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Crohn's disease
Other namesCrohn disease, Crohn syndrome, granulomatous enteritis, regional enteritis, Leśniowski-Crohn disease
Endoscopic image of severe Crohn's colitis showing diffuse loss of mucosal architecture, friability of mucosa in sigmoid colon and exudate on wall.
SpecialtyGastroenterology
SymptomsAbdominal pain, diarrhea (may be bloody), fever, weight loss,[1] fatigue, mouth sores, reduced appetite[2]
ComplicationsAnemia, skin rashes, arthritis, bowel cancer[1]
Usual onset20–29 years[3]
DurationLong term[1]
CausesUncertain
Risk factorsGenetic predisposition, living in a developed country,[4]
stress,[5] tobacco smoking,[6]
having undergone an appendectomy[7][8] or tonsillectomy[9]
Diagnostic methodBiopsy, medical imaging[1]
Differential diagnosisIrritable bowel syndrome, celiac disease, Behçet's disease, nonsteroidal anti-inflammatory drug enteropathy, intestinal tuberculosis[1][10]
MedicationCorticosteroids, biological therapy, immunosuppressants such as azathioprine, methotrexate[1]
PrognosisSlightly increased risk of death[11]
Frequency3.2 per 1,000 (developed world)[12]
Named after

Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract.[3] Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss.[1][3] Complications outside of the gastrointestinal tract may include anemia, skin rashes, arthritis, inflammation of the eye, and fatigue.[1] The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum.[1] Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer.[1]

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 a chronic inflammatory disorder, in which the body's immune system defends the gastrointestinal tract, possibly targeting microbial antigens.[14][16] While Crohn's is an immune-related disease, it does not seem to be an autoimmune disease (the immune system is not triggered by the body itself).[17] The exact underlying immune problem is not clear; however, it may be an immunodeficiency state.[16][18][19]

About half of the overall risk is related to genetics, with more than 70 genes involved.[1][20] Tobacco smokers are three times as likely to develop Crohn's disease as non-smokers.[6] It often begins after gastroenteritis.[1] Other conditions with similar symptoms include irritable bowel syndrome and Behçet's disease.[1]

There is no known cure for Crohn's disease.[1][3] Treatment options are intended to help with symptoms, maintain remission, and prevent relapse.[1] In those newly diagnosed, a corticosteroid may be used for a brief period of time to improve symptoms rapidly, alongside another medication such as either methotrexate or a thiopurine used 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] While surgery should be used as little as possible, it is necessary to address some abscesses, certain bowel obstructions, and cancers.[1] Checking for bowel cancer via colonoscopy is recommended every few 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 the developed 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 reduced life expectancy.[1] It tends to start in adolescence and young adulthood, though it can occur at any age.[25][1][3][26] Males and females are equally affected.[3]

Signs and symptoms

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The three most common sites of intestinal involvement in Crohn's disease are ileal, ileocolic and colonic[27].

Crohn's disease is characterized by recurring flares of intestinal inflammation, with diarrhea and abdominal pain as the primary symptoms. Symptoms may be non-specific and progress gradually, and many people have symptoms for years before diagnosis. Unlike ulcerative colitis, inflammation can occur anywhere in the gastrointestinal tract, most often in the ileum and colon, and can involve all layers of the intestine. Disease location tends to be stable, with a third of patients having colonic disease, a third having ileocolic disease, and a third having ileal disease. The disease may also involve perianal, upper gastrointestinal, and extraintestinal organs.[27]

Gastrointestinal

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  • Diarrhea affects 82% of people at the onset of Crohn's disease, with severity ranging from mild to severe enough to require substitution of water and electrolytes. With Crohn's disease, diarrhea is frequent and urgent rather than voluminous.[28]
  • Abdominal pain affects at least 70% of people during the course of Crohn's disease. It can result directly from intestinal inflammation, or from complications such as strictures and fistulas.[29] Pain most commonly occurs in the lower right abdomen.[30]
  • Rectal bleeding is less common than in ulcerative colitis, and is more likely to occur with inflammation in the colon or rectum. Bleeding in the colon or rectum is bright red, whereas bleeding in higher segments causes dark or black stools.[31]
  • Bloating, flatus, and other symptoms of irritable bowel syndrome occur in 41% of people in remission.[32]
  • Perianal involvement occurs in 18–43% of cases, more frequently if the colon and rectum are inflamed, and can cause fistulas, skin tags, hemorrhoids, fissures, ulcers, and strictures.[33]
  • Upper gastrointestinal involvement is rare, occurring in 0.5-16% of cases, and may cause symptoms such as pain while swallowing, difficulty swallowing, vomiting, and nausea.[34]

