Ulcerative Colitis
Definition of Ulcerative Colitis
Ulcer Colitis is a form of inflammatory bowel disease ulcerative colitis is aform of colitis, a disease of the colon , that includes characteristic ulcers, or open sores The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset . inflammatory bowel disease often confused with irritable bowel syndrome a troublesome ,but much less serious, condition.
lcerative colitis has similarities to Crohn’s disease, another form of inflammatory bowel disease . 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.
Although ulcerative colitis has no known cause, there is a presumed genetic component to susceptibility.
Ulcerative colitis is treated as an autoimmune disease.Treatment is with anti-inflammatory drugs, immunosuppression, and biological therapy targeting specific components of the immune response. Colectomy is occasionally necessary if the disease is severe, doesn’t respond to treatment, or if significant complications develop. A total proctocolectomy can be curative, but it may be associated with complications.
Cause of Ulserative Colits
Genetic Factors
A genetic component to the aetiology of ulcerative colitis can be hypothesized based on the following
- Aggregation of ulcerative colitis in families.
- Identical twin concordance rate of 10% and dizygotic twin concordance rate of 3%
- Ethnic differences in incidence
- Genetic markers and linkages
There are 12 regions of the genome that may be linked to ulcerative colitis, including, in the order of their discovery, chromosomes 16, 12, 6, 14, 5, 19, 1, and 3, but none of these loci has been consistently shown to be at fault, suggesting that the disorder arises from the combination of multiple genes. For example, chromosome band 1p36 is one such region thought to be linked to inflammatory bowel disease.
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 There may even be human leukocyte antigen associations at work. In fact, this linkage on chromosome 6 may be the most convincing and consistent of the genetic candidates.
Multiple autoimmune disorders have been recorded with the neurovisceral and cutaneous genetic porphyrias including ulcerative colitis, 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 potential porphyrinogenic drugs, including sulfasalazine.
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 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. High intake of unsaturated fat and vitamin B6 may enhance the risk of developing ulcerative colitis. Other identified dietary factors that may influence the development and/or relapse of the disease include meat protein and alcoholic beverages. Specifically, sulfur has been investigated as being involved in the etiology of ulcerative colitis, but this is controversial. Sulfur restricted diets have been investigated in patients with UC and animal models of the disease. The theory of sulfur as an etiological factor is related to the gut microbiota and mucosal sulfide detoxification in addition to the diet.
- 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.[
- Several scientific studies have posted that Accutane is a possible trigger of Crohn’s disease and ulcerative colitis in some individuals. Three cases in the United States have gone to trial thus far, with all three resulting in multi-million dollar judgements against the makers of isotretinoin. There were an additional 425 cases pending as of.
Alternative theories
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
Signs And Symptoms of Ulcerative Colitis
Gastrointestinal
The clinical presentation 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 chronic loss of blood from the GI tract leads to increased rates of anaemia. The disease may be accompanied with 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 affects many parts of the body. Sometimes these associated extra-intestinal symptoms are the initial signs of the disease, such as painful, arthritic knees in a teenager and may be seen in adults also. The presence of the disease may not be confirmed immediately, however, until the onset of intestinal manifestations.
Extent Of İnvolvement
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:
- Distal colitis, potentially treatable with enemas:
- Proctitis: Involvement limited to the rectum.
- Proctosigmoiditis: 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.
- Extensive colitis, inflammation extending beyond the reach of enemas:
- Pancolitis: Involvement of the entire colon, extending from the rectum to the cecum, beyond which the small intestine begins.
Severity Of Disease
In addition to the extent of involvement, people may also be characterized by the severity of their disease.
- Mild disease correlates with fewer than four stools daily, with or without blood, no systemic signs of toxicity, and a normal erythrocyte sedimentation rate (ESR). There may be mild abdominal pain or cramping. Patients may believe they areconstipated 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 more than four stools daily, but with minimal signs of toxicity. Patients may display anemia (not requiring transfusions), moderate abdominal pain, and low grade fever, 38 to 39 °C (100 to 102 °F).
- Severe disease, correlates with more than six bloody stools a day or observable massive and significant bloody bowel movement, and evidence of toxicity as demonstrated by fever, tachycardia, anemia or an elevated ESR.
