The three most common sites of intestinal involvement in Crohn's disease (left) compared to the areas affected byulcerative colitis (colitis ulcerosa, right)
Although the precise causes of Crohn's disease (CD) are unknown, it is believed to be caused by a combination of environmental,immune, and bacterial factors in genetically susceptible individuals.[3][13][14][15] It results in achronic inflammatory disorder, in which the body'simmune system defends the gastrointestinal tract, possibly targetingmicrobialantigens.[14][16] While Crohn's is an immune-related disease, it does not seem to be anautoimmune disease (the immune system is not triggered by the body itself).[17] The exact underlying immune problem is not clear; however, it may be animmunodeficiency state.[16][18][19]
About half of the overall risk is related to genetics, with more than 70genes involved.[1][20] Tobacco smokers are three times as likely to develop Crohn's disease as non-smokers.[6] Crohn's disease is often triggered after agastroenteritis episode.[1] Other conditions with similar symptoms includeirritable bowel syndrome andBehçet's disease.[1]
There is no known cure for Crohn's disease.[1][3]Treatment options are intended to help with symptoms, maintainremission, and preventrelapse.[1] In those newly diagnosed, acorticosteroid may be used for a brief period of time to improve symptoms rapidly, alongside another medication such as eithermethotrexate or athiopurine to prevent recurrence.[1] Cessation of smoking is recommended for people with Crohn's disease.[1] One in five people with the disease is admitted to the hospital each year, and half of those with the disease will require surgery at some time during a ten-year period.[1] Surgery is kept to a minimum whenever possible, but it is sometimes essential for treatingabscesses, certain bowel obstructions, and cancers.[1] Checking for bowel cancer viacolonoscopy is recommended every 1-3 years, starting eight years after the disease has begun.[1]
Crohn's disease affects about 3.2 per 1,000 people in Europe and North America;[12] it is less common in Asia and Africa.[21][22] It has historically been more common in thedeveloped world.[23] Rates have, however, been increasing, particularly in the developing world, since the 1970s.[22][23] Inflammatory bowel disease resulted in 47,400 deaths in 2015,[24] and those with Crohn's disease have a slightly reducedlife expectancy.[1] Onset of Crohn's disease tends to start in adolescence and young adulthood, though it can occur at any age.[25][1][3][26] Males and females are affected roughly equally.[3]
Many people with Crohn's disease have symptoms for years before the diagnosis.[33] The usual onset is in the teens and twenties, but can occur at any age.[26][1] Because of the 'patchy' nature of thegastrointestinal disease and the depth of tissue involvement, initial symptoms can be more subtle than those ofulcerative colitis.[citation needed] People with Crohn's disease experience chronic recurring periods of flare-ups andremission.[34] The symptoms experienced can change over time as inflammation increases and spreads. Symptoms can also be different depending on which organs are involved. It is generally thought that the presentation of Crohn's disease is different for each patient due to the high variability of symptoms, organ involvement, and initial presentation.
The intestines, especially the colon and terminal ileum, are the areas of the body affected most commonly.Abdominal pain is a common initial symptom of Crohn's disease,[3] especially in the lower right abdomen.[36] Flatulence, bloating, and abdominal distension are additional symptoms and may also add to the intestinal discomfort. Pain is often accompanied by non-bloodydiarrhea, however in some cases the diarrhea can be bloody. Inflammation in different areas of theintestinal tract can affect the quality of thefeces.Ileitis typically results in large-volume, watery feces, whilecolitis may result in a smaller volume of feces of greater frequency. Fecal consistency may range from solid to watery. In severe cases, an individual may have more than 20bowel movements per day, and may need to awaken at night to defecate.[1][37][38][39] Visible bleeding in the feces is less common in Crohn's disease than in ulcerative colitis, but is not unusual.[1] Bloody bowel movements are usually intermittent, and may be bright red, dark maroon, or evenblack in color. The color of bloody stool depends on the location of the bleed. In severe Crohn's colitis, bleeding may be copious.[37]
The stomach is rarely the sole or predominant site of CD. To date, there are only a few documented case reports of adults with isolated gastric CD and no reports in the pediatric population. Isolated stomach involvement is very unusual presentation accounting for less than 0.07% of all gastrointestinal CD.[40] However, theesophagus andstomach are increasingly understood to be affected in patients with intestinal CD. Recent studies suggest upper GI involvement occurs in 13-16% of cases, typically presenting after distal symptoms.[41][42][43] Upper gastrointestinal symptoms may include difficulty swallowing (dysphagia), painful swallowing (odynophagia), upper abdominal pain, and vomiting.[44][45]
The mouth may be affected by recurrent canker sores (aphthous ulcers). Recurrent aphthous ulcers are common; however, it is not clear whether this is due to Crohn's disease or simply that they are common in the general population. Other findings may include diffuse or nodular swelling of the mouth, a cobblestone appearance inside the mouth, granulomatous ulcers, orpyostomatitis vegetans. Medications that are commonly prescribed to treat CD, such as anti-inflammatory and sulfa-containing drugs, may cause lichenoid drug reactions in the mouth. Fungal infection such as candidiasis is also common due to the immunosuppression required in the treatment of the disease. Signs of anemia such as pallor and angular cheilitis or glossitis are also common due to nutritional malabsorption.[46]
Like many other chronic, inflammatory diseases, Crohn's disease can cause a variety ofsystemic symptoms.[1] Among children,growth failure is common. Many children are first diagnosed with Crohn's disease based oninability to maintain growth.[48] As it may manifest at the time of the growth spurt inpuberty, as many as 30% of children with Crohn's disease may have retardation of growth.[49] Fever may also be present, though fevers greater than 38.5 °C (101.3 °F) are uncommon unless there is a complication such as an abscess.[1] Among older individuals, Crohn's disease may manifest as weight loss, usually related to decreased food intake, since individuals with intestinal symptoms from Crohn's disease often feel better when they do not eat and mightlose their appetite.[48] People with extensivesmall intestine disease may also havemalabsorption ofcarbohydrates orlipids, which can further exacerbate weight loss.[50]
Inflammation of the interior portion of the eye, known asuveitis, can cause blurred vision and eye pain, especially when exposed to light (photophobia).[55] Uveitis can lead to loss of vision if untreated.[51]
Inflammation may also involve the white part of the eye (sclera) or the overlying connective tissue (episclera), which causes conditions calledscleritis andepiscleritis, respectively.[55]
Other very rare ophthalmological manifestations include:conjunctivitis,glaucoma, and retinal vascular disease.[56]
The pathophysiology of ocular inflammation in Crohn's disease patients is complex and remains uncertain. The association between inflammatory conditions of the eye and Crohn's disease is due to many Crohn's disease patients having genetic markers such as HLA-B07, HLA-B27 and HLA-DRB1*0103.[57] Additionally, cytokines IL-6, IL-10, and IL-17 which are produced in the bowel enter the circulatory system and travel to the eyes to trigger inflammation.[58]