Systemic

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Crohn's disease often presents with systemic symptoms, including:

  • Chronic fatigue, which lasts for at least 6 months and cannot be cured by rest, occurs in 80% of people with Crohn's disease, including 30% of people who are in remission.[35]
  • Fevers, typically low-grade, are often reported as initial symptoms of Crohn's disease. High-grade fevers are often a result of abscesses.[36]
  • Weight loss often occurs due to diarrhea and reduced appetite.[36]

Extraintestinal

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Extraintestinal manifestations occur in 21–47% of cases, and include symptoms such as:[27]

Complications

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Endoscopic image of colon cancer identified in sigmoid colon on screening colonoscopy for Crohn's disease.

Bowel damage due to inflammation occurs in half of cases within 10 years of diagnosis, and can lead to stricturing or penetrating disease forms. This can cause complications such as:

Malnutrition occurs in 38.9% of people in remission and 82.8% of people with active disease due to malabsorption in the small intestine, reduced appetite, and drug interactions.[40] This can cause complications such as:

Intestinal cancers may develop as a result of prolonged or severe inflammation.[42] This includes:

  • Colorectal cancer has a prevalence of 7% at 30 years after diagnosis and accounts for 15% of deaths in people with Crohn's. Risk is higher if the disease occurs in most of the colon. Endoscopic surveillance is performed to detect and remove polyps, while surgery is required for dysplasia beyond the mucosal surface.[42]
  • Small bowel cancer has a prevalence of 1.6%, at least 12-times greater in people with Crohn's disease. Unlike colorectal cancer, endoscopic surveillance is ineffective and not recommended for small bowel cancer.[43]

Causes

[edit]

Risk factors

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Smoking is a major modifiable risk factor for Crohn's disease, particularly in Western countries, where it doubles the risk. This risk is higher in females and varies with age. Smoking is also linked to earlier disease onset, increased need for immunosuppression, more surgeries, and higher recurrence rates. Ethnic differences have been noted, with studies in Japan linking passive smoking to the disease.[27] Proposed mechanisms for smoking's effects include impaired autophagy, direct toxicity to immune cells, and changes in the microbiome.[44]

Diet may influence the development of Crohn's disease by affecting the gut microbiome. The shift from high-fiber, low-fat foods to processed foods reduces microbiota diversity, increasing the risk of Crohn's disease.[27] Conversely, high-fiber diets may reduce risk by up to 40%, likely due to the production of anti-inflammatory short-chain fatty acids from fiber metabolism by gut bacteria.[44] The Mediterranean diet is also linked to a lower risk of later-onset Crohn's disease. Since diet's effect on the microbiome is temporary, its role in gut dysbiosis is controversial.[27]

Childhood antibiotic exposure is linked to a higher risk of Crohn's disease due to changes in the intestinal microbiome, which shapes the immune system in early life. Other medications, like oral contraceptives, aspirin, and NSAIDs, may also increase risk by up to two-fold. Conversely, breastfeeding and statin use may reduce risk, though breastfeeding's effects are inconsistent. Early life factors such as mode of delivery, pet exposure, and infections—related to the hygiene hypothesis—also significantly influence risk, likely due to influences on the microbiome.[44]

Genetics

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Genetics significantly influences the risk of Crohn's disease. First-degree relatives of affected individuals have a five-fold increased risk, while identical twins have a 38–50% risk if one twin is affected. Genome-wide association studies have identified around 200 loci linked to Crohn's, most found in non-coding regions that regulate gene expression and overlap with other immune-related conditions, such as ankylosing spondylitis and psoriasis.[44] While genetics can predict disease location, it does not determine complications like stricturing. A substantial portion of inherited risk is attributed to a few key polymorphisms.[27]

  • NOD2 mutations are the primary genetic risk factor for ileal Crohn's disease, impairing the function of immune cells, particularly Paneth cells. These mutations are found in 10–27% of individuals with Crohn's disease, predominantly in Caucasian populations. Heterozygotes (one mutated copy) have a three-fold risk, while homozygotes (two copies) have a 20–40 fold risk.[45]
  • ATG16L1 mutations impair autophagy and immune defense, and are more common in Caucasians.[27]
  • IL23R mutations increase inflammatory signaling of the interleukin-23 pathway, and are more common in Caucasians.[27]
  • TNFSF15 mutations are the primary genetic risk factor in Asian populations.[27]
  • IL10RA mutations impair the anti-inflammatory signaling of interleukin-10, causing early-onset Crohn's disease with high penetrance.

