Article: Ulcerative colitis

Ulcerative colitis (Colitis ulcerosa, UC) is a form of inflammatory bowel disease (IBD). Ulcerative colitis is a form of colitis, a disease of the intestine, specifically the large intestine or colon, that includes characteristic ulcers, or open sores, in the colon. The main symptom of active disease is usually diarrhea mixed with blood, of gradual onset. Ulcerative colitis is, however, a systemic disease that affects many parts of the body outside the intestine.

Because of the name, IBD is often confused with irritable bowel syndrome ("IBS"), a troublesome, but much less serious condition. Ulcerative colitis is similar to Crohn's disease, another form of IBD.

Ulcerative colitis is an intermittent disease, with periods of exacerbated symptoms, and periods that are relatively symptom-free. Although the symptoms of ulcerative colitis can sometimes diminish on their own, the disease usually requires treatment to go into remission.

Ulcerative colitis is a rare disease, with an incidence of about one person per 10,000 in North America. The disease tends to be more common in northern areas.

Although ulcerative colitis has no known cause, there is a presumed genetic component to susceptibility. The disease may be triggered in a susceptible person by environmental factors. Although dietary modification may reduce the discomfort of a person with the disease, ulcerative colitis is not thought to be caused by dietary factors. Although ulcerative colitis is treated as though it were an autoimmune disease, there is no consensus that it is such.

Treatment is with anti-inflammatory drugs and immunosuppression (suppressing the immune system). Colectomy (partial or total removal of the large bowel through surgery) is occasionally necessary, and is considered to be a cure for the disease.

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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.

Clinical presentation

GI symptoms

The clinical presentation[1] of ulcerative colitis depends on the extent of the disease process. Patients usually present with diarrhea mixed with blood and mucus, of gradual onset. They also may have signs of weight loss, abdominal pain and blood on rectal examination.

Ulcerative colitis is a systemic disease that affects many parts of the body. Sometimes the extra-intestinal manifestations of the disease are the initial signs, such as painful, arthritic knees in a teenager. It is, however, unlikely that the disease will be correctly diagnosed until the onset of the intestinal manifestations.

Extent of Involvement

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Diagram of the Human Intestine

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

  • Proctitis: Involvement limited to the rectum.
  • Proctosigmoiditis or distal colitis: Involvement of the rectosigmoid colon, the portion of the colon adjacent to the rectum.
  • Left-sided colitis: Involvement of the descending colon, which runs along the patient's left side, up to the splenic flexure and the beginning of the transverse colon.
  • Pancolitis: Involvement of the entire colon, extending from the rectum to the cecum, beyond which the small intestine begins.

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 thick, white 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. Patients may believe they are constipated when in fact they are experiencing tenesmus, which is a constant feeling of the need to empty the bowel accompanied by involuntary straining efforts, pain, and cramping with little or no fecal output. Rectal pain is 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, 38 to 39 °C (99.5 to 102.2 °F). 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 serous membrane 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, arthritis of the spine
    • Sacroiliitis, arthritis of the lower spine
  • 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, a deformity of the ends of the fingers
  • Primary sclerosing cholangitis, or inflammation of the bile duct

Similar Conditions

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, bacterial upsets often seen following administration of antibiotics
  • Ischemic colitis, inadequate blood supply to the intestine, which typically affects the elderly
  • Radiation colitis in patients with previous pelvic radiotherapy

