the primary defect in crohn's disease is actually one of relative immunodeficiency. this view has been bolstered recently by novel immunological and clinical studies that have confirmed gross aberrations in this early response, consistent with subsequent genetic studies that highlighted molecules important for innate immune function. the suggestion therefore is that crohn's pathogenesis actually results from partial immunodeficiency, a theory that coincides with the frequent recognition of a virtually identical, non-infectious inflammatory bowel disease arising in patients with congenital monogenic disorders impairing phagocyte function. risk factors risk factors crohn's diseaseulcerative colitis smokinghigher risk for smokerslower risk for smokers ageusual onset between 15 and 30 yearspeak incidence between 15 and 25 years while the exact cause or causes are unknown, crohn's disease seems to be due to a combination of environmental factors and genetic predisposition. crohn's is the first genetically complex disease in which the relationship between genetic risk factors and the immune system is understood in considerable detail. each individual risk mutation makes a small contribution to the overall risk of crohn's (approximately 1:200). the genetic data, and direct assessment of immunity, indicates a malfunction in the innate immune system. in this view, the chronic inflammation of crohn's is caused when the adaptive immune system tries to compensate for a deficient innate immune system. genetics nod2 protein model with schematic diagram. two n-terminal card domains (red) connected via helical linker (blue) with central nbd domain (green). at c-terminus lrr domain (cyan) is located. additionally, some mutations which are associated with certain disease patterns in crohn's disease are marked in red wire representation. crohn's has a genetic component. because of this, siblings of known people with crohn's are 30 times more likely to develop crohn's than the general population. the first mutation found to be associated with crohn's was a frameshift in the nod2 gene (also known as the card15 gene), followed by the discovery of point mutations. over 30 genes have been associated with crohn's; a biological function is known for most of them. for example, one association is with mutations in the xbp1 gene, which is involved in the unfolded protein response pathway of the endoplasmic reticulum. the gene variants of nod2/card15 seem to be related with small-bowel involvement. other well documented genes which increase the risk of developing crohn's disease are atg16l1, il23r, irgm, and slc11a1. there is considerable overlap between susceptibility loci for ibd and mycobacterial infections. genome-wide association studies have shown that crohn's disease is genetically linked to coeliac disease. crohn's has been linked to the gene lrrk2 with one variant potentially increasing the risk of developing the disease by 70%, while another lowers it by 25%. the gene is responsible for making a protein, which collects and eliminates waste product in cells, and is also associated with parkinson's disease. immune system there was a prevailing view that crohn's disease is a primary t cell autoimmune disorder; however, a newer theory hypothesizes that crohn's results from an impaired innate immunity. the later hypothesis describes impaired cytokine secretion by macrophages, which contributes to impaired innate immunity and leads to a sustained microbial-induced inflammatory response in the colon, where the bacterial load is high. another theory is that the inflammation of crohn's was caused by an overactive th1 and th17 cytokine response. in 2007, the atg16l1 gene was implicated in crohn's disease, which may induce autophagy and hinder the body's ability to attack invasive bacteria. another study theorized that the human immune system traditionally evolved with the presence of parasites inside the body and that the lack thereof due to modern hygiene standards has weakened the immune system. test subjects were reintroduced to harmless parasites, with positive responses. microbes it is hypothesized that maintenance of commensal microorganism growth in the gi tract is dysregulated, either as a result or cause of immune dysregulation. there is an apparent connection between crohn's disease, mycobacterium, other pathogenic bacteria, and genetic markers. a number of studies have suggested a causal role for mycobacterium avium subspecies paratuberculosis (map), which causes a similar disease, johne's disease, in cattle. in many individuals, genetic factors predispose individuals to mycobacterium avium subsp. paratuberculosis infection. this bacterium may produce certain compounds containing mannose, which may protect both itself and various other bacteria from phagocytosis, thereby possibly causing a variety of secondary infections. nod2 is a gene involved in crohn's genetic susceptibility. it is associated with macrophages' diminished ability to phagocytize map. this same gene may reduce innate and adaptive immunity in gastrointestinal tissue and impair the ability to resist infection by the map bacterium. macrophages that ingest the map bacterium are associated with high production of tnf-α. other studies have linked specific strains of enteroadherent e. coli to the disease. adherent-invasive escherichia coli (aiec), more common in people with cd, have the ability to make strong biofilms compared to non-aiec strains correlating with high adhesion and invasion indices of neutrophils and the ability to block autophagy at the autolysosomal step, which allows for intracellular survival of the bacteria and induction of inflammation. inflammation drives the proliferation of aiec and dysbiosis in the ileum, irrespective of genotype. aiec strains replicate extensively inside macrophages inducing the secretion of very large amounts of tnf-α. mouse studies have suggested some symptoms of crohn's disease, ulcerative colitis, and irritable bowel syndrome have the same underlying cause. biopsy samples taken from the colons of all three patient groups were found to produce elevated levels of a serine protease. experimental introduction of the serine protease into mice has been found to produce widespread pain associated with irritable bowel syndrome, as well as colitis, which is associated with all three diseases. regional and temporal variations in those illnesses follow those associated with infection with the protozoan blastocystis. the "cold-chain" hypothesis is that psychrotrophic bacteria such as yersinia and listeria species contribute to the disease. a statistical correlation was found between the advent of the use of refrigeration in the united states and various parts of europe and the rise of the disease. there is also a tentative association between candida colonization and crohn's disease. still, these relationships between specific pathogens and crohn's disease remain