Mechanism

[edit]
diagram of mechanism of Crohn's disease
The intestinal barrier and immune system in health and during Crohn's disease. In health, immune cells secrete TGFβ and retinoic acid to promote the differentiation of Tregs, which regulate the inflammatory behavior of effector T cells.[46] During Crohn's disease, microbiome alterations, intestinal barrier permeability, and deficient innate immunity enable pathogens to enter the gut tissue. This causes antigen-presenting cells to upregulate IL-12, IL-18, and IL-23, increasing the differentiation of Th1 and Th17 cells. These cells secrete inflammatory cytokines such as IL-17, IFNγ, and TNF to perpetuate inflammation.[44]

Crohn's disease is believed to be caused by a dysregulated immune response to gut bacteria, though the exact mechanism is unknown. This is evidenced by the disease's links to genes involved in bacteria defense and its occurrence in the ileum and colon, the most bacteria-dense segments of the intestine.[47] In Crohn's disease, a permeable intestinal barrier and a deficient innate immune response enable bacteria to enter intestinal tissue, causing an excessive inflammatory response from T helper 1 (Th1) and T helper 17 (Th17) cells. An altered microbiome may also be causatory and serve as the link to environmental factors.[44]

Intestinal barrier

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The epithelial barrier is a single layer of epithelial cells covered in antimicrobial mucus that protects the intestine from gut bacteria.[47] Epithelial cells are joined together by tight junction proteins, which are reduced by Crohn's-linked polymorphisms. In particular, claudin-5 and claudin-8 are reduced, while pore-forming claudin-2 is increased, causing intestinal permeability. Epithelial cells under stress emit inflammatory signals such as the unfolded protein response to stimulate the immune system, and Crohn's-linked polymorphisms to the ATG16L1 gene lower the threshold at which this response is triggered.[27]

Paneth cells exist in the epithelial barrier of the small intestine and secrete α-defensins to prevent bacteria from entering gut tissue.[47] Genetic polymorphisms associated with Crohn's disease can impair this ability and lead to Crohn's disease in the ileum. NOD2 is a receptor produced by Paneth cells to sense bacteria, and mutations to NOD2 can inhibit the antimicrobial activity of Paneth cells. ATG16L1, IRGM, and LRRK2 are proteins involved in selective autophagy, the mechanism by which Paneth cells secrete α-defensins, and mutations to these genes also impair the antimicrobial activity of Paneth cells.[27]

Intraepithelial lymphocytes (IELs) are immune cells that exist in the epithelial barrier, consisting mostly of activated T cells. They interact with gut bacteria directly and emit signals to regulate the intestinal immune system. IELs in Crohn's disease produce increased levels of inflammatory cytokines IL-17, IFNγ, and TNF.[27] It is hypothesized that inflammatory signals from the immune system and alterations to the gut microbiome influence IELs to produce inflammatory signals, contributing to Crohn's disease.[48]

Immune system

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Normally, intestinal macrophages have reduced inflammatory behavior while retaining their ability to consume and destroy pathogens. In Crohn's disease, the number and activity of macrophages is reduced, enabling the entrance of pathogens into intestinal tissue.[44] Macrophages degrade internal pathogens through autophagy, which is impaired by Crohn's-linked polymorphisms in genes such as NOD2 and ATG16L1.[27] Additionally, people with Crohn's tend to have a separate abnormal population of macrophages that secrete proinflammatory cytokines such as TNF and IL-6.[44]

Neutrophils are recruited from the bloodstream in response to inflammatory signals, and defend tissue by secreting antimicrobial substances and consuming pathogens.[47] In Crohn's disease, neutrophil recruitment is delayed and autophagy is impaired, allowing bacteria to survive in intestinal tissue.[44] Dysfunction in neutrophil secretion of reactive oxygen species, which are toxic to bacteria, is associated with very early onset Crohn's disease. Although neutrophils are important in bacterial defense, their subsequent accumulation in Crohn's disease damages the epithelial barrier and perpetuates inflammation.[27]