Crohn's disease that affects theileum may result in an increased risk ofgallstones. This is due to a decrease inbile acid resorption in the ileum, resulting inbile excretion n the stool. As a result, thecholesterol/bile ratio increases in thegallbladder, resulting in an increased risk for gallstones.[55] Although the association is greater in the context ofulcerative colitis, Crohn's disease may also be associated withprimary sclerosing cholangitis, a type of inflammation of thebile ducts.[59] Specifically, 0.96% of Crohn's disease patients also have primary sclerosing cholangitis.[60]
Liver involvement of Crohn's disease can includecirrhosis andsteatosis.Nonalcoholic fatty liver disease (nonalcoholic steatohepatitis, NAFLD) are relatively common and can slowly progress to end-stage liver disease. NAFLD sensitizes the liver to injury and increases the risk of developing acute or chronic liver failure following another liver injury.[56]
Nephrolithiasis,obstructive uropathy, andfistulization of the urinary tract directly result from the underlying disease process. Nephrolithiasis is due to calcium oxalate or uric acid stones. Calcium oxalate stones due to hyperoxaluria are typically associated with either distal ileal CD or ileal resection. Oxalate absorption increases in the presence of unabsorbed fatty acids in the colon. The fatty acids compete with oxalate to bind calcium, displacing the oxalate, which can then be absorbed as unbound sodium oxalate across colonocytes and excreted into the urine. Because sodium oxalate is only absorbed in the colon, calcium oxalate stones form only in patients with an intact colon. Patients with anileostomy are prone to formation of uric acid stones because of frequent dehydration. The sudden onset of severe abdominal, back, or flank pain in patients with IBD, particularly if different from the usual discomfort, should lead to inclusion of a renal stone in the differential diagnosis.[56]
Urological manifestations in patients with IBD may include ureteral calculi, enterovesicalfistula, perivesical infection, perinephric abscess, and obstructive uropathy withhydronephrosis. Ureteral compression is associated with retroperitoneal extension of the phlegmonous inflammatory process involving theterminal ileum andcecum, and may result inhydronephrosis severe enough to causehypertension.[56]
Immune complexglomerulonephritis presenting withproteinuria andhematuria has been described in children and adults with CD or UC. Diagnosis is by renal biopsy, and treatment parallels the underlying IBD.[56]
Amyloidosis (see endocrinological involvement) secondary to Crohn's disease has been described and is known to affect the kidneys.[56]
Pancreatitis may be associated with both UC and CD. The most common cause isiatrogenic and involves sensitivity to medications used to treat IBD (3% of patients), includingsulfasalazine,mesalamine,6-mercaptopurine, andazathioprine. Pancreatitis may present as symptomatic (in 2%) or more commonly asymptomatic (8–21%) disease in adults with IBD.[56]
Children and adults with IBD have been rarely (<1%) reported developingpleuropericarditis either at initial presentation or during active or quiescent disease. The pathogenesis of pleuropericarditis is unknown, although certain medications (e.g.,sulfasalazine andmesalamine derivatives) have been implicated in some cases. The clinical presentation may include chest pain,dyspnea, or in severe casespericardial tamponade requiring rapid drainage.Nonsteroidal anti-inflammatory drugs have been used as therapy, although this should be weighed against the hypothetical risk of exacerbating the underlying IBD.[56]
Laryngeal involvement in inflammatory bowel disease is extremely rare. Only 12 cases of laryngeal involvement in Crohn's disease have been reported as of 2019[update]. Moreover, only one case of laryngeal manifestations in ulcerative colitis has been reported as of the same date.[61] Nine patients complained of difficulty in breathing due toedema andulceration from thelarynx to thehypopharynx.[62] Hoarseness, sore throat, andodynophagia are other symptoms of laryngeal involvement of Crohn's disease.[63]
Considering extraintestinal manifestations of CD, those involving thelung are relatively rare. However, there is a wide array of lung manifestations, ranging from subclinical alterations, airway diseases and lungparenchymal diseases topleural diseases and drug-related diseases. The most frequent manifestation is bronchial inflammation andsuppuration with or without bronchiectasis. There are a number of mechanisms by which the lungs may become involved in CD. These include the same embryological origin of the lung and gastrointestinal tract by ancestral intestine, similar immune systems in the pulmonary and intestinal mucosa, the presence of circulating immune complexes and auto-antibodies, and the adverse pulmonary effects of some drugs.[64] A complete list of known pulmonary manifestations include: fibrosing alveolitis, pulmonaryvasculitis, apicalfibrosis,bronchiectasis,bronchitis,bronchiolitis,tracheal stenosis,granulomatous lung disease, and abnormal pulmonary function.[56]
Crohn's disease is associated with a type ofrheumatologic disease known asseronegative spondyloarthropathy.[55] This group of diseases is characterized by inflammation of one or morejoints (arthritis) or muscle insertions (enthesitis).[55] The arthritis in Crohn's disease can be divided into two types. The first type affects larger weight-bearing joints such as the knee (most common), hips, shoulders, wrists, or elbows.[55] The second type symmetrically involves five or more of the small joints of the hands and feet.[55] The arthritis may also involve thespine, leading toankylosing spondylitis if the entire spine is involved, or simplysacroiliitis if only thesacroiliac joint is involved.[55]
Central and peripheral neurological disorders are described in patients with IBD and include peripheralneuropathies,myopathies, focalcentral nervous system defects,convulsions, confusional episodes,meningitis,syncope,optic neuritis, andsensorineural loss.Autoimmune mechanisms are proposed for involvement with IBD. Nutritional deficiencies associated with neurological manifestations, such asvitamin B12 deficiency, should be investigated. Spinalabscess has been reported in both a child and an adult with initial complaints of severe back pain due to extension of a psoas abscess from the epidural space to the subarachnoid space.[56]
Crohn's disease is linked to many psychological disorders, includingdepression andanxiety, denial of one's disease, the need for dependence or dependent behaviors, feeling overwhelmed, and having a poor self-image.[73]
Many studies have found that patients with IBD report a higher frequency of depressive and anxiety disorders than the general population; most studies confirm that women with IBD are more likely than men to develop affective disorders and show that up to 65% of them may havedepression andanxiety disorder.[74][75]
Secondaryamyloidosis (AA) is another rare but serious complication ofinflammatory bowel disease (IBD), generally seen in Crohn's disease. At least 1% of patients with Crohn's disease develop amyloidosis. In the literature, the time lapse between the onset of Crohn's disease and the diagnosis of amyloidosis has been reported to range from 1 to 21 years.
Thrombocytosis andthromboembolic events resulting from ahypercoagulable state in patients with IBD can lead topulmonary embolism orthrombosis elsewhere in the body. Thrombosis has been reported in 1.8% of patients with UC and 3.1% of patients with CD. Thromboembolism and thrombosis are less frequently reported among pediatric patients, with three patients with UC and one with CD described in case reports.[56]
Histopathology of a non-necrotizing granuloma of colonic mucosa in a patient with Crohn's disease, H&E stain. It is seen as an aggregate of histiocytes in the center of the image, having ample eosinophilic cytoplasm.
