Ulcerative colitis – Wikipedia

Ulcerative colitisEndoscopic image of a colon affected by ulcerative colitis. The internal surface of the colon is blotchy and broken in places.SpecialtyGastroenterologySymptomsAbdominal pain, diarrhea mixed with blood, weight loss, fever, anemia[1]ComplicationsMegacolon, inflammation of the eye, joints, or liver, colon cancer[1][2]Usual onset1530 years or > 60 years[1]DurationLong term[1]CausesUnknown[1]Diagnostic methodColonoscopy with tissue biopsies[1]Differential diagnosisDysentery, Crohn's disease, ischemic colitis[3]TreatmentDietary changes, medication, surgery[1]MedicationSulfasalazine, mesalazine, steroids, immunosuppressants such as azathioprine, biological therapy[1]FrequencyUp to 5 per 1000 people[4]Deaths47,400 together with Crohn's (2015)[5]

Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum.[1][6] The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood.[1] Weight loss, fever, and anemia may also occur.[1] Often, symptoms come on slowly and can range from mild to severe.[1] Symptoms typically occur intermittently with periods of no symptoms between flares.[1] Complications may include megacolon, inflammation of the eye, joints, or liver, and colon cancer.[1][2]

The cause of UC is unknown.[1] Theories involve immune system dysfunction, genetics, changes in the normal gut bacteria, and environmental factors.[1][7] Rates tend to be higher in the developed world with some proposing this to be the result of less exposure to intestinal infections, or to a Western diet and lifestyle.[6][8] The removal of the appendix at an early age may be protective.[8] Diagnosis is typically by colonoscopy with tissue biopsies.[1] It is a kind of inflammatory bowel disease (IBD) along with Crohn's disease and microscopic colitis.[1]

Dietary changes, such as maintaining a high-calorie diet or lactose-free diet, may improve symptoms.[1] Several medications are used to treat symptoms and bring about and maintain remission, including aminosalicylates such as mesalazine or sulfasalazine, steroids, immunosuppressants such as azathioprine, and biologic therapy.[1] Removal of the colon by surgery may be necessary if the disease is severe, does not respond to treatment, or if complications such as colon cancer develop.[1] Removal of the colon and rectum can cure the disease.[1][8]

Together with Crohn's disease, about 11.2 million people were affected as of 2015.[9] Each year it newly occurs in 1 to 20 per 100,000 people, and 5 to 500 per 100,000 individuals are affected.[6][8] The disease is more common in North America and Europe than other regions.[8] Often it begins in people aged 15 to 30 years, or among those over 60.[1] Males and females appear to be affected in equal proportions.[6] It has also become more common since the 1950s.[6][8] Together, ulcerative colitis and Crohn's disease affect about a million people in the United States.[10] With appropriate treatment the risk of death appears the same as that of the general population.[2] The first description of ulcerative colitis occurred around the 1850s.[8]

The clinical presentation[13] of ulcerative colitis depends on the extent of the disease process. Patients usually present with diarrhea mixed with blood and mucus, of gradual onset that persists for an extended period (weeks). They may also have weight loss and blood on rectal examination. The inflammation caused by the disease along with the chronic bleeding from the GI tract leads to increased rates of anemia. The disease may be accompanied by different degrees of abdominal pain, from mild discomfort to painful bowel movements or painful abdominal cramping with bowel movements.

Ulcerative colitis is associated with a general inflammatory process that can affect many parts of the body. Sometimes, these associated extra-intestinal symptoms are the initial signs of the disease, such as painful arthritic knees in teenagers, which also may be seen in adults. A diagnosis of UC may not occur until the onset of intestinal manifestations, however.

Ulcerative colitis is normally continuous from the rectum up the colon. The disease is classified by the extent of involvement, depending on how far the disease extends:

In addition to the extent of involvement, people may also be characterized by the severity of their disease.[14]

As UC is believed to have a systemic (i.e., autoimmune) origin, patients may present with comorbidities leading to symptoms and complications outside the colon. The frequency of such extraintestinal manifestations has been reported as between 6 and 47%,[15] and include:

No direct causes for UC are known, but many possible factors such as genetics and stress play a role.