- Fulminant disease correlates with more than ten bowel movements daily, continuous bleeding, toxicity, abdominal tenderness and distension, blood transfusion requirement and colonic dilation (expansion). 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. Unless treated, fulminant disease will soon lead to death.
Extraintestinal Features
As ulcerative colitis 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 anywhere between 6 and 47 percent. These include the following:
- Aphthous ulcer 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):Deep venous thrombosis and pulmonary embolismAutoimmune hemolytic anemia
- 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
- Clubbing, a deformity of the ends of the fingers.
- Primary sclerosing cholangitis, a distinct disease that causes inflammation of the bile ducts
Risk Factors for Ulcerative Colitis
Ulcerative colitis affects about the same number of women and men. Risk factors may include:
- Age.Peak incidence between 15 and 25 years
- Race or ethnicity. Whites and Ashkenazi Jewish descent have higher risk.
- Family history
- Isotretinoin use. Several scientific studies have posted that Accutane is a possible trigger of Crohn’s disease and ulcerative colitis in some individuals. Three cases in the United States have gone to trial thus far, with all three resulting in multi-million dollar judgements against the makers of isotretinoin. There were an additional 425 cases pending as of.
- Diet: as the colon is exposed to many 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. High intake of unsaturated fat and vitamin B6 may enhance the risk of developing ulcerative colitis. Other identified dietary factors that may influence the development and/or relapse of the disease include meat protein and alcoholic beverages. Specifically, sulfur has been investigated as being involved in the etiology of ulcerative colitis, but this is controversial. Sulfur restricted diets have been investigated in patients with UC and animal models of the disease. The theory of sulfur as an etiological factor is related to the gut microbiota and mucosal sulfide detoxification in addition to the diet.
- 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.
Diagnosis of Ulcerative Colitis
- 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. 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
Biopsy sample (H&E stain) that demonstrates marked lymphocytic infiltration (blue/purple) of the intestinal mucosa and architectural distortion of the crypts.
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 perianal 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.
Histologic
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.
Differential Diagnosis
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 culturesIschemic colitis, inadequate blood supply to the intestine, which typically affects the elderly
- Pseudomembranous colitis, or Clostridium difficile-associated colitis, bacterial upsets often seen following administration of antibiotics
- Radiation colitis in patients with previous pelvic radiotherapy
- Chemical colitis resulting from introduction of harsh chemicals into the colon from an enema or other procedure.
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 the course of the diseases and treatments may be different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as indeterminate colitis.
Prevention from Ulcerative Colitis
Because the cause is unknown, prevention is also unknown.
Treatment of Ulcerative Colitis
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 maintain the remission and prevent complications.
Medication
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 immunosuppressing and short term healing properties, but due to the risks outweighing the benefits, they are not used long term in treatment. Immunosuppressive medications such as azathioprine, and biological agents such as infliximab and adalimumab are given lastly, only if patients cannot achieve remission with 5-ASA and Corticosteroids, due to their possible risk factors, including, but not limited to increased risk of cancers in teenagers and adults, TB 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.
Aminosalicylates
Sulfasalazine has been a major agent in the therapy of mild to moderate UC for over 50 years. In 1977, Mastan S. Kalsi et al. determined that 5-aminosalicylic acid (5-ASA and mesalazine) was the therapeutically active in sulfasalazine. Since then many 5-ASA compounds have been developed with the aim of maintaining efficacy but reducing the common side effects associated with the sulfapyridine moiety in sulfasalazine.
Biologics
Biologic treatments such as Infliximab (trade name Remicade), adalimumab (trade name Humira) and Golimumab (trade name Simponi) are commonly used to treat patients with Ulcerative Colitis who are no longer responding to corticosteroids. Usually these medications are only used after other options have been exasperated (i.e. patient has received high dose corticosteroids, immunomodulators such as Azathioprine and Mesalazine) but in certain cases, patients may skip these steps and start biologic treatments under doctor orders.
Unlike Aminosalicylates, Biologics can cause harsh side effects such as mild heart failure or worsening of heart failure, skin cancer (excluding melanoma), weakening of the immune system leading to possible fatal infections and Tuberculosis. For this reason patients on these treatments are closely monitored and must be given tests for Hepatitis and Tuberculosis at least once a year. Blood tests must also be taken every 4–8 weeks.