Comparison to Crohn's Disease

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

  • Ulcerative colitis:
    • Usually affects only the large intestine and rectum.
    • Usually involves the intestine in a continuous fashion from the rectum as far as the inflammation goes.
    • Usually affects the mucosa, or the innermost lining of tissues.
    • Has characteristic features on endoscopy including shallow, continuous ulcers and involvement of the rectum
    • Has a higher rate of primary sclerosing cholangitis, an inflammation of the bile ducts.[2]
    • Can usually be cured by surgical removal of the large intestine.
    • Has a higher rate of cancer associated with it.
    • Although treated as though it were an autoimmune disease, there is no consensus that it actually is such.
  • Crohn's disease:
    • Can occur anywhere in the gastrointestinal tract but commonly involves the terminal ileum
    • Has a patchy distribution in the intestine.
    • Has transmural inflammation where it spreads deep into the layers of affected tissues.
    • Can have granulomata on biopsy
    • May spare the rectum on endoscopy
    • Has characteristic features on endoscopy including deep, linear and serpiginous (or snake-like) ulcers
    • Can be associated with fistulae and peri-anal disease
    • Often returns following surgical removal of the affected part of the intestine.
    • Has a lower rate of cancer associated with it.
    • Widely regarded as an autoimmune disease.
'
Crohn's Disease Ulcerative Colitis
Involves terminal ileum? Commonly Seldom
Involves colon? Usually Always
Involves rectum? Seldom Usually
Peri-anal involvement? Commonly Seldom
Bile duct involvement? Not associated Higher rate of Primary sclerosing cholangitis
Distribution of Disease Patchy areas of inflammation Continuous area of inflammation
Endoscopy Linear and serpiginous (snake-like) ulcers Continuous ulcer
Depth of inflammation May be transmural, deep into tissues Shallow, mucosal
Fistulae, abnormal passageways between organs Commonly Seldom
Biopsy Can have granulomata
Surgical cure? Often returns following removal of affected part Usually cured by removal of colon
Smoking Higher risk for smokers Lower risk for smokers
Autoimmune disease? Generally regarded as an autoimmune disease No consensus
Cancer risk? Lower than ulcerative colitis Higher than Crohn's

Diagnosis and workup

General

The initial diagnostic workup for ulcerative colitis includes the following [3].[4]:

  • A complete blood count is done to check for anemia; thrombocytosis, a high platelet count, 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.
  • C-reactive protein can be measured, with an elevated level being another indication of inflammation.

Although ulcerative colitis is a disease of unknown causation, inquiry should be made as to unusual factors believed to trigger the disease.[5] Factors may include: recent cessation of tobacco smoking; recent administration of large doses of iron or vitamin B6; hydrogen peroxide in enemas or other procedures.

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.

Ulcerative colitis 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.

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. [6]. It is recommended that patients have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease activity [7]. See also [28]

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 [8].

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.

Genetic factors

A genetic component to the etiology of ulcerative colitis can be hypothesized based on the following [9]:

  • 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

Chromosome band 1p36 is linked to inflammatory bowel disease. [10]

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 [11].
  • Smoking: Unlike Crohn's disease, ulcerative colitis has a lesser prevalence in smokers than non-smokers [12]. This is caused by the nicotine in cigarette smoke which acts as an anti-inflammatory[13].
  • 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 [14].
  • Other childhood exposures, or infections

Autoimmune Disease?

Some sources list ulcerative colitis as an auto-immune disease, a disease in which the immune system malfunctions, attacking some part of the body. Although the disease is usually treated as though it were an autoimmune disease, there is no consensus that it actually is such (See List of autoimmune diseases).

As discussed above, ulcerative colitis is a systemic disease that affects many areas of the body outside the digestive system. Surgical removal of the large intestine often cures the disease, including the manifestations outside the digestive system.[15] This suggests that the cause of the disease is in the colon itself, and not in the immune system or some other part of the body.

Free Radical Induction Theory

The free radical induction theory proposes that the initial cause of ulcerative colitis is a malfunction in the patient's metabolism that results in excess levels of oxygen free radicals related hydrogen peroxide in the cells of the intestine. The radicals damage the structure of the colonic epithelial barrier, a one-cell thick membrane that separates the bacteria inside the intestine from the cells of the intestine. The damaged membrane sloughs off, bringing the intestinal cells into direct contact with bacteria. The immune system then mounts an attack on the bacteria, resulting in inflammation, and damage to the intestinal cells themselves. During remission, the membrane is restablished, but is subject to new damage. [16]

Unusual causes or triggers

Ulcerative colitis has been reported subsequent to administration of vitamin B6 and iron as dietary supplements, suggesting that these might be causative factors capable of triggering an episode. [17]

Chemical colitis is an inflammation of the colon resulting from the introduction of harsh chemicals such as soap or hydrogen peroxide through an enema or other procedure. Chemical colitis may resemble ulcerative colitis, and this possibility should be excluded during the diagnosis. There are some indications that chemical colitis may trigger an episode of ulcerative colitis in a person that has the disease, or a predisposition for the disease.

