Ulcerative colitis

Ulcerative colitis
Specialty	Gastroenterology

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Endoscopic image of ulcerative colitis affecting the left side of the colon. The image shows confluent superficial ulceration, and loss of mucosal architecture.

Ulcerative colitis (Colitis ulcerosa, UC) is a form of inflammatory bowel disease (IBD) featuring systemic inflammation specifically causing episodic mucosal inflammation of the colon (large bowel). The inflammation almost universally affects the rectum, and may spread in a continuous fashion more proximally in the colon. It has no known cause, although there is a presumed genetic component to susceptibility. Treatment is with immunosuppression (suppressing the immune system), although colectomy (partial or total removal of the large bowel through surgery) is occasionally necessary.

Clinical presentation

GI symptoms

The clinical presentation of ulcerative colitis depends on the extent of the disease process. Patients usually present with diarrhea mixed with blood, of gradual onset. They also may have signs of weight loss, abdominal pain and blood on rectal exam. Sometimes the initial sign of the disease is unrelated to the bowel, such painful knees.

Extent of Involvement

Different portions of the colon may be involved:

• Proctitis: Involvement limited to the rectum.

• Proctosigmoiditis or distal colitis: Involvement of the rectosigmoid colon.

• Left-sided colitis: Involvement up to the splenic flexure.

• Pancolitis: Involvement extending to the cecum.

Severity of Disease

UC patients may be characterized by the severity of their disease:

• Mild disease correlates with intermittent loose bloody stools (up to 4 times a day) with passage of mucus. Involvement is usually limited to the rectum (proctitis) or the rectosigmoid colon (proctosigmoiditis or distal colitis). There may be mild abdominal pain or cramping, constipation, or tenesmus. Rectal pain uncommon.

• Moderate disease correlates with frequent loose bloody stools (about 10 times a day), anemia (not requiring transfusions), moderate abdominal pain, and low grade fever. Involvement can extend up to the splenic flexure (left-sided colitis).

• Severe disease, or fulminant disease, correlates with more than 10 loose bloody stools a day, severe abdominal cramps, fever up to 39.5 C, anemia requiring transfusions, hypotension, and rapid weight loss with inadequate nutrition. Involvement may or may not extend to the cecum (pancolitis). Patients in this category may have inflammation extending beyond just the mucosal layer, causing impaired colonic motility and leading to toxic megacolon. If the serosa is involved, colonic perforation may ensue.

Extraintestinal features

As ulcerative colitis is a systemic disease, patients may present with symptoms and complications outside the colon. These include the following:

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Patients with ulcerative colitis can occasionally have aphthous ulcers involving the tongue, lips, palate and pharynx

• aphthous ulcers of the mouth
• Ophthalmic (involving the eyes):
  • Iritis or uveitis, which is inflammation of the iris
  • Episcleritis
• Musculoskeletal:
  • Seronegative arthritis, which can be a large-joint oligoarthritis (affecting one or two joints), or may affect many small joints of the hands and feet
  • Ankylosing spondylitis
  • Sacroiliitis
• Cutaneous (related to the skin):
  • Erythema nodosum, which is a panniculitis, or inflammation of subcutaneous tissue involving the lower extremities
  • Pyoderma gangrenosum, which is a painful ulcerating lesion involving the skin
• Deep venous thrombosis and pulmonary embolism
• autoimmune hemolytic anemia
• clubbing
• Primary sclerosing cholangitis

Diagnosis and workup

General

The initial diagnostic workup for ulcerative colitis includes the following :

• A complete blood count is done to check for anemia; thrombocytosis is occasionally seen
• Electrolyte studies and renal function tests are done, as chronic diarrhea may be associated with hypokalemia, hypomagnesemia and pre-renal failure.
• Liver function tests are performed to screen for bile duct involvement: primary sclerosing cholangitis.
• X-ray
• Urinalysis
• Stool culture, to rule out parasites and infectious causes.
• Erythrocyte sedimentation rate can be measured, with an elevated sedimentation rate indicating that an inflammatory process is present.