Nicotine
Unlike Crohn’s disease, ulcerative colitis has a lesser prevalence in smokers than non-smokers. Patients who choose to use smoking as a treatment should keep a record regarding smoking cessation and the onset or relapse of ulcerative colitis to verify associations. Studies using a transdermal nicotine patch have shown clinical and histological improvement.
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 participants showed significant improvement vs. 9% of placebo. 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.
Iron supplementation
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 this. Adequate disease control usually improves anemia of chronic disease, but iron deficiency may require treatment with oral iron supplements. Occasionally, parenteral iron is required.
Treatments in Development
Inflammation of the colon is a characteristic symptom of ulcerative colitis and a new series of drugs in development look to disrupt the inflammation process by selectively targeting an ion channel. A crucial step involved in the inflammation signaling cascade involves an intermediate conductance calcium activated potassium channel (IK channel) known as KCa3.1; a protein coded for in the human gene KCNN4. Ongoing research seeks to prevent T-cell activation and inflammation by inhibiting the KCa3.1 channel, selectively. Since there is an upregulation of IK channel activity during T cell activation, inhibition of the KCa3.1 is able to disrupt the production of Th1 cytokines IL-2 and TNF-∝. Production of these cytokines decreases because inhibition of KCa3.1 reduces the efflux of K+ which in turn diminishes the influx of Ca2+. By lowering elevated intracellular Ca2+ in patients with ulcerative colitis these novel drug candidates can inhibit the signaling cascade involved in the inflammation process and help relieve many of the symptoms associated with ulcerative colitis.
Preclinical study results in 2012 indicated that these selective inhibitors decreased colon inflammation in mice and rats cloned with the human KCa3.1 protein as effectively as the standard inflammatory bowel disease treatment of sulfasalazine. However, these novel selective IK channel blockers are significantly more potent and theoretically would be able to taken at a much more manageable dosage.
Benzothiazinone, NS6180, is a novel class KCa3.1 channel inhibitor in development.Through a number of in vitro experiments, NS6180 was qualified for KCa3.1 channel inhibition. In vivoexperiment of DNBS (2,4 – dinitrobenzene sulfonic acid) induced rat colitis, a frequently used animal model for inflammatory bowel disease, showed comparable efficacy and increased potency than sulfasalazine.
Surgery
Unlike Crohn’s disease, ulcerative colitis can generally be cured by surgical removal of the large intestine, also known as a colectomy. 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 (UC) 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.
Another surgical option for ulcerative colitis that is affecting most of the large bowel is called the ileo-anal pouchprocedure. This procedure 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 patients’ own small bowel and this pouch is then hooked back up internally to the rectal stump so that 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 now 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.
Bacterial recolonization
- Probiotics may have benefit. One study which 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 patients who have remained in remission for up to 13 years.
Alternative medicine
About 21% of inflammatory bowel disease patients use alternative treatments. A variety of dietary treatments show promise, but they require further research before they can be recommended.
In vitro research, animal evidence, and limited human study suggest that melatonin may be beneficial.
Dietary fiber, meaning indigestible plant matter, has been recommended for decades in the maintenance of bowel function. Of peculiar note is fiber from brassica, which seems to contain soluble constituents capable of reversing ulcers along the entire human digestive tract before it is cooked. Oatmeal is also commonly prescribed.
- Fish oil, and eicosapentaenoic acid (EPA) derived from fish oil, inhibits leukotriene activity, the latter which may be a key factor of inflammation. As an IBD therapy, there are no conclusive studies in support and no recommended dosage. But dosages of EPA between 180 to 1500 mg/day are recommended for other conditions, most commonly cardiac.
- Short chain fatty acid (butyrate) enema. The colon utilizes butyrate from the contents of the intestine as an energy source. The amount of butyrate available decreases toward the rectum. Inadequate butyrate levels in the lower intestine have been suggested as a contributing factor for the disease. This might be addressed through butyrate enemas. The results however are not conclusive.
- Herbal medications are used by patients with ulcerative colitis. Compounds that contain sulfhydryl may have an effect in ulcerative colitis (under a similar hypothesis that the sulfa moiety of sulfasalazine may have activity in addition to the active 5-ASA component). One randomized control trial evaluated the over-the-counter medication S-methylmethionine and found a significant decreased rate of relapse when the medication was used in conjunction with oral sulfasalazine.