Sulfide toxicity

Levels of sulfate-reducing bacteria tend to be higher in persons with ulcerative colitis. This could mean that there are 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.[18][19]

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 [20].

The geographic distribution of ulcerative colitis and Crohn's disease is similar worldwide [21], 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 [22]

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 to prevent a relapse of the disease. 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 a remission which involves relief of symptoms and mucosal healing of the lining of the colon and then longer term treatment to maintan the remission.

Drugs Used

Aminosalicylates

Aminosalicylates are the main anti-inflammatory drugs used to treat ulcerative colitis. Sometimes remission can be achieved, or at least maintained, with these drugs alone. If not, they are usually used in combination with the drugs listed in the ensuing sections.

The anti-inflammatory action in all these drugs is produced by 5-aminosalicylic acid (5-ASA), the active ingredient in Mesalazine. 5-ASA is produced from the other drugs in the intestine. The aminosalicylates used to treat ulcerative colitis include the following:

  • 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.

5-ASA is poorly-absorbed by the intestines, and hence provides topical relief within the intestine. It is therefore a non-systemic drug. 5-ASA is related to the systemic non-steroidal anti-inflammatory drugs (NSAIDs), such as Aspirin and Ibuprofin, which tend to promote intestinal bleeding, and which should therefore be avoided by persons with ulcerative colitis.

The free radical induction theory, discussed above, proposes that 5-ASA is serving not just as an anti-inflammatory, but also as a free radical trap, destroying the hydroxyl and other radicals that may damage colonic epithelial barrier. [23]

Sulfasalazine side-effects

In the intestine sulfasalazine is converted to 5-ASA and sulfapyridine, which is responsible for some of its side-effects, and which should be monitored in patients taking sulfasalazine. Sulfapyridine levels above 50 mcg/L are associated with the side-effects.

Patients on high dose sulfasalazine require folic supplementation (1 mg/day) (1000 mcg/day) to maintain normal cell division. This may, however, be counter-productive for patients who are also taking methotrexate, which is a folic acid inhibitor. Folic acid might also be counter-productive for patients taking 6-MP and related drugs that inhibit all cell division.

Corticosteroids

It is often necessary to use Corticosteroids in conjunction with NSAIDs to bring about remission of ulcerative colitis. Thereafter it may be possible to maintain remission with NSAIDs alone, or it may be necessary to continue administering corticosteroids to maintain.

Corticosteroids reduce inflammation by blocking portions of the leukocyte adhesion cascade which results in inflammation.

Side effects of corticosteroids include Cushing's syndrome, which most often exhibits itself as temporary facial puffyness, called "moon face". Cushing's syndrome can, however, involve psychosis, including manic behavior. These drugs have been known to trigger bipolar disorder. In prescribing these drugs it might be well to inquire as to any family history of bipolar disorder.

Corticosteroids should not be confused with anabolic steroids, the controversial performance-building "steroids" that are banned in certain sports.

The following corticosteroids are used as immune system suppressants in treatment of ulcerative colitis:

  • Cortisone
  • Prednisone
  • Hydrocortisone
  • Methylprednisolone
  • Budesonide, also known as Entocort, available for oral use or as an enema. Budesonide is metabolized faster than traditional steroids and appears to produce fewer side effects.

Immunosuppressive drugs

Immunosuppressive drugs inhibit the immune system generally. These include the cytostatic drugs that inhibit cell division, including the cloning of white blood cells that is a part of the immune response. Immunosuppressive drugs used with ulcerative colitis include:

  • Mercaptopurine, also known as 6-Mercaptopurine, 6-MP and Purinethiol.
  • Azathioprine, also known as Imuran (US) or Azasan, which metabolises to 6-MP.
  • Methotrexate, which inhibits folic acid

Mercaptopurine is a cytostatic drug that is an antimetabolite. The mercaptopurine molecule mimics purine, which is necessary for the synthesis of DNA. With mercaptopurine present, cells are not able to make DNA, and cell division is inhibited.