Innate lymphoid cells (ILCs) consist of subtypes including ILC1s, ILC2s, and ILC3s. ILC3s are particularly important for regenerating the epithelial barrier through secretion of IL-17 by NCR- ILC3s and IL-22 by NCR+ ILC3s. During Crohn's disease, inflammatory signals from antigen-presenting cells, such as IL-23, cause excessive IL-17 and IL-22 secretion. Although these cytokines protect the intestinal barrier, excessive production damages the barrier through increased inflammation and neutrophil recruitment. Additionally, IL-12 from activated dendritic cells influence NCR+ ILC3s to transform into inflammatory IFNγ-producing ILC1s.[49]

Naive T cells are activated primarily by dendritic cells, which then differentiate into anti-inflammatory T regulatory cells (Tregs) or inflammatory T helper cells to maintain balance. In Crohn's disease, macrophages and antigen-presenting cells secrete IL-12, IL-18, and IL-23 in response to pathogens, increasing Th1 and T17 differentiation and promoting inflammation via IL-17, IFNγ and TNF. IL-23 is particularly important, and IL-23 receptor polymorphisms that increase activity are linked with Crohn's disease. Tregs suppress inflammation via IL-10, and mutations to IL-10 and its receptor cause very early onset Crohn's disease.[27]

Microbiome

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People with Crohn's disease tend to have altered microbiomes, although no disease-specific microorganisms have been identified. An altered microbiome may link environmental factors with Crohn's, though causality is uncertain. Firmicutes tend to be reduced, particularly Faecalibacterium prausnitzii, which produces short-chain fatty acids that reduce inflammation. Bacteroidetes and proteobacteria tend to be increased, particularly adherent-invasive E. coli, which attaches to intestinal epithelial cells. Additionally, mucolytic and sulfate-reducing bacteria are elevated, contributing to damage to the intestinal barrier.[44]

Alterations in gut viral and fungal communities may contribute to Crohn's disease. Caudovirales bacteriophage sequences found in children with Crohn's suggest a potential biomarker for early-onset disease. A meta-analysis showed lower viral diversity in Crohn's patients compared to healthy individuals, with increased Synechococcus phage S CBS1 and Retroviridae viruses. Additionally, a Japanese study found that the fungal microbiota in Crohn's patients differs significantly from that of healthy individuals, particularly with an abundance of Candida.[27]

Diagnosis

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Diagnosis of Crohn's disease may be challenging since its symptoms overlap with other gastrointestinal diseases. An accurate diagnosis requires a combined assessment of clinical history, physical examination, and diagnostic tests.

Endoscopy

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Endoscopic image of Crohn's colitis showing deep ulceration.
Endoscopy image of colon showing serpiginous ulcer, a classic finding in Crohn's disease

Ileocolonoscopy is the primary procedure for diagnosing Crohn's disease in the ileum and colon, accurately identifying it in about 90% of cases.[50] During this exam, doctors closely examine the intestinal lining and take small tissue samples for further testing. Signs of Crohn's disease include uneven inflammation and 'skip lesions', which are patches of inflammation separated by healthy tissue. The ulcers can be small (less than 5 mm) or larger (over 5 mm), often appearing cobblestone-like. Their depth helps determine disease severity. Unlike ulcerative colitis, Crohn's disease usually does not affect the rectum or cause continuous inflammation around the bowel.[27]

In certain cases, such as disease in the upper small bowel, standard colonoscopy may be ineffective. Physicians may then opt for device-assisted enteroscopy or capsule endoscopy. While capsule endoscopy is effective in detecting abnormalities, it may not reliably diagnose Crohn's disease and carries a risk of retention, which is about 1.6% when Crohn's disease is suspected and increases to 13% if already diagnosed. To reduce this risk, physicians typically perform small-bowel imaging and use a patency capsule that disintegrates within 48 to 72 hours. Once the patency capsule has passed through the intestine, capsule endoscopy may be performed.[39]

Device-assisted enteroscopy is not typically the first choice for diagnosing small-bowel Crohn's disease due to its invasiveness and higher costs.[27] The procedure closely examines the small intestine using specialized tools, such as longer endoscopes or balloon-assisted devices, making it easier for doctors to visualize and treat issues.[51] It often requires sedation and is generally reserved for patients needing a tissue sample or immediate treatment.[27]

Cross-sectional Imaging

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CT scan of patient showing Crohn's disease in the fundus of the stomach