Crohn's disease can lead to several mechanical complications within theintestines, includingobstruction,[80]fistulae,[81] andabscesses.[82] Obstruction typically occurs fromstrictures oradhesions that narrow thelumen, blocking the passage of the intestinal contents. A fistula can develop between two loops of bowel, between the bowel andbladder, between the bowel andvagina, and between the bowel and skin. Abscesses are walled-off concentrations ofinfection, which can occur in theabdomen or in theperianal area. Crohn's is responsible for 10% of vesicoenteric fistulae, and is the most common cause ofileovesicalfistulae.[83]
Intestinalgranulomas are a walled-off portions of the intestine by macrophages in order to isolate infections. Granuloma formation is more often seen in younger patients, and mainly in the severe, active penetrating disease.[84] Granuloma is considered the hallmark of microscopic diagnosis in Crohn's disease (CD), but granulomas can be detected in only 21–60% of CD patients.[84]
Crohn's disease also increases the risk ofcancer in the area of inflammation. For example, individuals with Crohn's disease involving thesmall bowel are at higher risk forsmall intestinal cancer.[85] Similarly, people withCrohn's colitis have arelative risk of 5.6 for developingcolon cancer.[86] Screening for colon cancer withcolonoscopy is recommended for anyone who has had Crohn's colitis for at least eight years.[87]
Some studies suggest there is a role for chemoprotection in the prevention of colorectal cancer in Crohn's involving the colon; two agents have been suggested,folate andmesalamine preparations.[88] Also,immunomodulators andbiologic agents used to treat this disease may promote developing extra-intestinal cancers.[89]
Individuals with Crohn's disease are at risk ofmalnutrition for many reasons, including decreased food intake andmalabsorption. The risk increases following resection of thesmall bowel. Such individuals may require oral supplements to increase theircaloric intake, or in severe cases,total parenteral nutrition (TPN). Most people with moderate or severe Crohn's disease are referred to adietitian for assistance in nutrition.[92]
Small intestinal bacterial overgrowth (SIBO) is characterized by excessive proliferation of colonic bacterial species in the small bowel. Potential causes of SIBO include fistulae, strictures, or motility disturbances. Hence, patients with Crohn's disease are especially predisposed to develop SIBO. As result, CD patients may experience malabsorption and report symptoms such as weight loss, watery diarrhea,meteorism, flatulence, and abdominal pain, mimicking acute flare in these patients.[79]
Crohn's disease can be problematic duringpregnancy, and some medications can cause adverse outcomes for thefetus or mother. Consultation with anobstetrician andgastroenterologist about Crohn's disease and all medications facilitates preventive measures. In some cases, remission occurs during pregnancy. Certain medications can also lowersperm count or otherwise adversely affect a man'sfertility.[93]
Common complications of anostomy (a common surgery in Crohn's disease) are: mucosal edema, peristomal dermatitis, retraction, ostomy prolapse, mucosal/skin detachment, hematoma, necrosis, parastomal hernia, and stenosis.[94]
Theetiology of Crohn's disease is unknown. Many theories have been disputed, with four main theories hypothesized to be the primary mechanism of Crohn's disease. Inautoimmune diseases,antibodies andT lymphocytes are the primary mode of inflammation. These cells and bodies are part of theadaptive immune system, or the part of the immune system that learns to fight foreign bodies when first identified.[95]Autoinflammatory diseases are diseases where theinnate immune system, or the immune system we are genetically coded with, is designed to attack our own cells.[96] Crohn's disease likely has involvement of both the adaptive and innate immune systems.[97]
Crohn's disease can be described as a multifactorial autoinflammatory disease. The etiopathogenesis of Crohn's disease is still unknown. In any event, a loss of the regulatory capacity of the immune apparatus would be implicated in the onset of the disease. In this respect interestingly enough, as forBlau's disease (amonogenic autoinflammatory disease), theNOD2 gene mutations have been linked to Crohn's disease. However, in Crohn's disease, NOD2 mutations act as a risk factor, being more common among Crohn's disease patients than the background population, while in Blau's disease NOD2 mutations are linked directly to this syndrome, as it is anautosomal-dominant disease. All this new knowledge in thepathogenesis of Crohn's disease allows us to put this multifactorial disease in the group ofautoinflammatory syndromes.[96]
Some examples of how the innate immune system affects bowel inflammation have been described.[97] A meta-analysis of CDgenome-wide association studies revealed 71 distinct CD-susceptibilityloci. Interestingly, three very important CD-susceptibility genes (the intracellular pathogen-recognition receptor, NOD2; the autophagy-related 16-like 1,ATG16L1 and the immunity-related GTPase M,IRGM) are involved in innate immune responses against gut microbiota, while one (the X-box binding protein 1) is involved in regulation of the [adaptive] immune pathway viaMHC class II,[98] resulting in autoinflammatory inflammation. Studies have also found that increasedILC3 canoverexpressmajor histocompatibility complex (MHC) II. MHC class II can induceCD4+ T cellapoptosis, thus avoiding theT cell response to normal bowel micro bacteria. Further studies of IBD patients compared with non-IBD patients found that the expression of MHC II by ILC3 was significantly reduced in IBD patients, thus causing an immune reaction against intestinal cells or normal bowel bacteria and damaging the intestines. This can also make the intestines more susceptible to environmental factors, such as food or bacteria.[97]
The thinking is that because Crohn's disease has strong innate immune system involvement and has NOD2 mutations as a predisposition, Crohn's disease is more likely an autoinflammatory disease than an autoimmune disease.[97]
This section needs to beupdated. The reason given is: All current sources are from 2010. Please help update this article to reflect recent events or newly available information.(May 2024)
A substantial body of data has emerged in recent years to suggest that the primary defect in Crohn's disease is actually one of relativeimmunodeficiency.[99] 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 forinnate immune function. The suggestion therefore is that Crohn'spathogenesis 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 withcongenitalmonogenic disorders impairingphagocyte function.[99]
While the exact cause or causes are unknown, Crohn's disease seems to be due to a combination ofenvironmental factors andgenetic predisposition.[102] Crohn's is the first genetically complex disease in which the relationship between geneticrisk factors and the immune system is understood in considerable detail.[103] Each individual riskmutation 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 theinnate immune system.[104] In this view, the chronic inflammation of Crohn's is caused when theadaptive immune system tries to compensate for a deficient innate immune system.[105]
NOD2 protein model with schematic diagram. Two N-terminalCARD domains (red) connected via helical linker (blue) with centralNBD domain (green). At C-terminusLRR domain (cyan) is located. Additionally, some mutations which are associated with certain disease patterns in Crohn's disease are marked in red wire representation.[106]
Crohn's has a genetic component.[107] Because of this, siblings of known people with Crohn's are 30 times more likely to develop Crohn's than the general population.[108]
Crohn's has been linked to the geneLRRK2 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 aprotein, which collects and eliminateswaste product in cells, and is also associated withParkinson's disease.[120]
There was a prevailing view that Crohn's disease is a primaryT cell autoimmune disorder; however, a newer theory hypothesizes that Crohn's results from an impaired innate immunity.[121] The later hypothesis describes impairedcytokine secretion bymacrophages, which contributes to impaired innate immunity and leads to a sustained microbial-induced inflammatory response in the colon, where the bacterial load is high.[14][104] Another theory is that the inflammation of Crohn's was caused by an overactiveTh1 andTh17cytokine response.[122][123]
In 2007, the ATG16L1 gene was implicated in Crohn's disease, which may induceautophagy and hinder the body's ability to attack invasive bacteria.[114] Another study theorized that the human immune system traditionally evolved with the presence ofparasites 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.[124]
NOD2 is a gene involved in Crohn's genetic susceptibility. It is associated withmacrophages' diminished ability tophagocytize MAP. This same gene may reduce innate and adaptive immunity in gastrointestinal tissue and impair the ability to resist infection by the MAP bacterium.[132] Macrophages that ingest the MAP bacterium are associated with high production ofTNF-α.[133][134]
Other studies have linked specific strains ofenteroadherentE. coli to the disease.[135] Adherent-invasiveEscherichia coli (AIEC), more common in people with CD,[136][137][135] have the ability to make strongbiofilms compared to non-AIEC strains correlating with high adhesion and invasion indices[138][139] ofneutrophils and the ability to blockautophagy at the autolysosomal step, which allows for intracellular survival of the bacteria and induction of inflammation.[140] Inflammation drives the proliferation of AIEC anddysbiosis in the ileum, irrespective of genotype.[141] AIEC strains replicate extensively inside macrophages inducing the secretion of very large amounts of TNF-α.[142]
Mouse studies have suggested some symptoms of Crohn's disease, ulcerative colitis, andirritable 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 aserine protease.[143] Experimental introduction of the serineprotease 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.[144] Regional and temporal variations in those illnesses follow those associated with infection with the protozoanBlastocystis.[145]
The "cold-chain" hypothesis is thatpsychrotrophic bacteria such asYersinia andListeria 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.[146][147][148]
There is also a tentative association betweenCandida colonization and Crohn's disease.[149]
Still, these relationships between specific pathogens and Crohn's disease remain unclear.[150][151]
The increased incidence of Crohn's in theindustrialized world indicates an environmental component. Crohn's is associated with an increased intake of animalprotein,milk protein, and an increased ratio ofomega-6 toomega-3polyunsaturated fatty acids.[152]Those who consume vegetable proteins appear to have a lower incidence of Crohn's disease. Consumption of fish protein has no association.[152]Smoking increases the risk of the return of active disease (flares).[6] The introduction ofhormonal 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.[153]Isotretinoin is associated with Crohn's.[154][155][156]
Althoughstress is sometimes claimed to exacerbate Crohn's disease, there is no concrete evidence to support such claim.[3] Still, it is well known that immune function is related to stress.[157] Dietarymicroparticles, 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.[158][159] The use ofdoxycycline has also been associated with increased risk of developing inflammatory bowel diseases.[160][161][162] In one large retrospective study, patients who were prescribeddoxycycline for theiracne had a 2.25-fold greater risk of developing Crohn's disease.[161]
During acolonoscopy,biopsies of the colon are often taken to confirm the diagnosis. Certain characteristic features of thepathology seen point toward Crohn's disease; it shows a transmural pattern ofinflammation, meaning the inflammation may span the entire depth of theintestinal wall.[1]
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 astuberculosis. Biopsies may also show chronic mucosal damage, as evidenced by blunting of the intestinalvilli, 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.[164][165]
The diagnosis of Crohn's disease can sometimes be challenging,[33] and many tests are often required to assist the physician in making the diagnosis.[37] 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 thecapsule endoscopy[166] aids in endoscopic diagnosis. Intestinalultrasound should be considered an early step in the diagnosis and follow-up of patients with Crohn's disease even in patients with a proximal small bowel localization of the disease.[167][168]Giant (multinucleate) cells, a common finding in the lesions of Crohn's disease, are less common in the lesions oflichen nitidus.[169]
Endoscopic image of Crohn's colitis showing deep ulceration
CT scan showing Crohn's disease in the fundus of the stomach
Crohn's disease is one type ofinflammatory bowel disease (IBD). It typically manifests in the gastrointestinal tract and can be categorized by the specific tract region affected.