Endoscopic

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 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:

• Loss of the vascular appearance of the colon
• Erythema (or redness of the mucosa) and friability of the mucosa
• Superficial ulceration, which may be confluent, and
• Pseudopolyps.

The disease is usually continuous from the rectum, with the rectum almost universally being involved. There is rarely peri-anal disease, but cases have been reported. 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 confirm the diagnosis, and microbiological samples may be taken at the time of endoscopy. The pathology in ulcerative colitis typically involves distortion of crypt architecture, inflammation of crypts, frank crypt abcesses, and hemorrhage or inflammatory cells in the lamina propria.

Other tests and Observations

Although the following tests and observations are not needed for diagnosis, it might be useful to do these prior to intervention.

Some research indicates an association of the disease with Mycobacterium paratuberculosis, the infective agent for Johne's disease. Testing for the bacterium and antibodies at the outset might reveal a possible cause for the disease.

Because many patients exhibit lactose intolerence, a lactose breath hydrogen test could be performed at the outset. Those patients who are lactose intolerent should be advised to avoid dairy products containing lactose at the outset of treatment, removing a possible aggravating agent. Those patients who are not lactose intolerent may not need to unneccesarily disrupt their diet by avoiding dairy products.

Course and complications

Progression or Remission

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 disease.

Ulcerative colitis and colorectal cancer

There is a significantly increased risk of colorectal cancer in patients with ulcerative colitis after 10 years if involvement is beyond the splenic flexure. Those with only proctitis or rectosigmoiditis usually have no increased risk. . It is recommended that patients have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease activity .

Primary sclerosing cholangitis

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 .

Mortality

The effect of ulcerative colitis on mortality is unclear, but it is thought that the disease primarily affects quality of life, and not lifespan.

Causes

While the cause of ulcerative colitis is unknown, several, possibly interrelated, causes have been suggested.

Immune System Disorder

Ulcerative colitis is treated mainly as an autoimmune disease: the immune system, which is supposed to protect the body from infection, is instead attacking and damaging a part of the body. This could be a malfunction of the immune system itself, or an exagerated response to an actual infection. Genetic factors may predispose certain people to an immune system disorder, and environmental factors may trigger the response.

Infective Agents

It is possible that ulcerative colitis results from, or is a symptom of, an infection in the large intestine, or in some other area of the body. The observed inflammation could be the direct result of an infection, or it could be the result of immune system response to an infection in another part of the body, damaging the intestine in the process. As of yet, however, no infective agent, or type of infection, is clearly associated with the disease.

Genetic factors

A genetic component to the etiology of ulcerative colitis can be hypothesized based on the following :

• Aggregation of ulcerative colitis in families.
• Twin concordance studies, although the evidence is less than for Crohn's disease
• Ethnic differences in incidence
• Genetic markers and linkages

There is much research currently being done to elucidate further genetic markers in ulcerative colitis. Linkage with Human Leukocyte Antigen B-27, associated with other autoimmune diseases, has been proposed.

Environmental factors

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

• Diet: as the colon is exposed to many different dietary substances which may encourage inflammation, dietary factors have been hypothesized to play a role in the pathogenesis of both ulcerative colitis and Crohn's disease. There have been few studies to investigate such an association, but one study showed no association of refined sugar on the prevalence of ulcerative colitis .
• Smoking: Unlike Crohn's disease, ulcerative colitis has a lesser prevalence in smokers than non-smokers .
• Breastfeeding: There have been conflicting reports of the protection of breastfeeding in the development of inflammatory bowel disease. One Italian study showed a potential protective effect .
• Other childhood exposures, or infections

Epidemiology

The incidence of ulcerative colitis in North America is 10-12 cases per 100,000, with a peak incidence of ulcerative colitis occurring between the ages of 15 and 25. There is thought to be a bimodal distribution in age of onset, with a second peak in incidence occurring in the 6th decade of life. The disease affects females more than males .