Cross-sectional imaging techniques, like bowel ultrasonography (BUS), CT enterography (CTE), and MRI enterography (MRE), are essential for understanding how extensive Crohn's disease is and whether there are any complications, like blockages or abnormal connections between organs. All three methods are quite accurate for diagnosing Crohn's disease and spotting these complications.[27]

  • CTE involves radiation and requires the use of contrast agents (substances that help show details in images). Despite this, CTE is very effective, with over 80% accuracy in diagnosing the disease and its complications, including blockages and fistulas (abnormal connections).[27]
  • MRE is particularly good for detecting intestinal narrowing, with 89% sensitivity and 94% specificity. It is the preferred option for examining fistulas and abscesses in the pelvic area.[27]
  • BUS is a non-invasive method that doesn't involve radiation and is effective for assessing the intestinal wall and related issues, such as fistulas and abscesses. Despite its limitations, it can accurately identify signs of Crohn's disease when the bowel wall thickens to more than 3 mm, achieving high accuracy rates (88–100%) when also considering factors like fistulas and abscesses.[27]

Histology

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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.
H and E section of colectomy showing transmural inflammation.

The most reliable way to confirm a diagnosis of Crohn's disease is through a histological examination of biopsy samples or tissue removed during surgery. This process helps distinguish Crohn's disease from ulcerative colitis and other types of colitis, particularly infections. While no features are unique to Crohn's disease, typical signs include patchy chronic inflammation, irregularities in the intestinal lining, granulomas (not related to tissue injury), and abnormal villi structure in the terminal ileum. A pathologist specializing in inflammatory bowel disease is important for accurate Crohn's disease diagnoses. Even if biopsy results are unclear, doctors can still suggest a Crohn's disease diagnosis based on clinical symptoms, endoscopic findings, and imaging results.[27]

Disease activity indexes

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The Crohn's Disease Activity Index (CDAI) is a scoring system to assess the symptoms associated with Crohn's disease. It assigns a score based on eight clinical factors, including overall well-being, frequency of loose stools, abdominal pain, presence of abdominal masses, changes in weight, low hemoglobin levels, and use of opiates for diarrhea. The CDAI is primarily used in clinical trials to evaluate the effectiveness of treatments and to determine whether the disease is in remission. This is particularly significant, as approximately 50% of patients who report feeling well may still exhibit signs of active disease in the intestine, while some patients with symptoms may present with normal intestinal findings.[27]

The Harvey–Bradshaw Index (HBI) provides a more streamlined approach by assessing only clinical factors, thus eliminating the need for laboratory tests. Neither the CDAI nor the HBI incorporates diagnostic procedures such as endoscopies or imaging studies; instead, they focus exclusively on symptom tracking. The HBI is generally considered easier to apply than the CDAI and may be more suitable for certain clinical trials and routine practice due to its simplicity in calculation and reduced reliance on patient recall of symptoms.[27]

The Crohn's Disease Endoscopic Index of Severity (CDEIS) is a scoring system used during endoscopy to evaluate Crohn's disease severity. It assesses six factors: deep and shallow ulcers, nonulcerated and ulcerated stenosis, the area covered by ulcers, and the overall disease-affected area across five intestinal sections. Scores range from 0 to 44, with higher scores indicating more severe disease. While often seen as the standard for measuring severity, CDEIS can be complex to calculate and may underestimate severity if only one segment, particularly the ileum, is affected. There are also no clear score cutoffs for specific outcomes or treatment responses, limiting its effectiveness in determining remission.[52]

The Simple Endoscopic Score for Crohn's Disease (SES-CD) offers a more straightforward approach than the CDEIS scoring system, using four key factors to evaluate Crohn's disease during an endoscopy. These factors include the presence and size of ulcers, the area affected by ulcers, the overall extent of the disease, and any narrowing of the intestine (stenosis). The first three factors are scored from 0 to 3 in each of the five sections of the intestine, with a maximum score of 15 for each section. Stenosis is scored separately, ranging from 0 to 11. This results in a total SES-CD score that can range from 0 to 56, with higher scores indicating more severe disease.[52]

Laboratory testing

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While no lab test can definitively confirm or rule out Crohn's disease, results from serum and stool tests can help support the diagnosis:[39]