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.[170] 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.[1]
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.[171] 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 thefeces. 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.[171][172]
Acolonoscopy is the best test for making the diagnosis of Crohn's disease, as it allows direct visualization of the colon and theterminal 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, thegastroenterologist 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,[1]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 therectum, is suggestive of Crohn's disease, as are other endoscopic stigmata.[173]The utility of capsule endoscopy for this, however, is still uncertain.[174]
Asmall bowel follow-through may suggest the diagnosis of Crohn's disease and is useful when the disease involves only the small intestine. Because colonoscopy andgastroscopy allow direct visualization of only the terminal ileum and beginning of theduodenum, they cannot be used to evaluate the remainder of the small intestine. As a result, a barium follow-through X-ray, whereinbarium sulfate suspension is ingested andfluoroscopic images of the bowel are taken over time, is useful for looking for inflammation and narrowing of the small bowel.[173][175] Barium enemas, in which barium is inserted into the rectum and fluoroscopy is used to image the bowel, are rarely used in the work-up of Crohn's disease due to the advent of colonoscopy. They remain useful for identifying anatomical abnormalities when strictures of the colon are too small for a colonoscope to pass through, or in the detection of colonic fistulae (in this case contrast should be performed with iodate substances).[176]
CT andMRI scans are useful for evaluating the small bowel withenteroclysis protocols.[177] They are also useful for looking for intra-abdominal complications of Crohn's disease, such as abscesses, small bowel obstructions, or fistulae.[178] Magnetic resonance imaging (MRI) is another option for imaging thesmall bowel as well as looking for complications, though it is more expensive and less readily available.[179] MRI techniques such as diffusion-weighted imaging and high-resolution imaging are more sensitive in detecting ulceration and inflammation compared to CT.[180][181]
Imaging in pediatric Crohn's disease requires careful consideration to minimize radiation exposure while ensuring accurate diagnosis and monitoring. Magnetic Resonance Enterography (MRE) is favored over Computed Tomography Enterography (CTE) due to its lack of ionizing radiation and superior soft tissue contrast. MRE effectively assesses bowel wall thickening, inflammation, and complications such as strictures or fistulas. However, it demands longer scan times and patient cooperation, which can be challenging for younger children.[182]
Ultrasound (US), particularly contrast-enhanced ultrasound, serves as a valuable, radiation-free alternative for evaluating bowel wall thickness, vascularity, and inflammatory changes. It is especially useful for initial assessments and ongoing disease monitoring, though its effectiveness can be operator-dependent.[183]
In urgent situations where rapid imaging is necessary to evaluate severe disease complications, such as bowel perforation or abscess formation, CTE may be utilized despite its associated radiation exposure.[184]
Regular imaging follow-ups should be guided by clinical symptoms and biomarkers to minimize unnecessary scans.[185] Emerging imaging techniques continue to improve the safety and efficacy of pediatric Crohn’s disease evaluation.
Acomplete blood count may reveal anemia, which commonly is caused by blood loss leading to iron deficiency or byvitamin B12 deficiency, usually caused by ileal disease impairing vitamin B12 absorption. Rarely autoimmune hemolysis may occur.[186]Ferritin levels help assess if iron deficiency is contributing to the anemia.Erythrocyte sedimentation rate (ESR) andC-reactive protein help assess the degree of inflammation, which is important as ferritin can also be raised in inflammation.[187]
Other causes of anemia include medication used in treatment of inflammatory bowel disease, like azathioprine, which can lead to cytopenia, and sulfasalazine, which can also result infolate deficiency. Testing forSaccharomyces cerevisiae antibodies (ASCA) andantineutrophil cytoplasmic antibodies (ANCA) has been evaluated to identify inflammatory diseases of the intestine[188] and to differentiate Crohn's disease from ulcerative colitis.[189] Furthermore, increasing amounts and levels of serological antibodies such as ASCA, antilaminaribioside [Glc(β1,3)Glb(β); ALCA], antichitobioside [GlcNAc(β1,4)GlcNAc(β); ACCA], antimannobioside [Man(α1,3)Man(α)AMCA], antiLaminarin [(Glc(β1,3))3n(Glc(β1,6))n; anti-L] and antichitin [GlcNAc(β1,4)n; anti-C] associate with disease behavior and surgery, and may aid in the prognosis of Crohn's disease.[190][191][192][193]
Low serum levels of vitamin D are associated with Crohn's disease.[194] Further studies are required to determine the significance of this association.[194]
The most common disease that mimics the symptoms of Crohn's disease is ulcerative colitis, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.[1][37][38]
There is no cure for Crohn's disease andremission may not be possible or prolonged if achieved. In cases where remission is possible,relapse can be prevented andsymptoms controlled with medication, lifestyle and dietary changes, changes to eating habits (eating smaller amounts more often), reduction of stress, moderate activity, and exercise. Surgery is generally contraindicated and has not been shown to prevent relapse. Adequately controlled, Crohn's disease may not significantly restrict daily living.[208] Treatment for Crohn's disease involves first treating theacute problem and its symptoms, then maintaining remission of the disease.
