Ulcerative colitis

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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.

Contents

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Clinical presentation

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GI symptoms

The clinical presentation<ref>Hanauer SB. "Inflammatory bowel disease". New England Journal of Medicine 1996 Mar; 334(13):841-848. [1]</ref> of ulcerative colitis depends on how extensive the disease process.

Patients usually present with gradual onset of rectal bleeding with loose stools. They also may have signs of weight loss, abdominal pain and blood on rectal exam. UC patients may be characterized by the severity of their disease:

Mild disease correlates with intermittent loose bloody stools (< 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 (~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 > 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.

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Extraintestinal features

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

Image:Canker sore.jpg

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Diagnosis and workup

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General

The initial diagnostic workup for ulcerative colitis includes the following <ref>Al-Ataie MB et al. Emedicine: Ulcerative colitis. Available at [2].</ref>:

All patients gets the initial workup: CBC, electrolytes, renal function, liver function, X-ray, urinalysis (UA).

Stool cultures are sent to rule out infectious causes.

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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 abscesses, and hemorrhage or inflammatory cells in the lamina propria.

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Course and complications

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.

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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. <ref>Am Coll Gastroenterology, [3]</ref>. It is recommended that patients have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease activity <ref> ASGE practice guidelines, [4]</ref>.

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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 <ref>Olsson R et al. Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis. Gastroenterology 1991 May, 100 (5 Pt 1.):1319-23. [5]</ref>.

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

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Causes

While the cause of ulcerative colitis is unknown, infective agents have been suspected as etiological agents, and there may be a genetic component to susceptibility. Immune system over-activity has also been suspected as a cause.

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Genetic factors

A genetic component to the etiology of ulcerative colitis can be hypothesized based on the following <ref>Orholm M et al. Concordance of inflammatory bowel disease among Danish twins. Results of a nationwide study. Scand J Gastroenterol 2000 Oct, 35(10):1075-81. [6]</ref>:

  • 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 HLA-B27 has been proposed.

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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 <ref>Jarnerot G et al. Consumption of refined sugar by patients with Crohn's disease, ulcerative colitis, or irritable bowel syndrome. Scand J Gastroenterol 1983 Nov, 18(8): 999-1002. [7]</ref>.
  • Smoking: Unlike Crohn's disease, ulcerative colitis has a lesser prevalence in smokers than non-smokers <ref>Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 1989 Dec;34(12):1841-54. [8]</ref>.
  • 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 <ref>Corrao G et al. Risk of inflammatory bowel disease attributable to smoking, oral contraception and breastfeeding in Italy: a nationwide case-control study. Cooperative Investigators of the Italian Group for the Study of the Colon and the Rectum (GISC). Int J Epidemiol 1998 Jun;27(3):397-404. [9]</ref>.
  • Other childhood exposures, or infections
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Treatment

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.

Proctitis usually indicates involvement of the distal 10-15 cm of the colon. Approximately 30% of patients presents with proctitis initially. Standard treatment for active disease include 5-ASA suppositories and cortisone foam (Cortifoam(R)). Mesalamine 1 g SUPP QHS or Cortifoam QHS/BID is continued until remission, with response seen usually within three weeks. Maintenance therapy is with mesalamine 1g QHS or Q3HS. Steroid foam not shown to prevent relapse as maintenance therapy. Maintenance therapy is not recommended for those with a first episode that responded to the 5-ASA. Those with anal irritation or discomfort from the suppositories may switch to oral medications, such as Azulfidine, Pentasa, Asacol, or Colazol, although they are not as efficacious as suppositories for distal disease. Systemic steroids such as prednisone is only reserved for refractory disease. <ref>Kornbluth A, Sachar DB. "Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee". Am J Gastroenterol 2004 Jul; 99(7):1371-85. [10]</ref>

Proctosigmoiditis and left-sided colitis. Patients often respond to topical agents alone, such as 5-ASA or hydrocortisone enemas. Again, the 5-ASA is preferred for maintenance therapy. Initially a 4 g 5-ASA enema (Rowasa) is given nightly. If response is seen, they can be tapered to every third night. If no reponse, a morning 5-ASA or hydrocortisone enema (Cortenema) can be given. If still no response, oral 5-ASA with or without enemas can be given, such as sulfasalazine (Azulfidine), mesalamine (Asacol, Pentasa), olsalazine (Dipentum), or balsalazide (Colazal). If still no response, dose should be increased to maximum: sulfasalazine maxes at 4-6 g/day, mesalamine 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 5-ASA 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.

Extensive or pancolitis. Patients usually require a combination of oral 5-ASA or sulfasalazine along with topical 5-ASA or steroid enemas. Oral prednisone (40-60 mg/day) should be given only in severe cases or if oral 5-ASA fails. Once remission is induced, maintenance therapy is with standard oral 5-ASA 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.

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, 5-ASA 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.

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.

Dietary considerations. Lactose intolerance is noted in many UC patients and 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. In those with abdominal cramping or diarrhea, patients should avoid fresh fruits and vegetables, caffeine, carbonated drinks, and sorbitol-containing foods. Fermentable dietary fiber may be beneficial to maintain remission.

Other therapies.

  • Probiotics. Not recommended at this time.
  • Oral antibiotics. Not used routinely unless to avert a fatal infection
  • 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.
  • 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.
  • Infliximab.
  • Methotrexate. Results inconclusive.
  • Trichuris suis. IBD is less common in developing world, and this may be due to high level of helminth colonization which decreases the immune response (and thus risk of IBD). Ingestion of Trichuris suis ova has suggested improvement in UC patients but additional studies need to be done.
  • 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.
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Similar conditions and comparison to Crohn's disease

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

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.
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Alternative treatment

Although great progress has been made in the last 20 years in understanding and treating the disease, a definitive cure for ulcerative colitis still eludes modern medicine. Some patients turn to alternative therapies:

  • 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.
  • 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. [11]
  • 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 <ref>Borody TJ, Warren EF, Leis SM, Surace R, Ashman O, Siarakas S., Bacteriotherapy Using Fecal Flora: Toying With Human Motions, J Clin Gastroenterol. 2004 Jul;38(6):475-483. [12]</ref>. 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<ref>Borody TJ, Warren EF, Leis S, Surace R, Ashman O., Treatment of ulcerative colitis using fecal bacteriotherapy. J Clin Gastroenterol. 2003 Jul;37(1):42-7. [13]</ref>.
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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 <ref>Hanauer SB. "Inflammatory bowel disease". New England Journal of Medicine 1996 Mar; 334(13):841-848. [14]</ref>.

The geographic distribution of ulcerative colitis and Crohn's disease is similar worldwide <ref>Podolsky, DK. "Inflammatory bowel disease". New England Journal of Medicine 2002 Aug; 347(6):417-424. [15]</ref>, 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 <ref>Shivananda S et al., Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 1996 Nov;39(5):690-7. [16]</ref>

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.

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Ongoing research

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

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 <ref> Summers RW et al., Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology. 2005 Apr;128(4):825-32. [17]</ref>.

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 <ref>*Roediger et al. "Colonic sulfide in pathogenesis and treatment of ulcerative colitis.", Dig Dis Sci. 1997 Aug;42(8):1571-9. PMID 9286219</ref><ref>*Levine et al. "Fecal hydrogen sulfide production in ulcerative colitis.", Am J Gastroenterol. 1998 Jan;93(1):83-7. PMID 9448181</ref>.

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See also

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External links

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References

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