  • The antimicrobial antibody ASCA is a well-known blood test marker used in the diagnosis of Crohn's disease. Approximately 60–70% of individuals with Crohn's disease test positive for ASCA, while only 10–15% of those with ulcerative colitis and less than 5% of patients with other types of colitis have positive results.[27]
  • The autoantibody pANCA is found in 10–15% of Crohn's disease cases, in 60–70% of ulcerative colitis cases, and in less than 5% of patients with other types of colitis that aren't inflammatory bowel disease. Additionally, patients with Crohn's disease who test positive for pANCA often show symptoms similar to those of ulcerative colitis.[27]
  • C-reactive protein (CRP) is a blood marker that indicates inflammation and can help monitor Crohn's disease activity. However, about one third of patients with active disease may have normal CRP levels, while one third with high levels of CRP have inactive disease. Moreover, CRP's ability to predict disease progression is not well established.[27]
  • Fecal calprotectin is a stool test used to differentiate inflammatory bowel disease, like Crohn's disease, from irritable bowel syndrome. While there are no official cut-off values, it is commonly used to assess disease activity in Crohn's.[27] Elevated levels may also indicate other intestinal infections or inflammatory conditions, not just Crohn's disease.[39]

Differential diagnosis

[edit]

Crohn's disease has similar endoscopic, radiographic and histological features with other inflammatory or infectious diseases. 10% of people with Crohn's disease are initially diagnosed with indeterminate colitis.[27]

  • Behçet’s disease can cause intestinal inflammation, primarily featuring single ulcers and symptoms outside the intestines, which differ from Crohn's disease. Recurrent sores in the mouth and genitals raise suspicion for Behçet’s. A pathergy test, where the skin is lightly pricked to check for a red bump or ulcer, can help confirm the diagnosis. Eye inflammation (uveitis) and skin issues are also common in Behçet’s disease.[27]
  • Intestinal lymphoma lacks symptoms that differentiate it from other conditions; diagnosis can only be confirmed through histological examination of tissue samples.[27]
  • Intestinal tuberculosis can cause symptoms such as fever, night sweats, and ulcers in the transverse colon, along with a swollen ileocecal valve. Key tissue changes include granulomas, which may be caseating, confluent, or large. A positive smear test for acid-fast bacillus and imaging that detects necrotic lymph nodes are also important indicators of the disease.[27]
  • Ischemic colitis is also a possible alternative diagnosis to Crohn's disease. It often shows swelling and redness of the inner lining of the colon, while the rectum usually remains unaffected.[27]

Classification

[edit]

The Montreal classification system is a widely used framework for categorizing the phenotypes of Crohn's disease. It considers three primary factors: the age at diagnosis (divided into three groups: less than 16 years, 17 to 40 years, and over 40 years), the location of the disease (which can be ileal, colonic, ileocolonic, or isolated upper), and the behavior of the disease (including non-stricturing/non-penetrating, stricturing, penetrating, and perianal types).[53]

Management

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Main article: Management of Crohn's disease

The management of Crohn's disease is customized based on the severity, location, and behavior of the disease. Providers also assess the risk of aggressive disease to determine the need for more intensive treatment. Risk factors include diagnosis before age 30, extensive disease involvement, perianal complications, deep ulcers, and history of surgery. A key goal of treatment is to achieve mucosal healing, which restores the intestinal lining. Mucosal healing is linked to better outcomes, such as fewer flare-ups, reduced hospitalizations, steroid-free remission, and a longer interval without surgery.[27]

Corticosteroids

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Steroids are often used to quickly induce remission and relieve symptoms in Crohn's disease, but they are ineffective for maintaining remission. Options include intravenous steroids, prednisone, and budesonide, with budesonide preferred for its safety, though it's limited to mild to moderate cases in the ileum and right colon. Patients on systemic steroids should switch to other medications for long-term remission, as prolonged use can cause adrenal issues, weight gain, cataracts, hypertension, and diabetes. Additionally, systemic steroids may increase the risk of serious infections and mortality in moderate to severe Crohn's disease.[52]

Conventional immunosuppressants

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Thiopurines, like azathioprine and 6-mercaptopurine, maintain remission in Crohn's disease but do not induce it initially. Since thiopurines take 6 to 12 weeks to work, steroids are often used to manage symptoms during this time. Before starting thiopurines, liver metabolism is assessed and Epstein-Barr virus is tested in patients under 25. Around 15% to 20% of patients stop thiopurines due to side effects, including low blood cell counts, liver problems, nausea, vomiting, allergic reactions, and acute pancreatitis. Thiopurines also raise the risk of certain cancers and serious conditions, necessitating regular lab monitoring.[52]