Certain lifestyle changes can reduce symptoms, includingdietary adjustments,elemental diet, properhydration, andsmoking cessation. Recent reviews underlined the importance to adopt diets that are best supported by evidence, even if little is known about the impact of diets on these patients.[209][210]Diets that include higher levels of fiber and fruit are associated with reduced risk, while diets rich in total fats,polyunsaturated fatty acids, meat, andomega-6 fatty acids may increase the risk of Crohn's.[211] Maintaining a balanced diet with proper portion control can help manage symptoms of the disease. Eating small meals frequently instead of big meals may also help with a low appetite. Afood diary may help with identifying foods that trigger symptoms. Despite the recognized importance of dietary fiber for intestinal health, some people should follow alow residue diet to control acute symptoms especially if foods high ininsoluble fiber cause symptoms, e.g., due to obstruction or irritation of the bowel.[208] Some find relief in eliminatingcasein (a protein found in cow's milk) andgluten (a protein found in wheat, rye and barley) from their diets. They may have specific dietary intolerances (not allergies), for example,lactose.[212]Fatigue can be helped with regular exercise, a healthy diet, and enough sleep, and for those with malabsorption ofvitamin B12 due to disease or surgical resection of theterminal ileum, cobalamin injections. Smoking may worsen symptoms and the course of the disease, and stopping is recommended. Alcohol consumption can also worsen symptoms, and moderation or cessation is advised.[208]
Acute treatment uses medications to treat any infection (normallyantibiotics) and to reduce inflammation (normallyaminosalicylate anti-inflammatory drugs andcorticosteroids). When symptoms are in remission, treatment enters maintenance, with a goal of avoiding the recurrence of symptoms. Prolonged use of corticosteroids has significantside-effects; as a result, they are, in general, not used for long-term treatment. Alternatives include aminosalicylates alone, though only a minority are able to maintain the treatment, and many require immunosuppressive drugs.[195] It has been also suggested that antibiotics change the enteric flora, and their continuous use may pose the risk of overgrowth with pathogens such asClostridium difficile.[213]
The gradual loss of blood from the gastrointestinal tract, as well as chronic inflammation, often leads to anemia, and professional guidelines suggest routinely monitoring for this.[222][223][224]
Immunosuppressant therapies, infection risks and vaccinations
Many patients affected by Crohn's disease need immunosuppressant therapies, which are known to be associated with a higher risk of contracting opportunistic infectious diseases and of pre-neoplastic or neoplastic lesions such as cervical high-grade dysplasia and cancer.[225][226]Many of these potentially harmful diseases, such asHepatitis B,Influenza,herpes zoster virus,pneumococcal pneumonia, orhuman papilloma virus, can be prevented by vaccines. Each drug used in the treatment of IBD should be classified according to the degree of immunosuppression induced in the patient. Several guidelines suggest investigating patients’ vaccination status before starting any treatment and performing vaccinations againstVaccine-preventable disease when required.[227]Compared to the rest of the population, patients affected by IBD are known to be at higher risk of contracting somevaccine-preventable diseases such as flu and pneumonia.[228]Nevertheless, despite the increased risk of infections, vaccination rates in IBD patients are known to be suboptimal and may also be lower than vaccination rates in the general population.[229][230]
Crohn's cannot be cured bysurgery, as the disease eventually recurs, though it is used in the case of partial or full blockage of the intestine.[231] Surgery may also be required for complications such as obstructions, fistulas, or abscesses, or if the disease does not respond to drugs. After the first surgery, Crohn's usually comes back at the site where the diseased intestine was removed and the healthy ends were rejoined; it can also come back in other locations. After a resection, scar tissue builds up, which can causestrictures, which form when the intestines become too small to allow excrement to pass through easily, which can lead to a blockage. After the first resection, another resection may be necessary within five years.[citation needed] For patients with an obstruction due to a stricture, two options for treatment arestrictureplasty and resection of that portion of bowel. There is nostatistical significance between strictureplasty alone versus strictureplasty and resection in cases of duodenal involvement. In these cases, re-operation rates were 31% and 27%, respectively, indicating that strictureplasty is a safe and effective treatment for selected people with duodenal involvement.[232]
Postsurgical recurrence of Crohn's disease is relatively common. Crohn's lesions are nearly always found at the site of the resected bowel. The join (oranastomosis) after surgery may be inspected, usually during a colonoscopy, and disease activity graded. The "Rutgeerts score" is an endoscopic scoring system for postoperative disease recurrence in Crohn's disease. Postsurgical remission per the Rutgeerts score is graded as i0; while mild postsurgical recurrences are graded i1 and i2, and moderate to severe recurrences are graded i3 and i4.[233] Fewer lesions result in a lower grade. Based on the score, treatment plans can be designed to give the patient the best chance of managing the recurrence of the disease.[234]
Short bowel syndrome (SBS, also short gut syndrome or simply short gut) is caused by the surgical removal of part of the small intestine. It usually develops in those patients who have had half or more of their small intestines removed.[235]Diarrhea is the main symptom, but others may include weight loss, cramping, bloating, andheartburn. Short bowel syndrome is treated with changes in diet, intravenous feeding, vitamin and mineral supplements, and treatment with medications. In some cases of SBS,intestinal transplant surgery may be considered; though the number of transplant centres offering this procedure is quite small and it comes with a high risk due to the chance of infection and rejection of the transplanted intestine.[236]
Bile acid diarrhea is another complication following surgery for Crohn's disease in which theterminal ileum has been removed. This leads to the development of excessive watery diarrhea. It is usually thought to be due to an inability of the ileum to reabsorb bile acids after resection of the terminal ileum and was the first type ofbile acid malabsorption recognized.[237]
The use of oralprobiotic supplements to modify the composition and behaviour of the gastrointestinalmicrobiome has been researched to understand whether it may help to improve remission rate in people with Crohn's disease. However, only twocontrolled trials were available in 2020, with no clear overall evidence of higher remission nor lower adverse effects, in people with Crohn's disease receiving probiotic supplementation.[238]
Acupuncture is used to treat inflammatory bowel disease inChina, and is being used more frequently inWestern society.[244] At this time, evidence is insufficient to recommend the use of acupuncture.[243]
A 2006 survey in Germany found that about half of people with IBD used some form of alternative medicine, with the most common beinghomeopathy, and a study in France found that about 30% used alternative medicine.[245]Homeopathic preparations are not proven with this or any other condition,[246][247][248] with large-scale studies finding them to be no more effective than aplacebo.[249][250][251]
Crohn's disease is achronic condition for which there is no known cure. It is characterised by periods of improvement followed by episodes when symptoms flare up. With treatment, most people achieve a healthy weight, and the mortality rate for the disease is relatively low. It can vary from being benign to very severe, and people with CD could experience just one episode or have continuous symptoms. It usually reoccurs, although some people can remain disease-free for years or decades. Up to 80% of people with Crohn's disease are hospitalized at some point during the course of their disease, with the highest rate occurring in the first year after diagnosis.[11] Most people with Crohn's live a normal lifespan.[254] However, Crohn's disease is associated with a small increase in risk of small bowel and colorectal carcinoma (bowel cancer).[255]
The percentage of people with Crohn's disease has been determined inNorway and theUnited States and is similar at 6 to 7.1:100,000. TheCrohn's & Colitis Foundation of America cites this number as approx 149:100,000; NIH cites 28 to 199 per 100,000.[256][257] Crohn's disease is more common in northern countries, and with higher rates still in the northern areas of these countries.[258] The incidence of Crohn's disease is thought to be similar inEurope but lower inAsia andAfrica.[256] It also has a higher incidence inAshkenazi Jews[1][259] and smokers.[260]
Crohn's disease begins most commonly in people in their teens and 20s, and people in their 50s through to their 70s.[1][37][26] It is rarely diagnosed in early childhood. It usually affects female children more severely than males.[261] However, only slightly more women than men have Crohn's disease.[262] Parents, siblings or children of people with Crohn's disease are 3 to 20 times more likely to develop the disease.[263] Twin studies find that if one has the disease there is a 55% chance the other will too.[264]
The incidence of Crohn's disease is increasing in Europe[265] and in newly industrialised countries.[266] For example, in Brazil, there has been an annual increase of 11% in the incidence of Crohn's disease since 1990.[266]
Ileitis terminalis was first described by Polish surgeonAntoni Leśniowski in 1904, although it was not conclusively distinguished from intestinal tuberculosis.[268] In Poland, it is still called Leśniowski-Crohn's disease (Polish:choroba Leśniowskiego-Crohna).Burrill Bernard Crohn, an American gastroenterologist atNew York City'sMount Sinai Hospital, described fourteen cases in 1932, and submitted them to theAmerican Medical Association under the rubric of "Terminal ileitis: A new clinical entity". Later that year, he, along with colleaguesLeon Ginzburg and Gordon Oppenheimer, published the case series "Regional ileitis: a pathologic and clinical entity". However, due to the precedence of Crohn's name in the alphabet, it later became known in the worldwide literature as Crohn's disease.[27]
^abcCosnes J (June 2004). "Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice".Best Practice & Research. Clinical Gastroenterology.18 (3):481–496.doi:10.1016/j.bpg.2003.12.003.PMID15157822.