A genetic component to the etiology of UC can be hypothesized based on:[16]

Twelve regions of the genome may be linked to UC, including, in the order of their discovery, chromosomes 16, 12, 6, 14, 5, 19, 1, and 3,[18] but none of these loci has been consistently shown to be at fault, suggesting that the disorder is influenced by multiple genes. For example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease.[19]

Some of the putative regions encode transporter proteins such as OCTN1 and OCTN2. Other potential regions involve cell scaffolding proteins such as the MAGUK family. Human leukocyte antigen associations may even beat work. In fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates.[18]

Multiple autoimmune disorders have been recorded with the neurovisceral and cutaneous genetic porphyrias including UC, Crohn's disease, celiac disease, dermatitis herpetiformis, diabetes, systemic and discoid lupus, rheumatoid arthritis, ankylosing spondylitis, scleroderma, Sjogren's disease and scleritis. Physicians should be on high alert for porphyrias in families with autoimmune disorders and care must be taken with the use of potential porphyrinogenic drugs, including sulfasalazine.

Many hypotheses have been raised for environmental factors contributing to the pathogenesis of ulcerative colitis. They include:

Ulcerative colitis is an autoimmune disease characterized by T-cells infiltrating the colon.[30] In contrast to Crohn's disease, which can affect areas of the gastrointestinal tract outside of the colon, ulcerative colitis usually involves the rectum and is confined to the colon, with occasional involvement of the ileum. This so-called "backwash ileitis" can occur in 1020% of patients with pancolitis and is believed to be of little clinical significance.[31] Ulcerative colitis can also be associated with comorbidities that produce symptoms in many areas of the body outside the digestive system. Surgical removal of the large intestine often cures the disease.[14]

Levels of sulfate-reducing bacteria tend to be higher in persons with ulcerative colitis, which could indicate higher levels of hydrogen sulfide in the intestine. An alternative theory suggests that the symptoms of the disease may be caused by toxic effects of the hydrogen sulfide on the cells lining the intestine.[34]

An increased amount of colonic sulfate-reducing bacteria has been observed in some patients with ulcerative colitis, resulting in higher concentrations of the toxic gas hydrogen sulfide. Human colonic mucosa is maintained by the colonic epithelial barrier and immune cells in the lamina propria (see intestinal mucosal barrier). N-butyrate, a short-chain fatty acid, gets oxidized through the beta oxidation pathway into carbon dioxide and ketone bodies. It has been shown that N-butyrate helps supply nutrients to this epithelial barrier. Studies have proposed that hydrogen sulfide plays a role in impairing this beta-oxidation pathway by interrupting the short chain acetyl-CoA dehydrogenase, an enzyme within the pathway. Furthermore, it has been suggested that the protective benefit of smoking in ulcerative colitis is due to the hydrogen cyanide from cigarette smoke reacting with hydrogen sulfide to produce the non-toxic isothiocyanate, thereby inhibiting sulfides from interrupting the pathway.[36] An unrelated study suggested that the sulfur contained in red meats and alcohol may lead to an increased risk of relapse for patients in remission.[34]

Ulcerative colitis patients typically present with rectal bleeding, diarrhea, tenesmus (urgent desire to evacuate the bowels but with the passage of little stool), and lower abdominal pain. The severity of disease at clinical presentation is important in determining the appropriate therapy. Patients with mildly active disease will have fewer than 4 bowel movements daily and no signs of toxicity. Individuals with moderate-severity UC have more frequent bowel movements with bleeding. Approximately 70% of patients with ulcerative colitis will have moderately active disease at presentation. Patients with severely active disease will have signs of toxicity with fever, tachycardia, and anemia. Patients with fulminant or toxic colitis or toxic megacolon often have more than 10 bowel movements in a day, continuous bleeding, abdominal distention and tenderness, and radiologic evidence of edema and, in some cases, bowel dilation. These people most often require immediate colectomy because 10% have perforated colon at the time of surgery.