Methotrexate is used to induce and maintain remission in Crohn's disease, being slightly more effective than thiopurines and taking 8 to 16 weeks to work. About 17% of patients stop taking it due to side effects like nausea, vomiting, headaches, and fatigue. It can affect liver health and, rarely, lower blood cell counts, requiring regular blood tests. Methotrexate may also cause anemia and mouth sores, so daily folic acid is recommended. Additionally, it may increase the risk of certain skin cancers and lymphoma. Methotrexate is discontinued during pregnancy due to the risks of miscarriage and birth defects.[52]

Biologics

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Anti-TNF therapy is the most effective treatment for inducing and maintaining remission, with FDA-approved agents including infliximab, adalimumab, and certolizumab pegol.[52] It blocks the inflammatory protein TNF and induces cell death in activated T cells.[54] Responses may occur within a week, but full effects can take up to six weeks. Loss of response can happen due to the development of antidrug antibodies, necessitating a switch in agents or drug classes. Anti-TNF agents are often combined with thiopurines or methotrexate to minimize antibody development. Side effects include injection-site reactions, a higher risk of infection, a slight increase in melanoma risk, and rare cases of cytopenias and liver toxicity.[52]

Vedolizumab is the first treatment designed specifically for the gut in moderate to severe Crohn's disease. It blocks the molecule α4β7 that helps white blood cells enter the gut, reducing inflammation. Unlike natalizumab, it does not carry a risk of the serious brain infection PML. While vedolizumab can induce remission, it works slowly, taking about 12 weeks to show effects, and its overall effectiveness is limited. However, patients who respond well can maintain remission for up to a year. Since it specifically targets the gut, it does not significantly increase the risk of serious side effects or infections, except for mild nasal infections.[52]

Ustekinumab, approved for moderate to severe Crohn's disease in October 2016, has been FDA-approved for psoriasis since 2009. It appears to be comparable to anti-TNF therapy in both the induction and maintenance of remission, functioning by blocking the inflammatory molecules IL-12 and IL-23. The onset of action is similar to that of anti-TNF treatments, with responses typically observed within six weeks. Notably, Ustekinumab does not seem to increase the risk of serious infections, although the studies conducted in Crohn's disease have been relatively short-term.[52]

Surgery

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Resected ileum from a person with Crohn's disease

Many individuals with Crohn's disease may require a bowel resection to remove part of the intestine due to blockages, lesions, infections, or ineffective medications. Since surgery is not a cure, the goal is to preserve as much of the small bowel as possible[52], and extensive resections can lead to short bowel syndrome.[55]. In cases with widespread strictures, only the most prominent stricture is typically resected, while minor strictures may be dilated through strictureplasty. After a resection, the healthy ends of the intestine are rejoined in a primary anastomosis.[52]

Approximately six to twelve months after surgery, patients usually undergo a colonoscopy to check for inflammation, using the Rutgeerts scoring system to assess the likelihood of recurrence. About 50% may experience a return of symptoms within five years, and nearly 40% may need a second surgery within ten years,[52] often due to inflammation near the anastomosis.[56] While drug therapy aims to prevent recurrences, its effectiveness remains uncertain.[52]

Diet

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  • Enteral nutrition, which administers nutrients as a powder or liquid, is the primary method for inducing remission in children with Crohn's disease. It can induce remission in up to 80% of cases. Outside of Japan, it is not used to treat Crohn's disease in adults due to unpalatable formulations.[57]
  • Parenteral nutrition, which administers nutrients directly into the bloodstream, may be used to supply nutrients to patients when there is extensive inflammation that impairs absorption. Parenteral nutrition has the same effectiveness as enteral nutrition in inducing remission.[58]
  • The Mediterranean diet, rich in fruits, vegetables, unsaturated fats, and lean protein, is beneficial to general health but has not been found to reduce the rate of flares in Crohn's disease.[59]
  • Cooking and processing fruits and vegetables to reduce fibrousness increases tolerance of those foods in people with intestinal strictures.[59]

