ULCERATIVE COLITIS Author: Dr Sandro Ardizzone1 Creation date: September 2003 Scientific Editor: Prof Gabriele Bianchi Porro 1Chair of Gastroenterology , L. Sacco University – Hospital, Via GB Grassi, 74 20157 Milan, Italy. [email protected] Abstract Introduction Epidemiology Etiology Pathophysiology Symptoms, signs, and laboratory findings Diagnostic methods Differential diagnosis Therapy Prognosis Surgery References Abstract Ulcerative colitis (UC) is an inflammatory chronic disease primarily affecting the colonic mucosa; the extent and severity of colon involvement are variable. In its most limited form it may be restricted to the distal rectum, while in its most extended form the entire colon is involved. UC belongs to the inflammatory bowel diseases (IBD), which is a general term for a group of chronic inflammatory disorders of unknown etiology involving the gastrointestinal tract. UC is usually associated with recurrent attacks with complete remission of symptoms in the interim. In Western Europe and in the USA, UC has an incidence of approximately 6 to 8 cases per 100.000 populations and an estimated prevalence of approximately 70 to 150 per 100.000 populations. The leading initial symptom of UC is diarrhea with blood and mucus, sometimes with pain. Fever and weight loss are less frequent. Extra intestinal symptoms can be an initial manifestation or can occur later in the course of the disease. Eighty percent of the patients have only proctitis or proctosigmoiditis, and only 20% have extensive colitis. However, in about 50% of patients with initial proctosigmoiditis, proximal extension occurs later, and in some patients the opposite takes place. Depending of the stage of the disease, endoscopy reveals reddening of the mucosa, increased vulnerability, mucosal bleeding, irregular ulcers, pseudopolyps, granularity, and loss of vascular architecture. Several drugs interacting with various points along the immune and inflammatory cascades are currently available for the treatment of UC. Corticosteroids, aminosalicylates, immunomodulators are the mainstay of medical treatment. Keywords Ulcerative colitis, inflammatory bowel diseases, colonic mucosa, gastrointestinal tract, proctitis, proctosigmoiditis, corticosteroids, aminosalicylates, immunomodulators Introduction manifestations often resulting in an Inflammatory bowel disease (IBD) is a general unpredictable course. term for a group of chronic inflammatory Ulcerative colitis is an inflammatory chronic disorders of unknown etiology involving the disease primarily affecting the colonic mucosa; gastrointestinal tract.Chronic IBD may be divided the extent and severity of colon involvement are into two major groups, ulcerative colitis (UC) variable. In its most limited form it may be and Crohn's disease (CD), clinically restricted to the distal rectum, while in its most characterized by recurrent inflammatory extended form the entire colon is involved. involvement of intestinal segments with several However, 80% of the patients present with Ardizzone S. Ulcerative colitis. Orphanet encyclopedia. September 2003: http://www.orpha.net/data/patho/GB/uk-UC.pdf 1 disease extending from the rectum to the splenic role of environmental factors in the appearance flexure, and only 20% have pancolitis. and progression of CD and UC. Although the causes of IBD remain unclear, The effect of cigarette smoking or the opposite considerable progress has been made recently effect of this factor on the outcome of each form in the identification of important pathophysiologic of IBD represents the most intriguing connection mechanisms, and further and newer knowledge between environmental factors and IBD. Most has been obtained from recent studies reports have shown that non-smoking is a concerning their epidemiology, natural history, feature of patients with UC, whereas smoking is diagnosis and treatment. a feature of patients with CD. Smoking is an independent risk factor for clinical, surgical, and endoscopic recurrence in CD but influences Epidemiology disease activity after surgery. On the contrary, Ulcerative colitis is usually associated with the relative risk of developing UC in heavy ex- recurrent attacks with complete remission of smokers, all ex-smokers, non-smokers, and symptoms in the interim. The disease is more smokers has been evaluated to be respectively common in Caucasians than in Blacks or 4.4, 2.5, 1.0 and 0.6. Nicotine is probably the Orientals with an increased incidence (three to main active ingredient in this association, but the six fold) in Jewish. Both sexes are equally mechanisms remain unknown. Cigarette affected. In Western Europe and in the USA, UC smoking has been shown to affect cellular and has an incidence of approximately 6 to 8 cases humoral immunity, and