The initial diagnostic workup for ulcerative colitis includes the following:[14][37]

Although ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease.[14]

The simple clinical colitis activity index was created in 1998 and is used to assess the severity of symptoms.[38][39]

The best test for diagnosis of ulcerative colitis remains endoscopy. Full colonoscopy to the cecum and entry into the terminal ileum is attempted only if the diagnosis of UC is unclear. Otherwise, a flexible sigmoidoscopy is sufficient to support the diagnosis. The physician may elect to limit the extent of the exam if severe colitis is encountered to minimize the risk of perforation of the colon. Endoscopic findings in ulcerative colitis include the following:

Ulcerative colitis is usually continuous from the rectum, with the rectum almost universally being involved. Perianal disease is rare. The degree of involvement endoscopically ranges from proctitis or inflammation of the rectum, to left sided colitis, to pancolitis, which is inflammation involving the ascending colon.

Biopsies of the mucosa are taken to definitively diagnose UC and differentiate it from Crohn's disease, which is managed differently clinically. Microbiological samples are typically taken at the time of endoscopy. The pathology in ulcerative colitis typically involves distortion of crypt architecture, inflammation of crypts (cryptitis), frank crypt abscesses, and hemorrhage or inflammatory cells in the lamina propria. In cases where the clinical picture is unclear, the histomorphologic analysis often plays a pivotal role in determining the diagnosis and thus the management. By contrast, a biopsy analysis may be indeterminate, and thus the clinical progression of the disease must inform its treatment.

The following conditions may present in a similar manner as ulcerative colitis, and should be excluded:

The most common disease that mimics the symptoms of ulcerative colitis is Crohn's disease, as both are inflammatory bowel diseases that can affect the colon with similar symptoms. It is important to differentiate these diseases since their courses and treatments may differ. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.

Standard treatment for ulcerative colitis depends on the extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications to prevent a relapse. The concept of induction of remission and maintenance of remission is very important. The medications used to induce and maintain a remission somewhat overlap, but the treatments are different. Physicians first direct treatment to inducing remission, which involves relief of symptoms and mucosal healing of the colon's lining, and then longer term treatment to maintain remission and prevent complications. Acute severe ulcerative colitis requires hospitalisation, exclusion of infections, and corticosteroids.[45]

For acute stages of the disease, a low fiber diet may be recommended.[46][47]

Ulcerative colitis can be treated with a number of medications, including 5-ASA drugs such as sulfasalazine and mesalazine. Corticosteroids such as prednisone can also be used due to their immunosuppressive and short-term healing properties, but because their risks outweigh their benefits, they are not used long-term in treatment. Immunosuppressive medications such as azathioprine and biological agents such as infliximab and adalimumab are given only if people cannot achieve remission with 5-ASA and corticosteroids. Such treatments are used less commonly due to their possible risk factors, including but not limited to increased risk of cancers in teenagers and adults,[48] tuberculosis, and new or worsening heart failure (these side effects are rare).

A formulation of budesonide was approved by the FDA for treatment of active ulcerative colitis in January 2013.[49] Tofacitinib was approved for treatment of moderately to severely active ulcerative colitis in 2018 in the US, the first oral medication indicated for long term use in this condition.[50] The evidence on methotrexate does not show a benefit in producing remission in people with ulcerative colitis.[51] Off-label use of drugs such as ciclosporin and tacrolimus has shown some benefits.[52][53] Fexofenadine, an antihistamine drug used in treatment of allergies, has shown promise in a combination therapy in some studies.[54][55] Opportunely, low gastrointestinal absorption (or high absorbed drug gastrointestinal secretion) of fexofenadine results in higher concentration at the site of inflammation. Thus, the drug may locally decrease histamine secretion by involved gastrointestinal mast cells and alleviate the inflammation.

