the IL-2 receptor gene, and NOD2 [184, 185]. Being homozygous at NOD2 increases the risk of developing Crohn's by 20−40 times while being heterozygous increases it by 2−4 times [186]. Crohn's pathogenesis is linked to NOD2 c.3019-3020insC and ATG16L1p.Thr300Ala, respectively as has been shown by novel immunopathogenesis study [187]. It has been shown that patients with early onset of Crohn have mutations in IL-10 receptor genes [188]. Crohn can be divided into three phenotypic subtypes: inflammatory, structuring, and fistulizing. The inflammatory Crohn phenotype is characterized by inflammation of the gastrointestinal tract with no evidence of stricturing or fistulizing. Over time, this inflammation may result in fibrosis and luminal narrowing, resulting in stricturing disease. The fibrosis is reversible and there would be a need for surgical intervention. Transmural inflammation can also result in the development of a fistulous tract or sinus in patients with fistulizing Crohn. The bowel can develop a fistula with any adjacent organ (such as the bladder, vagina, or other parts of the bowel) [189]. Crohn typically manifests as weight loss, diarrhea with blood, iron deficiency, chronic and postprandial abdominal pain, fever, lack of rectal urgency, and nighttime awakenings [190]. C-reactive protein levels, sedimentation rates, or other acute phase reactants (e.g. ferritin and platelets) are commonly elevated in Crohn patients. Low B12 levels are also common. Family histories of IBD also significantly influence Crohn patients [178]. Just like other GI autoimmune diseases, some tests are used together to confirm the diagnosis such as serological tests, endoscopy, and histological tests for biopsies. Crohn is diagnosed by autoantibodies, such as anti- Saccharomyces cerevisiae antibodies (ASCAs), anti-outer membrane porin C antibodies, anti-Pseudomonas fluorescens-associated sequence I2 antibodies, and anti-CBir1 antibodies. Additionally, perinuclear antineutrophil cytoplasmic antibodies (pANCAs), antimannobioside carbohydrate antibodies, anti-laminaribioside carbohydrate antibodies, anti-chitobioside carbohydrate antibodies, as well as anti-laminarin antibodies [191–193]. In endoscopy findings for a diagnosis of Crohn are often characterized by a patchy distribution of inflammation and skip lesions. It might be apparent in endoscopy the presence of aphthous erosions or longitudinal ulcers.