^Frisch M, Gridley G (October 2002). "Appendectomy in adulthood and the risk of inflammatory bowel diseases".Scandinavian Journal of Gastroenterology.37 (10):1175–1177.doi:10.1080/003655202760373380.PMID12408522.
^abcDessein R, Chamaillard M, Danese S (September 2008). "Innate immunity in Crohn's disease: the reverse side of the medal".Journal of Clinical Gastroenterology.42 (Suppl 3 Pt 1):S144 –S147.doi:10.1097/MCG.0b013e3181662c90.PMID18806708.
^Stefanelli T, Malesci A, Repici A, Vetrano S, Danese S (May 2008). "New insights into inflammatory bowel disease pathophysiology: paving the way for novel therapeutic targets".Current Drug Targets.9 (5):413–418.doi:10.2174/138945008784221170.PMID18473770.
^Lalande JD, Behr MA (July 2010). "Mycobacteria in Crohn's disease: how innate immune deficiency may result in chronic inflammation".Expert Review of Clinical Immunology.6 (4):633–641.doi:10.1586/eci.10.29.PMID20594136.S2CID25402952.
^abCrohn BB, Ginzburg L, Oppenheimer GD (May 2000). "Regional ileitis: a pathologic and clinical entity. 1932".The Mount Sinai Journal of Medicine, New York.67 (3):263–268.PMID10828911.
^abPimentel M, Chang M, Chow EJ, Tabibzadeh S, Kirit-Kiriak V, Targan SR, et al. (December 2000). "Identification of a prodromal period in Crohn's disease but not ulcerative colitis".The American Journal of Gastroenterology.95 (12):3458–3462.doi:10.1111/j.1572-0241.2000.03361.x.PMID11151877.S2CID2764694.
^Taylor BA, Williams GT, Hughes LE, Rhodes J (August 1989). "The histology of anal skin tags in Crohn's disease: an aid to confirmation of the diagnosis".International Journal of Colorectal Disease.4 (3):197–199.doi:10.1007/BF01649703.PMID2769004.S2CID7831833.
^Greuter T, Piller A, Fournier N, Safroneeva E, Straumann A, Biedermann L, et al. (November 2018). "Upper Gastrointestinal Tract Involvement in Crohn's Disease: Frequency, Risk Factors, and Disease Course".Journal of Crohn's & Colitis.12 (12):1399–1409.doi:10.1093/ecco-jcc/jjy121.PMID30165603.
^Laube R, Liu K, Schifter M, Yang JL, Suen MK, Leong RW (February 2018). "Oral and upper gastrointestinal Crohn's disease".Journal of Gastroenterology and Hepatology.33 (2):355–364.doi:10.1111/jgh.13866.PMID28708248.
^Greenstein AJ, Janowitz HD, Sachar DB (September 1976). "The extra-intestinal complications of Crohn's disease and ulcerative colitis: a study of 700 patients".Medicine.55 (5):401–412.doi:10.1097/00005792-197609000-00004.PMID957999.
^Bernstein CN, Blanchard JF, Rawsthorne P, Yu N (April 2001). "The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study".The American Journal of Gastroenterology.96 (4):1116–1122.doi:10.1111/j.1572-0241.2001.03756.x.PMID11316157.
^Harbord M, Annese V, Vavricka SR, Allez M, Barreiro-de Acosta M, Boberg KM, et al. (March 2016). "The First European Evidence-based Consensus on Extra-intestinal Manifestations in Inflammatory Bowel Disease".Journal of Crohn's & Colitis.10 (3):239–254.doi:10.1093/ecco-jcc/jjv213.PMID26614685.
^Orchard TR, Chua CN, Ahmad T, Cheng H, Welsh KI, Jewell DP (September 2002). "Uveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes".Gastroenterology.123 (3):714–718.doi:10.1053/gast.2002.35396.PMID12198697.
^Kumar V, Abbas AK, Fausto N (July 30, 2004). "The Gastrointestinal Tract".Robbins and Cotran: Pathologic Basis of Disease (7th ed.). Philadelphia, Pennsylvania: Elsevier Saunders. p. 847.ISBN978-0-7216-0187-8.
^Barberio B, Massimi D, Cazzagon N, Zingone F, Ford AC, Savarino EV (December 2021). "Prevalence of Primary Sclerosing Cholangitis in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis".Gastroenterology.161 (6):1865–1877.doi:10.1053/j.gastro.2021.08.032.hdl:11577/3401611.PMID34425093.
^Hasegawa N, Ishimoto S, Takazoe M, Tsunoda K, Fujimaki Y, Shiraishi A, et al. (July 2009). "Recurrent hoarseness due to inflammatory vocal fold lesions in a patient with Crohn's disease".The Annals of Otology, Rhinology, and Laryngology.118 (7):532–535.doi:10.1177/000348940911800713.PMID19708494.S2CID8472904.
^Bernstein M, Irwin S, Greenberg GR (September 2005). "Maintenance infliximab treatment is associated with improved bone mineral density in Crohn's disease".The American Journal of Gastroenterology.100 (9):2031–2035.doi:10.1111/j.1572-0241.2005.50219.x.PMID16128948.S2CID28982700.
^abcThrash B, Patel M, Shah KR, Boland CR, Menter A (February 2013). "Cutaneous manifestations of gastrointestinal disease: part II".Journal of the American Academy of Dermatology.68 (2): 211.e1-33, quiz 244–6.doi:10.1016/j.jaad.2012.10.036.PMID23317981.S2CID1819416.
^Kapsoritakis AN, Psychos AK, Sfiridaki A, Zintzaras E, Potamianos SP (June 2006). "Finger clubbing and erythropoietin serum levels in active IBD".Inflammatory Bowel Diseases.12 (6):535–536.doi:10.1097/00054725-200606000-00014.PMID16775499.
^Itzkowitz SH, Present DH, et al. (Crohn's and Colitis Foundation of America Colon Cancer in IBD Study Group) (March 2005). "Consensus conference: Colorectal cancer screening and surveillance in inflammatory bowel disease".Inflammatory Bowel Diseases.11 (3):314–321.doi:10.1097/01.mib.0000160811.76729.d5.PMID15735438.
^Parakkal D, Sifuentes H, Semer R, Ehrenpreis ED (November 2011). "Hepatosplenic T-cell lymphoma in patients receiving TNF-α inhibitor therapy: expanding the groups at risk".European Journal of Gastroenterology & Hepatology.23 (12):1150–1156.doi:10.1097/MEG.0b013e32834bb90a.PMID21941193.S2CID27267004.
^Evans JP, Steinhart AH, Cohen Z, McLeod RS (2003). "Home total parenteral nutrition: an alternative to early surgery for complicated inflammatory bowel disease".Journal of Gastrointestinal Surgery.7 (4):562–566.doi:10.1016/S1091-255X(02)00132-4.PMID12763417.S2CID195305419.
^Henckaerts L, Figueroa C, Vermeire S, Sans M (May 2008). "The role of genetics in inflammatory bowel disease".Current Drug Targets.9 (5):361–368.doi:10.2174/138945008784221161.PMID18473763.
^abMarks DJ, Harbord MW, MacAllister R, Rahman FZ, Young J, Al-Lazikani B, et al. (February 2006). "Defective acute inflammation in Crohn's disease: a clinical investigation".Lancet.367 (9511):668–678.doi:10.1016/S0140-6736(06)68265-2.PMID16503465.S2CID13898663.