Sulfasalazine has been a major agent in the therapy of mild to moderate ulcerative colitis for over 50 years. In 1977, it was shown that 5-aminosalicylic acid (5-ASA, mesalazine/mesalamine) was the therapeutically active component in sulfasalazine.[56] Many 5-ASA drugs have been developed with the aim of delivering the active compound to the large intestine to maintain therapeutic efficacy but with reduction of the side effects associated with the sulfapyridine moiety in sulfasalazine. Oral 5-ASA drugs are particularly effective in inducing and in maintaining remission in mild to moderate ulcerative colitis.[57][58] Rectal suppository, foam or liquid enema formulations of 5-ASA are used for colitis affecting the rectum, sigmoid or descending colon, and have been shown to be effective especially when combined with oral treatment.[59]

Biologic treatments such as the TNF inhibitors infliximab, adalimumab, and golimumab are commonly used to treat people with UC who are no longer responding to corticosteroids. Tofacitinib, vedolizumab, and etrolizumab can also produce good clinical remission and response rates in UC.[7] Usually, these medications are only used if other options have been exhausted (i.e., the person has received and not responded favorably to high-dose corticosteroids and immunomodulators such as azathioprine and mesalazine).

Unlike aminosalicylates, biologics can cause serious side effects such as an increased risk of developing extra-intestinal cancers,[48] heart failure; and weakening of the immune system, resulting in a decreased ability of the immune system to clear infections and reactivation of latent infections such as tuberculosis. For this reason, patients on these treatments are closely monitored and are often given tests for hepatitis and tuberculosis at least once a year.

Unlike Crohn's disease, ulcerative colitis has a lesser prevalence in smokers than non-smokers.[60][61]Studies using a transdermal nicotine patch have shown clinical and histological improvement.[62]

In one double-blind, placebo-controlled study conducted in the United Kingdom, 48.6% of patients who used the nicotine patch, in conjunction with their standard treatment, showed complete resolution of symptoms. Another randomized, double-blind, placebo-controlled, single-center clinical trial conducted in the United States showed that 39% of patients who used the patch showed significant improvement, versus 9% of those given a placebo.[63] Use of a transdermal nicotine patch without the addition of other standard treatments such as mesalazine has relapse occurrence rates similar to standard treatment without the use of nicotine.

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 anemia with blood tests repeated every three months in active disease and annually in quiescent disease.[64] Adequate disease control usually improves anemia of chronic disease, but iron deficiency anemia should be treated with iron supplements. The form in which treatment is administered depends both on the severity of the anemia and on the guidelines that are followed. Some advise that parenteral iron be used first because patients respond to it more quickly, it is associated with fewer gastrointestinal side effects, and it is not associated with compliance issues.[65] Others require oral iron to be used first, as patients eventually respond and many will tolerate the side effects.[64][66] All guidelines advise that parenteral iron should be administered in cases of severe anemia (a hemoglobin level less than 100 g/L).

Unlike in Crohn's disease, the gastrointestinal aspects of ulcerative colitis can generally be cured by surgical removal of the large intestine, though extraintestinal symptoms may persist. This procedure is necessary in the event of: exsanguinating hemorrhage, frank perforation, or documented or strongly suspected carcinoma. Surgery is also indicated for patients with severe colitis or toxic megacolon. Patients with symptoms that are disabling and do not respond to drugs may wish to consider whether surgery would improve the quality of life.

Ulcerative colitis affects many parts of the body outside the intestinal tract. In rare cases, the extra-intestinal manifestations of the disease may require removal of the colon.[14]

Another surgical option for ulcerative colitis that is affecting most of the large bowel is called the ileo-anal pouch procedure. This is a two- to three-step procedure in which the large bowel is removed, except for the rectal stump and anus, and a temporary ileostomy is made. The next part of the surgery can be done in one or two steps and is usually done at six- to twelve-month intervals from each prior surgery.

In the next step of the surgery, an internal pouch is made of the patient's own small bowel, and this pouch is then hooked back up internally to the rectal stump so that the patient can once again have a reasonably functioning bowel system, all internal. The temporary ileostomy can be reversed at this time so that the patient is internalized for bowel functions, or, in another step to the procedure, the pouch, and rectal stump anastamosis can be left inside the patient to heal for some time while the patient still uses the ileostomy for bowel function. Then, on a subsequent surgery, the ileostomy is reversed and the patient has internalized bowel function again.

