Inflammatory bowel disease
|Inflammatory bowel diseases|
|Classification and external resources|
|eMedicine||med/1169 emerg/106 oph/520|
The main forms of IBD are Crohn's disease and ulcerative colitis (UC). Inflammatory bowel diseases are considered autoimmune diseases, in which the body's own immune system attacks elements of the digestive system.
Accounting for far fewer cases are other forms of IBD, which are not always classified as typical IBD:
- Collagenous colitis
- Lymphocytic colitis
- Ischaemic colitis
- Diversion colitis
- Behçet's disease
- Indeterminate colitis
The main difference between Crohn's disease and UC is the location and nature of the inflammatory changes. Crohn's can affect any part of the gastrointestinal tract, from mouth to anus (skip lesions), although a majority of the cases start in the terminal ileum. Ulcerative colitis, in contrast, is restricted to the colon and the rectum. Microscopically, ulcerative colitis is restricted to the mucosa (epithelial lining of the gut), while Crohn's disease affects the whole bowel wall ("transmural lesions").
Finally, Crohn's disease and ulcerative colitis present with extra-intestinal manifestations (such as liver problems, arthritis, skin manifestations and eye problems) in different proportions.
Rarely, a definitive diagnosis neither of Crohn's disease nor of ulcerative colitis can be made because of idiosyncrasies in the presentation. In this case, a diagnosis of indeterminate colitis may be made. Although a recognised definition, not all centres refer to this.
Signs and symptoms
|Crohn's disease||Ulcerative colitis|
and with blood
|Tenesmus||Less common||More common|
|Fever||Common||Indicates severe disease|
|Weight loss||Often||More seldom|
Although Crohn's and UC are very different diseases, both may present with any of the following symptoms: abdominal pain, vomiting, diarrhea, rectal bleeding, severe internal cramps/muscle spasms in the region of the pelvis and weight loss. Anemia is the most prevalent extraintestinal complication of inflammatory bowel disease. Associated complaints or diseases include arthritis, pyoderma gangrenosum, primary sclerosing cholangitis, and non-thyroidal illness syndrome (NTIS). Diagnosis is generally by assessment of inflammatory markers in stool followed by colonoscopy with biopsy of pathological lesions.
||Crohn's disease||Ulcerative colitis|
|Terminal ileum involvement||Commonly||Seldom|
|Bile duct involvement||No increase in rate of primary sclerosing cholangitis||Higher rate|
|Distribution of Disease||Patchy areas of inflammation (Skip lesions)||Continuous area of inflammation|
|Endoscopy||Deep geographic and serpiginous (snake-like) ulcers||Continuous ulcer|
|Depth of inflammation||May be transmural, deep into tissues||Shallow, mucosal|
|Granulomas on biopsy||May have non-necrotizing non-peri-intestinal crypt granulomas||Non-peri-intestinal crypt granulomas not seen|
|Crohn's disease||Ulcerative colitis|
|Cytokine response||Associated with Th17||Vaguely associated with Th2|
IBD is a complex disease which arises as a result of the interaction of environmental and genetic factors. It is increasingly thought that alterations to enteral bacteria can contribute to inflammatory gut diseases The enteral bacteria can be altered by environmental factors, such as Concentrated milk fats (a common ingredient of processed foods and confectionery) or oral medications such as antibiotics and oral iron preparations.
The genetic contribution is poorly understood and seems to arise from the small contribution of dozens of genes. In 2012 163 IBD susceptibility loci were confirmed which means that 163 alleles that can increase the susceptibility to the disease. These 163 loci explain from a 8.2% to a 13.6% of variance in Crohn’s disease and 4.1% to 7.5% in ulcerative colitis.
The 163 loci were related with 300 known genes. The functional enrichment analysis of this group of genes using Gene Ontology showed that there are many genes related with cytokine production, lymphocyte activation and the response to bacterial infection. In an effort to identify likely causal genes a probabilistic causal gene network was constructed. Here a sub-network including NOD2, Il10 and CARD9 seems to indicate a close relationship between IBD and genes related with host interaction with bacteria. Of particular relevance is the presence of the gene HCK which seems to play an important role anti-inflammation. In the figure beside there is a NOD2-focused cluster in the causal gene sub-network.
|Crohn's disease||Ulcerative colitis|
|Mesalazine||Less useful||More useful|
|Antibiotics||Effective in long-term||Generally not useful|
|Surgery||Often returns following
removal of affected part
|Usually cured by removal
Optimal treatment of inflammatory bowel disease depends on what form it consists of. For example, mesalazine is more useful in ulcerative colitis than in Crohn's disease. Generally, depending on the level of severity, IBD may require immunosuppression to control the symptom, such as prednisone, TNF inhibition, azathioprine (Imuran), methotrexate, or 6-mercaptopurine. More commonly, treatment of IBD requires a form of mesalazine.
Often, anti-inflammatory steroids are used to control disease flares and were once acceptable as a maintenance drug. In use for several years in Crohn's disease patients and recently in patients with ulcerative colitis, biologicals have been used such as TNF inhibitors. Severe cases may require surgery, such as bowel resection, strictureplasty or a temporary or permanent colostomy or ileostomy. Alternative medicine treatments for bowel disease exist in various forms, however such methods concentrate on controlling underlying pathology in order to avoid prolonged steroidal exposure or surgical excisement.