The geographic distribution of ulcerative colitis and Crohn's disease is similar worldwide , with highest incidences in the United States, Canada, the United Kingdom, and Scandinavia. Higher incidences are seen in northern locations compared to southern locations in Europe and the United States

As with Crohn's disease, ulcerative colitis is thought to occur more commonly among Ashkenazi Jewish peoples than non-Jewish people, although immigrant data from the United States does not support this hypothesis.

Treatment with Drugs

Standard treatment for ulcerative colitis depends on extent of involvement and disease severity. The goal is to induce remission initially with medications, followed by the administration of maintenance medications.

Drugs Used

Drugs used include the following:

• Non-steroidal anti-inflammatory drugs (NSAIDs) that tend to be poorly-absorbed by the intestines, and hence provide topical relief within the intestine:
  • Mesalazine, also known as 5-aminosalicylic acid (5-ASA), Asacol, Pentasa and Mesalamine.
  • Sulfasalazine, also known as Azulfidine. This drug belongs a traditional class of antibiotics, but decomposes in the intestine, releasing 5-ASA.
  • Balsalazide, also known as Colazal, intended to release 5-ASA only in the large intestine.
  • Olsalazine, also known as Dipentum, intended to release 5-ASA only in the large intestine.

• Corticosteroids, serving as immune system suppressants:
  • cortisone
  • prednisone
  • hydrocortisone
  • methylprednisolone

• Anti-tumor Necrosis Factor Inhibitors:
  • Infliximab

Treatment for Proctitis

Proctitis usually indicates involvement of the distal 10-15 cm of the colon. Approximately 30% of patients initially present with proctitis. Standard treatment for active disease include Mesalazine suppositories and cortisone foam (Cortifoam(R)). Mesalazine 1 g SUPP QHS or Cortifoam QHS/BID is continued until remission, with response seen usually within three weeks. Maintenance therapy is with Mesalazine 1g QHS or Q3HS. Steroid foam is not shown to prevent relapse as maintenance therapy. Maintenance therapy is not recommended for those with a first episode that responded to the Mesalazine. Those with anal irritation or discomfort from the suppositories may switch to oral medications, such as sulfasalazine, Mesalazine, or Colazol, although they are not as efficacious as suppositories for distal disease. Systemic steroids such as prednisone are reserved for refractory disease.

Treatment for Proctosigmoiditis and Left-sided Colitis

Proctosigmoiditis and left-sided colitis. Patients often respond to topical agents alone, such as Mesalazine, or hydrocortisone enemas. Again, the Mesalazine is preferred for maintenance therapy. Initially a 4 g Mesalazine enema (Rowasa) is given nightly. If response is seen, they can be tapered to every third night. If no reponse, a morning Mesalazine, or hydrocortisone enema (Cortenema) can be given. If still no response, oral sulfa drugs, with or without enemas, can be given, such as sulfasalazine, Mesalazine (Asacol, Pentasa), olsalazine (Dipentum), or balsalazide (Colazal). If still no response, dose should be increased to maximum: sulfasalazine maxes at 4-6 g/day, Mesalazine maxes at 4.8 g/day, and olsalazine at 3 g/day. They are usually divided tid or bid. Oral 5-ASA requires four to six weeks to exert effect. Once remission is induced, maintenance levels can be used: sulfasalazine 2 g/day, mesalamine 1.2-2.4 g/day, or olsalazine 1 g/day. Patients on high dose sulfasalazine requires folic supplementation (1 mg/day) because it inhibits folate absorption. If oral Mesalazine is still not working, prednisone should be given, starting at 40-60 mg/day, and takes effect within 10-14 days. Dose should then be tapered by about 5 mg/week until it can be stopped altogether.