Other treatments

[edit]
  • Mesalamine is not effective for inducing or maintaining remission in Crohn's disease, but is nevertheless commonly used as a treatment due to its perceived benefits and low risk of side effects.[27]
  • Antibiotics are not effective in inducing or maintaining remission in Crohn's disease. However, they are effective in treating perianal fistulas and inflammation when used alongside anti-TNF therapy.[27]
  • Fecal microbiota transplants have shown potential effectiveness in preliminary studies. However, larger studies are needed to verify its efficacy.[60]
  • Acupuncture influences the immune system by stimulating the vagus nerve. Early studies have shown efficacy in improving clinical symptoms, but larger studies are needed.[61]
  • Cannabis is a potential therapy for Crohn's disease by targeting the endocannabinoid system. Although it has shown benefits in animal models, its efficacy as a treatment is uncertain.[62]
  • Cognitive behavioral therapy has shown short-term positive psychological effects in people with Crohn's disease, but it has no long-term effect on physical or psychological health.[63]

Outlook

[edit]

Crohn's disease is a chronic condition requiring ongoing management, as there is currently no cure. Inflammation is typically controlled through medications such as steroids and immunosuppressants, and in severe cases, surgery may be necessary. The clinical course of the disease is classified into four patterns:[64]

  • Remission: Severity decreases in response to treatment, leading to sustained remission.[64]
  • Improved and Stable: Severity lessens, but mild inflammation persists.[64]
  • Relapsing: The disease fluctuates between periods of remission and severe inflammation.[64]
  • Refractory: Severe inflammation continues without respite.[64]

Approximately 40% to 56% of individuals with Crohn's disease achieve clinical remission after one year of infliximab treatment, increasing to 56% to 58% when combined with an immunosuppressant. Additionally, 16% to 39% attain both clinical and endoscopic remission, showing no signs of inflammation in the intestine. Once in remission, individuals have an 80% chance of maintaining this state for the following year. Conversely, 10% to 15% of individuals may experience ongoing active disease without remission.[64]

Chronic inflammation from Crohn's disease increases the risk of heart problems, cancers, arthritis, osteoporosis (weakened bones), and mental health issues. Some medications can also raise the chances of infections and cancers. Because of these combined risks, people with Crohn's disease tend to have a shorter lifespan compared to those who are healthy. In Canada, studies show that women affected with Crohn's disease live about 7.7 years less than unaffected women, and affected men live about 7.7 years less than otherwise expected.[65]

Epidemiology

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Crohn's disease is most prevalent in North America and Western Europe, particularly among Ashkenazi jews and possibly more common in women.[52] The annual incidence in North America is 0–20.2 new cases per 100,000 people, while incidence in Europe is 0.3–12.7 per 100,000. The prevalence of Crohn's disease is 322 per 100,000 in Germany, 319 per 100,000 in Canada,[27] and 300 per 100,000 in the United States.[63] The prevalence of Crohn's disease has risen in newly industrialized countries, with rates of 18.6 per 100,000 in Hong Kong and 3.9 per 100,000 in Taiwan.[27]

The typical age of onset is between 20 and 30 years, with a smaller peak around 50 years, leading to a median onset age of 30.[52] About 20 to 25% of patients presenting with inflammatory bowel disease are children under 18 years old, while 80% are adolescents. Additionally, the incidence of Crohn's disease in children is on the rise, with 2.5–11.4 new cases per 100,000 and a prevalence of 58 per 100,000.[66]

History

[edit]
Main article: List of people diagnosed with Crohn's disease

Inflammatory bowel diseases were described by Giovanni Battista Morgagni (1682–1771) and by Scottish physician Thomas Kennedy Dalziel in 1913.[67]

Ileitis terminalis was first described by Polish surgeon Antoni Leśniowski in 1904, although it was not conclusively distinguished from intestinal tuberculosis.[68] In Poland, it is still called Leśniowski-Crohn's disease (Polish: choroba Leśniowskiego-Crohna). Burrill Bernard Crohn, an American gastroenterologist at New York City's Mount Sinai Hospital, described fourteen cases in 1932, and submitted them to the American Medical Association under the rubric of "Terminal ileitis: A new clinical entity". Later that year, he, along with colleagues Leon 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.[69]

Name controversy

[edit]

The disease was named after gastroenterologist Burrill Bernard Crohn, who in 1932, together with Leon Ginzburg (1898–1988) and Gordon D. Oppenheimer (1900–1974) at Mount Sinai Hospital in New York, described a series of patients with inflammation of the terminal ileum of the small intestine, the area most commonly affected by the illness.[69] The appropriateness of the disease being named after Crohn has been questioned.[70][71] While Crohn, in his memoir, describes his original investigation of the disease, Ginzburg provided strong evidence of how he and Oppenheimer were the first to study the disease.[72]

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Further reading

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