^Comalada M, Peppelenbosch MP (September 2006). "Impaired innate immunity in Crohn's disease".Trends in Molecular Medicine.12 (9):397–399.doi:10.1016/j.molmed.2006.07.005.PMID16890491.
^Cuthbert AP, Fisher SA, Mirza MM, King K, Hampe J, Croucher PJ, et al. (April 2002). "The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease".Gastroenterology.122 (4):867–874.doi:10.1053/gast.2002.32415.PMID11910337.
^Clevers H (February 2009). "Inflammatory bowel disease, stress, and the endoplasmic reticulum".The New England Journal of Medicine.360 (7):726–727.doi:10.1056/NEJMcibr0809591.PMID19213688.
^Vermeire S (June 2004). "NOD2/CARD15: relevance in clinical practice".Best Practice & Research. Clinical Gastroenterology (Review).18 (3):569–575.doi:10.1016/j.bpg.2003.12.008.PMID15157828.
^Chermesh I, Azriel A, Alter-Koltunoff M, Eliakim R, Karban A, Levi BZ (July 2007). "Crohn's disease and SLC11A1 promoter polymorphism".Digestive Diseases and Sciences.52 (7):1632–1635.doi:10.1007/s10620-006-9682-3.PMID17385031.S2CID11429585.
^Walker MM, Murray JA (August 2011). "An update in the diagnosis of coeliac disease".Histopathology (Review).59 (2):166–179.doi:10.1111/j.1365-2559.2010.03680.x.PMID21054494.S2CID5196629.Recent genome-wide association studies have shown that chronic inflammatory and autoimmune diseases are linked genetically to coeliac disease; for example, type 1 diabetes mellitus, Grave's disease and Crohn's disease.
^Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB, et al. (June 2007). "Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice".Gastroenterology.132 (7):2359–2370.doi:10.1053/j.gastro.2007.03.104.PMID17570211.
^Mpofu CM, Campbell BJ, Subramanian S, Marshall-Clarke S, Hart CA, Cross A, et al. (November 2007). "Microbial mannan inhibits bacterial killing by macrophages: a possible pathogenic mechanism for Crohn's disease".Gastroenterology.133 (5):1487–1498.doi:10.1053/j.gastro.2007.08.004.PMID17919633.
^Clancy R, Ren Z, Turton J, Pang G, Wettstein A (May 2007). "Molecular evidence for Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn's disease correlates with enhanced TNF-alpha secretion".Digestive and Liver Disease.39 (5):445–451.doi:10.1016/j.dld.2006.12.006.PMID17317344.
^Nakase H, Tamaki H, Matsuura M, Chiba T, Okazaki K (November 2011). "Involvement of mycobacterium avium subspecies paratuberculosis in TNF-α production from macrophage: possible link between MAP and immune response in Crohn's disease".Inflammatory Bowel Diseases.17 (11):E140 –E142.doi:10.1002/ibd.21750.PMID21990211.
^Lesko SM, Kaufman DW, Rosenberg L, Helmrich SP, Miller DR, Stolley PD, et al. (November 1985). "Evidence for an increased risk of Crohn's disease in oral contraceptive users".Gastroenterology.89 (5):1046–1049.doi:10.1016/0016-5085(85)90207-0.PMID4043662.
^Reddy D, Siegel CA, Sands BE, Kane S (July 2006). "Possible association between isotretinoin and inflammatory bowel disease".The American Journal of Gastroenterology.101 (7):1569–1573.doi:10.1111/j.1572-0241.2006.00632.x.PMID16863562.S2CID27663573.
^Lee TW, Russell L, Deng M, Gibson PR (August 2013). "Association of doxycycline use with the development of gastroenteritis, irritable bowel syndrome and inflammatory bowel disease in Australians deployed abroad".Internal Medicine Journal.43 (8):919–926.doi:10.1111/imj.12179.PMID23656210.S2CID9418654.
^abMargolis DJ, Fanelli M, Hoffstad O, Lewis JD (December 2010). "Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease".The American Journal of Gastroenterology.105 (12):2610–2616.doi:10.1038/ajg.2010.303.PMID20700115.S2CID20085592.
^Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB, et al. (2007). "Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice".Gastroenterology.132 (7):2359–70.doi:10.1053/j.gastro.2007.03.104.PMID17570211.
^Crawford JM (1994). "17. The Gastrointestinal tract". In Cotran RS, Kumar V, Robbins SL (eds.).Robbins Pathologic Basis of Disease (5th ed.). W.B. Saunders.ISBN0-7216-5032-5.OCLC29702821.
^abGasche C, Scholmerich J, Brynskov J, D'Haens G, Hanauer SB, Irvine EJ, et al. (February 2000). "A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998".Inflammatory Bowel Diseases.6 (1):8–15.doi:10.1002/ibd.3780060103.PMID10701144.
^Dubinsky MC, Fleshner PP (June 2003). "Treatment of Crohn's Disease of Inflammatory, Stenotic, and Fistulizing Phenotypes".Current Treatment Options in Gastroenterology.6 (3):183–200.doi:10.1007/s11938-003-0001-1.PMID12744819.S2CID21302609.
^abHara AK, Leighton JA, Heigh RI, Sharma VK, Silva AC, De Petris G, et al. (January 2006). "Crohn disease of the small bowel: preliminary comparison among CT enterography, capsule endoscopy, small-bowel follow-through, and ileoscopy".Radiology.238 (1):128–134.doi:10.1148/radiol.2381050296.PMID16373764.
^Triester SL, Leighton JA, Leontiadis GI, Gurudu SR, Fleischer DE, Hara AK, et al. (May 2006). "A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with non-stricturing small bowel Crohn's disease".The American Journal of Gastroenterology.101 (5):954–964.doi:10.1111/j.1572-0241.2006.00506.x.PMID16696781.S2CID25684863.
^Carucci LR, Levine MS (March 2002). "Radiographic imaging of inflammatory bowel disease".Gastroenterology Clinics of North America.31 (1):93–117, ix.doi:10.1016/S0889-8553(01)00007-3.PMID12122746.
^Rajesh A, Maglinte DD (January 2006). "Multislice CT enteroclysis: technique and clinical applications".Clinical Radiology.61 (1):31–39.doi:10.1016/j.crad.2005.08.006.PMID16356814.
^Chamouard P, Richert Z, Meyer N, Rahmi G, Baumann R (July 2006). "Diagnostic value of C-reactive protein for predicting activity level of Crohn's disease".Clinical Gastroenterology and Hepatology.4 (7):882–887.doi:10.1016/j.cgh.2006.02.003.PMID16630759.
^Papp M, Altorjay I, Dotan N, Palatka K, Foldi I, Tumpek J, et al. (March 2008). "New serological markers for inflammatory bowel disease are associated with earlier age at onset, complicated disease behavior, risk for surgery, and NOD2/CARD15 genotype in a Hungarian IBD cohort".The American Journal of Gastroenterology.103 (3):665–681.doi:10.1111/j.1572-0241.2007.01652.x.PMID18047543.S2CID6015339.
^Seow CH, Stempak JM, Xu W, Lan H, Griffiths AM, Greenberg GR, et al. (June 2009). "Novel anti-glycan antibodies related to inflammatory bowel disease diagnosis and phenotype".The American Journal of Gastroenterology.104 (6):1426–1434.doi:10.1038/ajg.2009.79.PMID19491856.S2CID25021606.
^Dotan I (December 2007). "Serologic markers in inflammatory bowel disease: tools for better diagnosis and disease stratification".Expert Review of Gastroenterology & Hepatology.1 (2):265–274.doi:10.1586/17474124.1.2.265.PMID19072419.S2CID32035337.