In administering mercaptopurine it is necessary to monitor the levels of mercaptopurine metabolites in the blood to establish the correct dosage for a patient. An initial concern is hepatotoxicity.

Mercaptopurine inhibits the production of white blood cells generally. Because this makes the body more susceptible to infection, patients need to watched for infections. Vaccinations should also be done with caution.

Frequent blood cell counts are also recommended during administration of mercaptopurine. The drug may be toxic to bone marrow, where many blood components are made. If there is an abnormally large drop in white blood cell count, or any blood cell count, administration of the drug should be halted at least temporarily.

Methotrexate is another immunosuppressive drug. It works by inhibiting folic acid, which is necessary for DNA replication and, therefore, cell division.

TNF Inhibitors

TNF is a protein that is released by activated white blood cells, triggering more inflammation, an immune system response and more damage to the mucosa of the colon because of the immune activation. Certain drugs inhibit TNF, hence reducing inflammation and immune system involvement. Infliximab was approved by the FDA for treating ulcerative colitis in March 2005. It is ususally given as an intravenous infusions at weeks 0,2 and 6 and then every six seeks thereafter. It is very useful for inducing and maintaining a remission of ulcerative colitis. Some physicians think that infliximab works better when used in combination with immunmodulators such as 6-mercaptopurine or azathioprine, but there is no definitive evidence based medicine to conclude that infliximab must be used with 6-mp or azathioprine.

  • Infliximab

Treatment for Proctitis

Proctitis usually involves the distal, or lower, 10-15 cm (4 to 6 inches) of the colon, including the rectum. Approximately 30% of ulcerative colitis patients initially present with proctitis.

Standard treatment for active disease includes 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. 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 effective as suppositories for proctitis. Maintenance therapy is not recommended for those with a first episode that responded to the Mesalazine. Steroid foam is not shown to prevent relapse.

Systemic steroids such as prednisone are not used unless proctitis fails to respond to the above treatments. [24]

Treatment for Proctosigmoiditis and Left-sided Colitis

Proctosigmoiditis and left-sided colitis involves the lower colon, from the rectum up the left side of the patient.

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, the enemas 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 anti-inflammatory 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 anti-inflammatory drugs require four to six weeks to work.

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 require 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. Prednisone should take effect within 10-14 days. The 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.

Surgery

Unlike Crohn's disease, ulcerative colitis can generally be cured by surgical removal of the large intestine. 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 is a disease that 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. [25]

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. Eicosapentaenoic acid (EPA), derived from fish oil. This is an Eicosanoid that inhibits leukotriene activity. It is effective as an adjunct therapy. Usual dose is 15-18 capsules a day. [29]
  • Short chain fatty acid (butyrate) enema. Results not conclusive.

Antioxidants

The free radical induction theory suggests that the initial cause of ulcerative colitis may be a metabolic defect that allows a build up of chemicals related to hydrogen peroxide beneath the membrane that protects the cells of the intestinal wall from the bacteria inside the intestine, resulting in destruction of the membrane. During remission the membrane is restablished, but may be subject to new damage, resulting in a flare up of the disease. [26] To the extent this may be true, it would be appropriate to take antioxidants, dietary supplements that may support the body's defenses against oxidants like hydrogen peroxide. Antioxidants include:

  • Vitamins A, C and E
  • Coenzyme Q10
  • Selenium and manganese.

Vitamin B6 and iron may be associated with increased hydrogen peroxide levels, and should not be taken in excess under this theory. [27]

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 [28]. 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[29].

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 [30].

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 [31][32].

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. [30]

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.

See also

  • Aphthous stomatitis
  • Crohn's disease
  • Ileo-anal pouch
  • Ileostomy
  • Inflammatory bowel disease
  • Primary sclerosing cholangitis
  • Colon cancer
  • 5-ASA
  • Infliximab
  • Radical Induction Theory of Ulcerative Colitis