Treatment for Extensive or pancolitis

Extensive or pancolitis. Patients usually require a combination of oral Mesalazine or sulfasalazine along with topical Mesalazine or steroid enemas. Oral prednisone (40-60 mg/day) should be given only in severe cases or if oral Mesalazine fails. Once remission is induced, maintenance therapy is with standard oral Mesalazine doses. Supplemental iron (ferrous sulfate or ferrous gluconate) may be given due to chronic blood loss. Loperamide may be given for symptomatic relief of chronic diarrhea, but should not be given in suspected toxic megacolon.

Treatment for Severe or fulminant colitis

Severe or fulminant colitis. Patients need to be hospitalized immediately with subsequent bowel rest, nutrition, and IV steroids. Typical starting choices are hydrocortisone 100 mg IV q8h, prednisolone 30 mg IV q12h, or methylprednisolone 16-20 mg IV q8h. The last two are preferred due to less sodium retention and potassium wasting. 24-hour continuous infusion is preferred than the stated dosing. If the patient has not had any corticosteroids within the last 30 days, IV ACTH 120 units/day as continuous infusion is superior than the IV steroids mentioned above. In either case, if symptoms persist after 2-3 days, Mesalazine or hydrocortisone enemas daily or bid can be given. The use of antibiotics in those with severe colitis is not clear. However, there are those patients who have sub-optimal response to corticosteroids and continue to run a low grade fever with bandemia. Typically they can be treated with IV ciprofloxacin and metronidazole. However, in those with fulminant colitis or megacolon, with high fever, leukocytosis with high bandemia, and peritoneal signs, broad spectrum antibiotics should be given (i.e., ceftazidime, cefepime, imipeneum, meropenem, etc). Abdominal x-ray should also be ordered. If intestinal dilation is seen, patients should be decompressed with NG tube and or rectal tube.

Treatment for Refractory ulcerative colitis

Refractory ulcerative colitis. Patients with toxic megacolon (colonic dilation > 6 cm and toxic appearing) who do not respond to steroid therapy within 72 hours should be consulted for colectomy. Those with less severe disease but do not respond to IV steroids within 7-10 days should be considered for colectomy or IV cyclosporine. IV cyclosporine at a rate of 2 mg/kg/day and if no response in 7-10 days, colectomy should be considered. If response is seen, oral cyclosporine at 8 mg/kg/day should be continued for 3-4 months while 6-MP or azathioprine is introduced. Those already on 6-MP or azathioprine should continue with these medications. A cholesterol level should be checked in patients taking cyclosporine as low cholesterol may predispose to seizures. Also, prophylaxis against PCP (Pneumocystis carinii) pneumonia is advised.

Drugs being Tested

• Nicotine. Studies have suggested that smoking has a protective effect on UC. Transdermal nicotine may be effective in inducing remission but maintenance of remission requires additional therapy.
• Methotrexate. Results inconclusive.
• Heparin. Heparin has antiinflammatory effects but role is inconclusive.
• Anti-integrin antibodies. Integrins are proteins that modulate migration of leukocytes to the gut. More studies are needed.

Alternative Treatments

Dietary Modification

• Lactose intolerance is noted in many ulcerative colitis patients. Those with suspicious symptoms should get a lactose breath hydrogen test. If lactose is restricted, calcium may need to be supplemented to avoid bone loss.

• Patients with abdominal cramping or diarrhea should avoid fresh fruits and vegetables, caffeine, carbonated drinks and sorbitol-containing foods.

• Fermentable dietary fiber may be beneficial to maintain remission.

Fats and Oils

• Fish oil. Eicosapentaneoic acid (EPA), derived from fish oil. inhibits leukotriene activity and is effective as an adjunct therapy. Usual dose is 15-18 capsules a day.

• Short chain fatty acid (butyrate) enema. Results not conclusive.