^Broomé U, Bergquist A (February 2006). "Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer".Seminars in Liver Disease.26 (1):31–41.doi:10.1055/s-2006-933561.PMID16496231.S2CID260320940.
^Mahadeva U, Martin JP, Patel NK, Price AB (July 2002). "Granulomatous ulcerative colitis: a re-appraisal of the mucosal granuloma in the distinction of Crohn's disease from ulcerative colitis".Histopathology.41 (1):50–5.doi:10.1046/j.1365-2559.2002.01416.x.PMID12121237.S2CID29476514.
^Lewis NR, Scott BB (July 2006)."Systematic review: the use of serology to exclude or diagnose coeliac disease (a comparison of the endomysial and tissue transglutaminase antibody tests)".Alimentary Pharmacology & Therapeutics (Review).24 (1):47–54.doi:10.1111/j.1365-2036.2006.02967.x.PMID16803602.S2CID16823218.Both the endomysial antibody and tissue transglutaminase antibody have very high sensitivities (93% for both) and specificities (>99% and >98% respectively) for the diagnosis of typical coeliac disease with villous atrophy. (...) As the detection of at least partial villous atrophy was used to make a diagnosis of coeliac disease in the vast majority of studies, we can't assume that the same LRs apply to coeliac patients with lesser abnormality such as an increase in intraepithelial lymphocytes or electron-microscopic changes only. In fact, if such lesser abnormalities were used as criteria for diagnosing (and excluding) coeliac disease, the sensitivity of the tests could be lower (i.e. more false negatives), especially since a number of studies suggest that the EMA and tTG antibody tests are less sensitive with lesser degrees of mucosal abnormality
^Rodrigo L, Garrote JA, Vivas S (September 2008)."[Celiac disease]".Medicina Clinica (Review) (in Spanish).131 (7):264–270.doi:10.1016/S0025-7753(08)72247-4.PMID18775218. Archived fromthe original on March 19, 2016. RetrievedMarch 13, 2016.Estos marcadores presentan en general una elevada sensibilidad y especificidad (cercanas al 90%) en presencia de atrofia marcada de las vellosidades intestinales. Sin embargo, muestran una notable disminución de la sensibilidad (del orden del 40-50%) en casos con atrofia vellositaria leve o cambios mínimos.These markers generally have high sensitivity and specificity (around 90%) in the presence of marked atrophy of the villi. However, they show a marked decrease in sensitivity (of the order of 40-50%) in cases with mild villous atrophy or minimal changes.
^abAgabegi ED, Agabegi SS (2008). "Inflammatory bowel disease (IBD)".Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 152–156.ISBN0-7817-7153-6.
^Feller M, Huwiler K, Schoepfer A, Shang A, Furrer H, Egger M (February 2010). "Long-term antibiotic treatment for Crohn's disease: systematic review and meta-analysis of placebo-controlled trials".Clinical Infectious Diseases.50 (4):473–80.doi:10.1086/649923.PMID20067425.
^Ananthakrishnan AN, Kaplan GG, Bernstein CN, Burke KE, Lochhead PJ, Sasson AN, et al. (July 2022). "Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus".The Lancet. Gastroenterology & Hepatology.7 (7):666–678.doi:10.1016/S2468-1253(22)00021-8.PMID35487235.
^Hou JK, Abraham B, El-Serag H (April 2011). "Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature".The American Journal of Gastroenterology.106 (4):563–573.doi:10.1038/ajg.2011.44.PMID21468064.S2CID10337669.
^Escott-Stump S (2008).Nutrition and Diagnosis-Related Care, 7th edition. Baltimore, MD: Lippincott Williams & Wilkins. pp. 1020 (pp 431).ISBN978-1-60831-017-3.
^Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, et al. (International Efficacy of Natalizumab as Active Crohn's Therapy (ENACT-1) Trial Group; Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group) (November 2005)."Natalizumab induction and maintenance therapy for Crohn's disease".The New England Journal of Medicine.353 (18):1912–1925.doi:10.1056/NEJMoa043335.PMID16267322.
^Mowat C, Cole A, Windsor A, Ahmad T, Arnott I, Driscoll R, et al. (IBD Section of the British Society of Gastroenterology) (May 2011). "Guidelines for the management of inflammatory bowel disease in adults".Gut.60 (5):571–607.doi:10.1136/gut.2010.224154.PMID21464096.S2CID8269837.
^Beaugerie L, Itzkowitz SH (April 2015). "Cancers complicating inflammatory bowel disease".The New England Journal of Medicine.372 (15):1441–1452.doi:10.1056/NEJMra1403718.PMID25853748.
^Toruner M, Loftus EV, Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, et al. (April 2008). "Risk factors for opportunistic infections in patients with inflammatory bowel disease".Gastroenterology.134 (4):929–936.doi:10.1053/j.gastro.2008.01.012.PMID18294633.
^Farraye FA, Melmed GY, Lichtenstein GR, Kane SV (February 2017). "ACG Clinical Guideline: Preventive Care in Inflammatory Bowel Disease".The American Journal of Gastroenterology.112 (2):241–258.doi:10.1038/ajg.2016.537.PMID28071656.
^Ananthakrishnan AN, McGinley EL (March 2013). "Infection-related hospitalizations are associated with increased mortality in patients with inflammatory bowel diseases".Journal of Crohn's & Colitis.7 (2):107–112.doi:10.1016/j.crohns.2012.02.015.PMID22440891.
^Malhi G, Rumman A, Thanabalan R, Croitoru K, Silverberg MS, Hillary Steinhart A, et al. (June 2015). "Vaccination in inflammatory bowel disease patients: attitudes, knowledge, and uptake".Journal of Crohn's & Colitis.9 (6):439–444.doi:10.1093/ecco-jcc/jjv064.PMID25908717.
^Ozuner G, Fazio VW, Lavery IC, Milsom JW, Strong SA (November 1996). "Reoperative rates for Crohn's disease following strictureplasty. Long-term analysis".Diseases of the Colon and Rectum.39 (11):1199–1203.doi:10.1007/BF02055108.PMID8918424.S2CID33628350.
^Joos S, Brinkhaus B, Maluche C, Maupai N, Kohnen R, Kraehmer N, et al. (2004). "Acupuncture and moxibustion in the treatment of active Crohn's disease: a randomized controlled study".Digestion.69 (3):131–139.doi:10.1159/000078151.PMID15114043.S2CID7852406.
^Joos S (June 2011). "Review on efficacy and health services research studies of complementary and alternative medicine in inflammatory bowel disease".Chinese Journal of Integrative Medicine.17 (6):403–409.doi:10.1007/s11655-011-0758-3.PMID21660673.S2CID207298246.
^Ladyman J (2013)."Towards a Demarcation of Science from Pseudoscience". In Pigliucci M, Boudry M (eds.).Philosophy of Pseudoscience: Reconsidering the Demarcation Problem.University of Chicago Press. pp. 45–59.ISBN978-0-226-05182-6.Yet homeopathy is a paradigmatic example of pseudoscience. It is neither simply bad science nor science fraud, but rather profoundly departs from scientific method and theories while being described as scientific by some of its adherents (often sincerely).
^Shang A, Huwiler-Müntener K, Nartey L, Jüni P, Dörig S, Sterne JA, et al. (2005). "Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy".Lancet.366 (9487):726–732.doi:10.1016/S0140-6736(05)67177-2.PMID16125589.S2CID17939264.
^Moum B, Vatn MH, Ekbom A, Aadland E, Fausa O, Lygren I, et al. (April 1996). "Incidence of Crohn's disease in four counties in southeastern Norway, 1990-93. A prospective population-based study. The Inflammatory Bowel South-Eastern Norway (IBSEN) Study Group of Gastroenterologists".Scandinavian Journal of Gastroenterology.31 (4):355–361.doi:10.3109/00365529609006410.PMID8726303.