Usually the treatment is started by administering drugs with high anti-inflammatory effects, such as prednisone. Once the inflammation is successfully controlled, the patient is usually switched to a lighter drug to keep the disease in remission, such as Asacol, a mesalazine. If unsuccessful, a combination of the aforementioned immunosuppression drugs with a mesalazine (which may also have an anti-inflammatory effect) may or may not be administered, depending on the patient. Budesomide is the easiest medication for the elderly and children.
There is evidence of an infections contribution to inflammatory bowel disease in some patients and this subgroup of patients may benefit from antibiotic therapy. Anaemia is a common finding in both ulcerative colitis and Crohn's disease. Due to raised levels of inflammatory cytokines which lead to the increased expression of hepcidin, parenteral iron is the preferred treatment option as it bypasses the gastrointestinal system, has lower incidence of adverse events and enables quicker treatment. Hepcidin itself is also an anti-inflammatory agent. In the murine model very low levels of iron restrict hepcidin synthesis, worsening the inflammation that is present. Recently, enteral nutrition has been confirmed to be efficient to improve hemoglobin level in patients with inflammatory bowel disease, especially combined with erythropoietin.
Due to the fact that the disease might be triggered by the blooms of a rare type of gut bacteria some anti-bacterial drugs like chloroxine might be able to dispense the problem. A wider study is needed to confirm this.
|Crohn's disease||Ulcerative colitis|
|Nutrient deficiency||Higher risk|
|Colon cancer risk||Slight||Considerable|
|Prevalence of extraintestinal complications|
While IBD can limit quality of life because of pain, vomiting, diarrhea, and other socially unacceptable symptoms, it is rarely fatal on its own. Fatalities due to complications such as toxic megacolon, bowel perforation and surgical complications are also rare.
While patients of IBD do have an increased risk of colorectal cancer, this is usually caught much earlier than the general population in routine surveillance of the colon by colonoscopy, and therefore patients are much more likely to survive.
A recent literature review by Gandhi et al. described that IBD patients over the age of 65 and females are at increased risk of coronary artery disease despite the lack of traditional risk factors.
The goal of treatment is toward achieving remission, after which the patient is usually switched to a lighter drug with fewer potential side effects. Every so often, an acute resurgence of the original symptoms may appear; this is known as a "flare-up". Depending on the circumstances, it may go away on its own or require medication. The time between flare-ups may be anywhere from weeks to years, and varies wildly between patients - a few have never experienced a flare-up.
Globally, as of 2010, IBD resulted in 34,000 deaths.
The following treatment strategies are not used routinely, but appear promising in most forms of inflammatory bowel disease.
Initial reports suggest that "helminthic therapy" may not only prevent but even control IBD: a drink with roughly 2,500 ova of the Trichuris suis helminth taken twice monthly decreased symptoms markedly in many patients. It is even speculated that an effective "immunization" procedure could be developed—by ingesting the cocktail at an early age.
In 2005 New Scientist published a joint study by Bristol University and the University of Bath on the apparent healing power of cannabis on IBD. Reports that cannabis eased IBD symptoms indicated the possible existence of cannabinoid receptors in the intestinal lining, which respond to molecules in the plant-derived chemicals. CB1 cannabinoid receptors – which are known to be present in the brain – exist in the endothelial cells which line the gut, it is thought that they are involved in repairing the lining of the gut when damaged.
The team deliberately damaged the cells to cause inflammation of the gut lining and then added synthetically produced cannabinoids; the result was that gut started to heal: the broken cells were repaired and brought back closer together to mend the tears. It is believed that in a healthy gut, natural endogenous cannabinoids are released from endothelial cells when they are injured, which then bind to the CB1 receptors. The process appears to set off a wound-healing reaction, and when people use cannabis, the cannabinoids bind to these receptors in the same way.
Previous studies have shown that CB1 receptors located on the nerve cells in the gut respond to cannabinoids by slowing gut motility, therefore reducing the painful muscle contractions associated with diarrhea. The team also discovered another cannabinoid receptor, CB2, in the guts of IBD sufferers, which was not present in healthy guts. These receptors, which also respond to chemicals in cannabis, appear to be associated with apoptosis – programmed cell death – and may have a role in suppressing the overactive immune system and reducing inflammation by mopping up excess cells.
Alicaforsen is a first generation antisense oligodeoxynucleotide designed to bind specifically to the human ICAM-1 messenger RNA through Watson-Crick base pair interactions in order to subdue expression of ICAM-1. ICAM-1 propagates an inflammatory response promoting the extravasation and activation of leukocytes (white blood cells) into inflamed tissue. Increased expression of ICAM-1 has been observed within the inflamed intestinal mucosa of ulcerative colitis, pouchitis and Crohn's sufferers where ICAM-1 over production correlated with disease activity. This suggests that ICAM-1 is a potential therapeutic target in the treatment of these diseases.
In 2014, an alliance among the Broad Institute, Amgen and Massachusetts General Hospital formed with the intention to "collect and analyze patient DNA samples to identify and further validate genetic targets."
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