unclear. environmental factors the increased incidence of crohn's in the industrialized world indicates an environmental component. crohn's is associated with an increased intake of animal protein, milk protein, and an increased ratio of omega-6 to omega-3 polyunsaturated fatty acids. those who consume vegetable proteins appear to have a lower incidence of crohn's disease. consumption of fish protein has no association. smoking increases the risk of the return of active disease (flares). the introduction of hormonal contraception in the united states in the 1960s is associated with a dramatic increase in incidence, and one hypothesis is that these drugs work on the digestive system in ways similar to smoking. isotretinoin is associated with crohn's. although stress is sometimes claimed to exacerbate crohn's disease, there is no concrete evidence to support such claim. still, it is well known that immune function is related to stress. dietary microparticles, such as those found in toothpaste, have been studied as they produce effects on immunity, but they were not consumed in greater amounts in patients with crohn's. the use of doxycycline has also been associated with increased risk of developing inflammatory bowel diseases. in one large retrospective study, patients who were prescribed doxycycline for their acne had a 2.25-fold greater risk of developing crohn's disease. pathophysiology pathophysiology crohn's diseaseulcerative colitis cytokine responseassociated with th17vaguely associated with th2 during a colonoscopy, biopsies of the colon are often taken to confirm the diagnosis. certain characteristic features of the pathology seen point toward crohn's disease; it shows a transmural pattern of inflammation, meaning the inflammation may span the entire depth of the intestinal wall. ulceration is an outcome seen in highly active disease. there is usually an abrupt transition between unaffected tissue and the ulcer—a characteristic sign known as skip lesions. under a microscope, biopsies of the affected colon may show mucosal inflammation, characterized by focal infiltration of neutrophils, a type of inflammatory cell, into the epithelium. this typically occurs in the area overlying lymphoid aggregates. these neutrophils, along with mononuclear cells, may infiltrate the crypts, leading to inflammation (crypititis) or abscess (crypt abscess). granulomas, aggregates of macrophage derivatives known as giant cells, are found in 50% of cases and are most specific for crohn's disease. the granulomas of crohn's disease do not show "caseation", a cheese-like appearance on microscopic examination characteristic of granulomas associated with infections, such as tuberculosis. biopsies may also show chronic mucosal damage, as evidenced by blunting of the intestinal villi, atypical branching of the crypts, and a change in the tissue type (metaplasia). one example of such metaplasia, paneth cell metaplasia, involves the development of paneth cells (typically found in the small intestine and a key regulator of intestinal microbiota) in other parts of the gastrointestinal system. diagnosis the diagnosis of crohn's disease can sometimes be challenging, and many tests are often required to assist the physician in making the diagnosis. even with a full battery of tests, it may not be possible to diagnose crohn's with complete certainty; a colonoscopy is approximately 70% effective in diagnosing the disease, with further tests being less effective. disease in the small bowel is particularly difficult to diagnose, as a traditional colonoscopy allows access to only the colon and lower portions of the small intestines; introduction of the capsule endoscopy aids in endoscopic diagnosis. giant (multinucleate) cells, a common finding in the lesions of crohn's disease, are less common in the lesions of lichen nitidus. endoscopic image of crohn's colitis showing deep ulceration ct scan showing crohn's disease in the fundus of the stomach section of colectomy showing transmural inflammation resected ileum from a person with crohn's disease classification distribution of gastrointestinal crohn's disease. crohn's disease is one type of inflammatory bowel disease (ibd). it typically manifests in the gastrointestinal tract and can be categorized by the specific tract region affected. a disease of both the ileum (the last part of the small intestine that connects to the large intestine), and the large intestine, ileocolic crohn's accounts for fifty percent of cases. crohn's ileitis, manifest in the ileum only, accounts for thirty percent of cases, while crohn's colitis, of the large intestine, accounts for the remaining twenty percent of cases and may be particularly difficult to distinguish from ulcerative colitis. gastroduodenal crohn's disease causes inflammation in the stomach and the first part of the small intestine called the duodenum. jejunoileitis causes spotty patches of inflammation in the top half of the small intestine, called the jejunum. the disease can attack any part of the digestive tract, from mouth to anus. however, individuals affected by the disease rarely fall outside these three classifications, with presentations in other areas. crohn's disease may also be categorized by the behavior of disease as it progresses. these categorizations formalized in the vienna classification of the disease. there are three categories of disease presentation in crohn's disease: stricturing, penetrating, and inflammatory. stricturing disease causes narrowing of the bowel that may lead to bowel obstruction or changes in the caliber of the feces. penetrating disease creates abnormal passageways (fistulae) between the bowel and other structures, such as the skin. inflammatory disease (or nonstricturing, nonpenetrating disease) causes inflammation without causing strictures or fistulae. endoscopy a colonoscopy is the best test for making the diagnosis of crohn's disease, as it allows direct visualization of the colon and the terminal ileum, identifying the pattern of disease involvement. on occasion, the colonoscope can travel past the terminal ileum, but it varies from person to person. during the procedure, the gastroenterologist can also perform a biopsy, taking small samples of tissue for laboratory analysis, which may help confirm a diagnosis. as 30% of crohn's disease involves only the ileum, cannulation of the terminal ileum is required in making the diagnosis. finding a patchy distribution of disease, with involvement of the colon or ileum, but not the rectum, is suggestive of crohn's disease, as are other endoscopic stigmata. the utility of capsule endoscopy for this, however, is still uncertain. a "cobblestone"-like appearance is seen in approximately 40% of cases of crohn's disease upon colonoscopy, representing areas of ulceration separated by narrow areas of healthy tissue. radiologic tests a small bowel follow-through may suggest the diagnosis of crohn's disease and