Herbals

• Kampo medicine is used in Japan; Oren-gedoku-to is one such traditional herbal medicine being used both in Japan and China since the Han Dynasty. The traditional Chinese medicine name for this is Huang-Liang-Jie-Du-Tang; its and English name is Coptis Detoxifying Formula.

Bacterial Recolonization

• Probiotics may have benefit. One study looked at a probiotic known as VSL-3 has shown promise for people with ulcerative colitis.

• Fecal bacteriotherapy involves the infusion of human probiotics through fecal enemas . It suggests that the cause of ulcerative colitis may be a previous infection by a still unknown pathogen. This initial infection resolves itself naturally, but somehow causes an imbalance in the colonic bacterial flora, leading to a cycle of inflammation which can be broken by "recolonizing" the colon with bacteria from a healthy bowel. There have been several reported cases of patient who have remained in remission for up to 13 years.

Intestinal Parasites

Inflammatory bowel disease is less common in the developing world. Some have suggested that this may be because intestinal parasites are more common in underdeveloped countries. Some parasites are able to reduce the immune response of the intestine, an adaptation that helps the parasite colonize the intestine. The decrease in immune response could reduce or eliminate the inflammatory bowel disease

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. The therapy tests the hygiene hypothesis which argues that the absence of helminths in the colons of patients in the western world may lead to inflammation. Both helminthic therapy and fecal bacteriotherapy induce a characteristic Th2 white cell response in the diseased areas, which is somewhat paradoxical given that ulcerative colitis immunology was thought to classically involve Th2 overproduction .

Ongoing research

Recent evidence from the ACT-1 trial suggests that infliximab may have a greater role in inducing and maintaining disease remission.

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. The role of hydrogen sulfide in pathogenesis is unclear. It has been suggested that the protective benefit of smoking that some patients report is due to hydrogen cyanide from cigarette smoke reacting with hydrogen sulfide to produce the nontoxic isothiocyanate. Another unrelated study suggested sulphur contained in red meats and alcohol may lead to an increased risk of relapse for patients in remission .

One controversial theory claims that Mycobacterium paratuberculosis which is responsible for Johne's disease in cows, sheep and goats has many similarities to Crohn's and a lesser extent ulcerative colitis. The theory is further that the M. paratuberculosis bacteria are only indirectly responsible, since it is the immune system of the person that overreacts in an allergic fashion to this intestinal bacteria. [17]

Similar conditions and comparison to Crohn's disease

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

• Crohn's disease
• Infectious colitis, which is typically detected on stool cultures
• Pseudomembranous colitis, or Clostridium difficile-associated colitis
• Ischemic colitis, which typically affects the elderly
• Radiation colitis in patients with previous pelvic radiotherapy

Ulcerative colitis and Crohn's colitis can be difficult to distinguish. Certain characteristics can distinguish the two:

• Ulcerative colitis affects only the colon, while Crohn's disease can affect the entire digestive tract.
• Ulcerative colitis is usually confined to the mucosal of the colon. Crohn's colitis, tends to be patchy, and affect deeper layers of the colon, being transmural in nature.
• Ulcerative colitis is associated with a higher incidence of primary sclerosing cholangitis and may be associated with a higher incidence of colon cancer than Crohn's colitis
• There are characteristic radiological and endoscopic differences between the two diseases.

See also

• Aphthous stomatitis
• Crohn's disease
• Ileostomy
• Inflammatory bowel disease
• Primary sclerosing cholangitis
• Colon cancer
• 5-ASA
• Infliximab

External links

• Crohn's and Colitis Foundation of America
• Crohn's Zone - Support for Crohn's and Colitis
• IBD Directory - Listings for Crohn's and colitis resources
• IBD Sucks - an online forum for people with Colitis, Crohn's, and IBS
• National Association for Colitis and Crohn's disease (UK)
• Teen IBD - Support for teens with Colitis & Crohn's
• Information on Ulcerative Colitis - including diet and supplements