A type of leukocyte apheresis, known as granulocyte and monocyte adsorptive apheresis, still requires large-scale trials to determine whether or not it is effective.[70] Results from small trials have been tentatively positive.[71]

About 21% of inflammatory bowel disease patients use alternative treatments.[76] A variety of dietary treatments show promise, but they require further research before they can be recommended.[77]

Patients with ulcerative colitis usually have an intermittent course, with periods of disease inactivity alternating with "flares" of disease. Patients with proctitis or left-sided colitis usually have a more benign course: only 15% progress proximally with their disease, and up to 20% can have sustained remission in the absence of any therapy. Patients with more extensive disease are less likely to sustain remission, but the rate of remission is independent of the severity of the disease.

The risk of colorectal cancer is significantly increased in patients with ulcerative colitis after ten years if involvement is beyond the splenic flexure. Those patients with only proctitis or rectosigmoiditis usually have no increased risk.[14] It is recommended that patients have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease activity, at one to two year intervals.[91]

Ulcerative colitis has a significant association with primary sclerosing cholangitis (PSC), a progressive inflammatory disorder of small and large bile ducts. As many as 5% of patients with ulcerative colitis may progress to develop primary sclerosing cholangitis.[92]

Research has not revealed any difference in overall risk of dying in patients with ulcerative colitis from that of the background population. The cause-of-death distribution may be different from that of the background population.[93] It is thought that the disease primarily affects quality of life, and not lifespan.

Changes that can be seen in chronic ulcerative colitis include granularity, loss of the vascular pattern of the mucosa, loss of haustra, effacement of the ileocecal valve, mucosal bridging, strictures and pseudopolyps.[94]

The geographic distribution of UC and Crohn's disease is similar worldwide,[95] with the highest number of new cases a year of UC found in Canada, New Zealand, Scotland and the United Kingdom.[96] It begins most commonly between the ages of 15 and 25. A second peak of onset is the 6th decade of life.[97] In general, higher rates are seen in northern locations compared to southern locations in Europe[98] and the United States.[99]

As with Crohn's disease, the rates of UC are greater among Ashkenazi Jews and decreases progressively in other persons of Jewish descent, non-Jewish Caucasians, Africans, Hispanics, and Asians.[31] Appendectomy prior to age 20 for appendicitis[100] and current tobacco use[101] are protective against development of UC (although former tobacco use is associated with a higher risk of developing the disease.[101])

As of 2004, the number of new cases of UC in the United States is between 2.2 and 14.3 per 100,000 per year.[102] The number of people affected in the United States is between 37 and 246 per 100,000.[102]

In Canada, between 1998 and 2000, the number of new cases per year was 12.9 per 100,000 population or 4,500 new cases. The number of people affected was estimated to be 211 per 100,000 or 104,000.[103]

In the United Kingdom 10 per 100,000 people newly develop the condition a year while the number of people affected is 243 per 100,000. Approximately 146,000 people in the United Kingdom have been diagnosed with UC.[104]

Helminthic therapy using the whipworm Trichuris suis has been shown in a randomized control trial from Iowa to show benefit in patients with ulcerative colitis.[105] The therapy tests the hygiene hypothesis which argues that the absence of helminths in the colons of patients in the developed world may lead to inflammation. Both helminthic therapy and fecal bacteriotherapy induce a characteristic Th2 white cell response in the diseased areas, which was unexpected given that ulcerative colitis was thought to involve Th2 overproduction.[106]

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.[107] ICAM-1 propagates an inflammatory response promoting the extravasation and activation of leukocytes (white blood cells) into inflamed tissue.[107] Increased expression of ICAM-1 has been observed within the inflamed intestinal mucosa of ulcerative colitis sufferers, where ICAM-1 over production correlated with disease activity.[108] This suggests that ICAM-1 is a potential therapeutic target in the treatment of ulcerative colitis.[109]

Gram positive bacteria present in the lumen could be associated with extending the time of relapse for ulcerative colitis.[110]

A series of drugs in development looks to disrupt the inflammation process by selectively targeting an ion channel in the inflammation signaling cascade known as KCa3.1.[111] In a preclinical study in rats and mice, inhibition of KCa3.1 disrupted the production of Th1 cytokines IL-2 and TNF- and decreased colon inflammation as effectively as sulfasalazine.[111]

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Ulcerative colitis - Wikipedia