ULCERATIVE COLITIS

ULCERATIVE COLITIS ( part 1)
Etiology
Ulcerative colitis (UC) is an inflammatory disease of unknown cause that involves the mucosa of the colon and rectum.
· Psychosomatic factors are thought to play some role in its etiology, and although inconclusive, there are controlled trials that assess the impact of mind, central nervous system, and neuromodulation on the overly active immune response in the intestinal mucosa.
· UC is most likely caused by a combination of genetic and environmental factors.
· Heredity may play a role in the cause, because there is a 5 to 15% incidence of the disease occurring in families compared with a 0.1% occurrence in the general population.
· To confirm a genetic basis, there is a significant increase in the occurrence of inflammatory bowel disease (IBD) in monozygotic twins compared with that in dizygotic twins.
· In addition, Jews have a twofold to fourfold increased incidence compared with other races living in the same area; Ashkenazic Jews have a higher prevalence than Sephardic Jews.
An infectious cause of UC has been postulated, but no bacterial or viral agent has been isolated.
· It is possible, however, that an infectious agent may incite the initial damage and then be eliminated via local defense mechanisms.
· The lesion may be perpetuated by a defective mucosal immune response.
Much effort is being made to understand the role of cytokines in IBD and to design a rationale for cytokine treatment.
· Cytokines play a central role in the modulation of the intestinal immune system. They are produced and secreted by the various cellular types within the intestinal wall.
· Some of these cytokines have proinflammatory functions (interleukin [IL]-1, tumor necrosis factor [TNF], IL-6, IL-8, and IL-12), whereas others have anti-inflammatory functions (IL-1 receptor antagonist [IL-1ra], IL-4, IL-10, IL-11, and transforming growth factor-β [TGF-β]).
· An imbalance between proinflammatory and anti-inflammatory cytokines was found in the inflamed mucosa of patients with IBD as well as in patients with diverticulitis and infectious colitis, supporting the role of the immune system in the etiology of IBD.
An immunologic cause for the disease is also supported by the fact that UC is associated with a variety of autoimmune disorders such as systemic lupus erythematosus, ankylosing spondylitis, and chronic active hepatitis.
Pathologic Features
· UC is present in the rectum and progresses proximately to involve the remainder of the colon in a continuous manner.
· The disease process most commonly ends abruptly at the ileocecal junction.
· In some individuals, there is mucosal inflammation of the terminal ileum; this has been known as "backwash ileitis." Whether this is a real entity remains controversial.
· The extent of the disease may vary from involvement of the rectum and sigmoid alone to total colonic involvement.
· In a small group of patients, segmental involvement of one or more portions of the colon without evidence of the disease in the rectosigmoid region can occur, but this is very rare.
On gross examination, the lesions of UC begin as pinpoint hemorrhage spots associated with a hyperemic and edematous mucosal reaction.
· This friability of the mucosa produces the bleeding that is seen with the disease.
· Ulcerations may be superficial and smooth or ragged and undermined.
· Eventually, the entire mucosa of the colon and rectum may be replaced by these ulcers.
· With chronicity, marked narrowing, thickening, and rigidity of the bowel occur as the muscular coats are replaced by scar tissue.
· Polypoid masses or pseudopolyps, caused by hyperplasias of remaining small islands of mucosas and by the margins of ulcerations, may be present and may persist or recede as the inflammatory process becomes quiescent.
Microscopic examination of the inflamed colon shows
diffuse macroulcerations and microulcerations, with adjacent edema, polymorphonuclear leukocyte infiltration, and eosinophilic cellular invasion of the mucosa.
There also is destruction of villi.
Microscopic crypt abscesses are common and penetrate just into the submucosa with the production of wide areas of ulceration of the overlying mucosa.
There usually is a definite increase in the number of Paneth cells in the colonic crypts, which is thought to more likely be a response to UC than a factor in its cause.
Granulomas, which are typically seen in Crohn's disease (CD), are conspicuously lacking in UC.