increase colonic mucus per 100.000 populations and an estimated production; both smoking and nicotine have prevalence of approximately 70 to 150 per been shown to reduce colonic motility. Finally, 100.000 populations. While peak occurrence of results from in vivo studies have shown that both diseases (UC and CD) is between ages 15 nicotine also has an inhibitory effect on T-helper- and 35, it has been reported in every decade of 2 cell (Th2) function, which predominates in UC, life. A familial incidence of IBD is currently but has no effect on Th-1 cells, predominant in recorded. CD. Epidemiological data indicate that non-steroidal anti-inflammatory drugs can trigger Etiology exacerbations of UC and even, occasionally, The cause of UC is unknown. Although less induce de novo disease. Possible mechanisms evident than in CD, it is clear from twin studies include decreased production of protective that a genetic background is also present in UC. mucosal prostanoid and increased leukocyte Indeed, a stronger association exists between adherence and migration. Although these effects genes of the human leucocyte antigen region - were initially thought to be due to inhibition of involved in regulating the immune response - cyclo-oxygenase-1 (COX-1), selective COX-2 and UC. Despite unclear effects due to ethnic inhibitors seem as potent as indomethacin in this origin and disease heterogeneity, this context. association is strongest in patients with Psychological stress by some 40% of patients extensive UC; a positive association with DR2 with UC, has been reported to be a potential (in particular, DRB1*1502 subtype) and the rare trigger. Substantial evidence links psychological alleles DRB1*0103 and DRB1*12, and a stress with increased illness and, possibly, negative association with DR4 and Drw6 have increased susceptibility to infection through been reported. However, genes associated with stress-related impairment of functional immune susceptibility to UC are probably not within the responses. Duration of stress might also be human leucocyte antigen region, and genome- important since long-term but not short-term wide scanning studies have shown a linkage stress seems to increase the risk of between UC and regions of chromosomes 3, 7, exacerbations of disease. and 12. Moreover, there are genes that appear Another very interesting environmental factor to affect the severity and extent of the disease, conditioning UC is appendicectomy. Indeed, steroid response, steroid requirements, and appendicectomy, at a young age, has the extra - intestinal manifestations. Finally, strongest preventive effect on the development polymorphisms of the IL-1 receptor antagonist of UC. This finding has been corroborated by that might affect severity and extent of disease case-control studies, and a very large have been reported, particularly in patients population-based study recently confirmed the positive for pANCA, as well as for MUC3, a gene inverse relationship between appendicectomy encoding intestinal mucins that might also be and UC in patients submitted to surgery before associated with the pathogenesis of UC. age 20 years. In the latter study, the risk of UC Among the many puzzles concerning IBD was reduced only in patients who underwent etiology, one of the least understood and, appendicectomy for appendicitis or mesenteric perhaps, most difficult to tackle, presently, is the Ardizzone S. Ulcerative colitis. Orphanet encyclopedia. September 2003: http://www.orpha.net/data/patho/GB/uk-UC.pdf 2 lymphadenitis, but not in those who underwent extension occurs later, and in some patients the incidental appendicectomy or appendicectomy opposite takes place. A change in the extent of for non-specific abdominal pain. This finding disease should be suspected when new suggests that an inflammatory condition at a symptoms arise. The course of the disease can young age that results in appendicectomy, rather vary widely. Spontaneous remission from a flare- than appendicectomy itself protects against later up occurs in 20 to 50% of the patients, but 50 to development of UC. Another possible 70% have a relapse during the first year after explanation for this inverse association is that diagnosis. genetic predisposition to UC might protect against development of appendicitis. Table1: Initial symptoms of UC Diarrhea 96.4% Pathophysiology Blood in stool 89.3% While the cause of UC remains unknown, a Pain 81;3% number of findings in recent years point to an Generally unwell 40.2% over stimulation or inadequate regulation of the Weight loss 38.4% mucosal immune system as a major Arthralgia 27.7% pathophysiologic pathway, and particular Fever 20.5% emphasis has been given to either the study of Skin changes 20.5% mucosal inflammation or immunologic