Clinical Course
UC is highly variable in severity, clinical course, and ultimate prognosis, although in general the severity of the disease varies with the extent and severity of the changes in the bowel wall.
· It has a peak incidence in persons 20 to 40 years old and is slightly more common in females.
· After its onset, the disease may take one of several courses.
· It may be fulminating and reach its peak in 2 to 3 weeks, or it may pass into a chronic stage with remissions and exacerbations.
· The chronic form of UC presents as three clinical types.
o Approximately 60 to 75% of patients have intermittent attacks of symptoms with complete symptomatic remissions between attacks.
o A few patients (5 to 15%) are troubled by continuous symptoms without any remission.
o Only a small proportion of patients (5 to 10%) have only one attack with no subsequent symptoms.
· The most common symptoms are diarrhea and the passage of blood and mucus.
· Unlike Crohn's colitis, in which hematochezia is often lacking, bloody diarrhea is the hallmark of UC.
· The amount of blood may vary from a small amount of bright red blood, which is mistaken for hemorrhoidal bleeding, to massive bleeding.
The diarrhea may be minimal, or patients may have 10 to 20 bowel movements per day. Occasionally, patients may complain of constipation; these patients usually have inflammation limited to the rectum and sigmoid, and the disease causes a type of functional obstruction. In addition to passing watery stools, patients may have tenesmus and pass a bloody mucous discharge.
· In patients with acute colitis, abdominal pain is a frequent manifestation.
· It tends to be colicky.
· On examination of the abdomen, there may be tenderness over the colon, especially in the left lower quadrant.
· Large doses of steroids may mask clinical signs in acute disease.
With milder forms of distal colitis, there may be only slight impairment of general health.
· In severe cases, the constitutional effects can be profound and the patient may become rapidly debilitated and emaciated.
· Associated with these effects is pyrexia, although a temperature of more than 38° C is unusual except in the very rare fulminating type of colitis or in cases in which there is an intra-abdominal perforation.
· Loss of weight and anemia tend to occur in proportion to the severity of symptoms.
Diagnosis
· The diagnosis of UC should be suspected in patients with a history of bloody diarrhea in whom an infectious cause has been eliminated.
· Barium radiographic studies, sigmoidoscopy, and colonoscopy can be used as complementary techniques to confirm the diagnosis.
· Colonoscopic examination and biopsies tend to be more accurate than a barium enema in assessment of the colon, particularly for detecting early changes and determining the extent of the disease.
· A proctosigmoidoscopy or colonoscopy reveals the typical gross features already described.
· Frequently, there also is a purulent exudate with bloody mucus, an adherent membrane, or both.
· A double-contrast barium enema, which is preferred to a single-contrast study, shows virtually no changes from normal in the early stages of the disease.
· Hence, direct visualization is preferred to make the diagnosis.
· With chronic disease, on barium enema, one can expect to find distortion of the mucosal pattern, loss of haustral markings associated with narrowing of the lumen, and shortening of the colon.
· To complete the gastrointestinal investigation, a small bowel study or enterocylsis should be performed to exclude the possibility of CD of the terminal ileum.
Natural History
· Of utmost importance in the treatment of patients with UC is the fact that with chronicity, UC carries a definite and significant risk for the development of carcinoma of the colon and rectum.]
· The observed incidence of carcinoma in adults with UC is 7 to 30 times greater than that in a controlled population.
· The risk of cancer appears to be related to two factors:
o (1) the duration of the colitis and
o (2) the extent of colonic involvement.
It is recognized that the incidence of carcinoma increases with the duration of the disease.
· Several studies calculated the accumulated incidence of carcinoma to be 3% at 10 years, 9.6% at 15 years, and 10.8 to 24.2% at 20 years.
· Although there is disagreement as to the exact incidence of cancer, it is generally accepted that the risk of cancer is minimal before there has been 10 years of disease activity and that it increases after this time.
· The risk after 20 years may rise at a much steeper rate.
The extent of the colitis also appears to be important in determining the risk of the development of carcinoma.
o Patients with only documented proctitis have a minimal risk of developing a carcinoma.
o Patients with pancolitis are at the highest risk, and patients with left-sided colitis have an intermediate risk.
o In a retrospective study of 267 patients, Greenstein et al. reported on 27 patients who developed adenocarcinoma. Twenty-one of these lesions occurred in 158 patients with total colon disease, whereas 5 occurred in 109 patients with left-sided disease. They also noted that the carcinoma in left-sided colitis occurred at least a decade later than that in patients with pancolitis. (This study may be criticized methodologically due to the biases inherent in a retrospective review.)
A controversial area is the risk of colorectal cancer in patients in whom the colitis began in the prepubertal years.
o It may be that the risk is related only to the longer duration of disease rather than to the time of onset.
o Similarly, it was previously believed that patients whose disease was continuously active were more at risk for carcinoma. It is our view that the activity of the disease is not important in determining the risk of carcinoma. In fact, many patients with quiescent disease often present with advanced lesions because they are asymptomatic and tend not to seek medical advice and thus come under surveillance.

· In the past, prophylactic proctocolectomy was recommended for patients with long-standing disease, regardless of their disease activity, because of the risk of the development of cancer.
· However, with the availability of colonoscopy for surveillance of the entire colon and with increasing expertise in the evaluation of endoscopic and pathologic changes, the trend is to recommend that patients undergo endoscopic surveillance in a search for premalignant lesions in the colonic epithelium.
· The objective of this course of action is to recognize premalignant changes before the onset of carcinoma.
· To this end, the term dysplasia has been used in reference to these precancerous epithelial abnormalities.