Ulcerative colitis Dr.Shi-neng Zhang Professor Department of Gastroenterology Sun Yat-sen University BY
Ulcerative colitis (UC) is a chronic disease of unknown etiology characterized by inflammation of the mucosa and submucosa of the large intestine. The inflammation usually involves the rectum down to the anal margin and extends proximally in the colon for a variable distance. There is no difference between men and women. The worldwide incidence is 0.5~24 new cases per 100 000 individuals, and prevalence is 100~200 cases per 100 000. Introduction
UC: is a form of (IBD). It is a form of colitis, of 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. UC 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.
External environment It is indisputable that the emergence of IBD in various parts of the world is associated with social and economical progress, as initially observed in Northern Europe and North America, then the rest of Europe, South America and Japan, and further the Asian Pacific region, as we are now witnessing. A large number of unrelated environmental factors are considered risk factors for IBD, including smoking , diet, drugs (oral contraceptive and NSAIDs). Current concept of etiopathogenesis
Genetics There is an increased familial incidence of IBD, both for Crohn’s disease and ulcerative colitis. This is due in large part to technological advances in DNA analsis and sequencing, such as genome-wide associational, and the use of huge multicenter or multinational databases. The era modern IBD genetics began in 2001 with the discovery of mutations in the NOD2/CARD15 gene, the first susceptibility gene in CD. Polymorphisms of TLR4 have been associated with an increased risk for UC as well as CD.
Microbial factors Among the components of IBD pathogenesis, the investigation of role of infectious agents and the gut commensal flora is an area in which relatively less progress has occurred. There are two main reasons for this (1) Only isolated reports on new infectious agents with an etiologic potential for IBD have been published in several years, and (2) major methodological difficuties are encountered in the study of the flora in the human gut.
Immunological factors The investigation of IBD pathogenesis has been dominated for a long time by studies of mucosal immunity and, in particular, studies of the function of local T cells in Cd and UC tissues. CD4+CD25- T cells(Tr1 cells) CD4+CD25+Foxp3+ T cells(T regs) IL-23, IFN-r,TNF-a
Additional factors In addition to the environmental, genes, microbes, and the immune system, other factors also participate in IBD pathogenesis, and two in particular are worth mentioning: Fibrosis ： Angiogenesis ： It has recently been shown to be a novel and important component of IBD pathogenesis, and one likely to contribute to the chronicity of the disease. Angiogenesis blockage is effective in decreasing inflammation in experimental colitis.
Although UC 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, UC is not thought to be caused by dietary factors. Although UC is treated as though it were an autoimmune disease, there is no consensus that it is such.
Pathologic changes in the colon in UC readily predict the clinical features of the disease. Unlike the segmental lesions of CD, UC involves primarily the mucosa of the colon, the mucosa is inflamed continuously. The involved mucosa is red and granular and bleeds diffusely. The macroscopic lesions may progress from small, petechial ulcerations to deeper, linear ulcers separated by islands of inflamed but intact mucosa. In severe cases, large areas of the colon may be denuded. Pathology
The characteristic pathology is one of chronic inflammation characterized by large numbers of lymphocytes and histocytes in the diseased mucosa and submucosa with an acute inflammatory infiltrate composed of neutrophils variably present. The alterating processes of superfical ulceration and granulation followed by re-epithelialization can lead to the development of polypoid excrescences. These are inflammatory polyps(pseudopolyps) that are not neoplastic.
UC is an intermittent disease, with periods of exacerbated symptoms, and periods that are relatively symptom-free. Although the symptoms of UC can sometimes diminish on their own, the disease usually requires treatment to go into remission.
UC 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.
The five most common symptoms of UC are rectal bleeding, diarrhea, abdominal pain, weight loss, and fever. The clinical presentation of UC 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, and blood on rectal examination. The disease is usually accompanied with different degrees of abdominal pain, from mild discomfort to severely painful cramps. Clinical manifestations
Extent of involvement UC 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, UC patients 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 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 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 Severe disease, correlates with more than six bloody stools a day, 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. Patients in this category may have severe 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.
Course and complications Progression or remission Patients with UC 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
UC and colorectal cancer There is a significantly increased risk of colorectal cancer in patients with UC after 10 years if involvement is beyond the splenicflexure. Those with only proctitis or rectosigmoiditis usually have no increased risk. It is recommended that patients have screening colonoscopies with random biopsies to look for dysplasia after eight years of disease
Invasive adenocarcinoma is diagnosed when neoplastic epithelium traverses the muscularis mucosae
Stromal desmoplasia is prominent (compare with lamina propria)
IBD: Ulcerative Colitis - Dysplasia
Primary sclerosing cholangitis (PSC) UC has a significant association with (PSC), a progressive inflammatory disorder of small and large bile ducts. As many as 5% of patients with UC may progress to develop (PSC). Mortality The effect of UC on mortality is unclear, but it is thought that the disease primarily affects quality of life, and not lifespan.
The best test for diagnosis of UC 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 UC 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.
Endoscopic UC 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
Endoscopic image of ulcerative colitis affecting the left side of the colon. The image shows confluent superficial ulceration and loss of mucosal architecture. Crohn's disease may be similar in appearance, a fact that can make diagnosing UC a challenge.
Colonic pseudopolyps of a patient with intractable ulcerative colitis. Colectomy specimen.
Histologic Biopsies of the mucosa are taken to definitively diagnose UC and differentiate it from Crohn's diseas, Microbiological samples are typically taken at the time of endoscopy. The pathology in UC 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 management.
Diagnosis The diagnosis of UC is usually made on the basis of its clinical features, the demonstration of inflammation of the rectal and sigmoidal mucosa on proctosigmoidosocpy, and the exclusion of specific infectious by appropriate stool culture and examination for parasites. The diagnosis may be supported by radiologic examination, colooscopy, and rectal biopsy.
The following conditions may present in a similar manner and should be excluded:
Infectious colitis , which is typically detected on stool cultures
Pseudom embranous 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
Chemical colitis resulting from introduction of harsh chemicals into the colon from an enema or other procedure.
Comparison to Crohn's Disease The most common disease that mimics the symptoms of UC is Crohn's disease, as both are IBD 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.
Comparisons of various factors in Crohn's disease and ulcerative colitis Shallow, mucosal May be transmural, deep into tissues Depth of inflammation Continuous ulcer Linear and serpiginous (snake-like) ulcers Endoscopy Continuous area of inflammation Patchy areas of inflammation Distribution of Disease Higher rate of Primary sclerosing cholangitis Not associated Bile duct involvement? Seldom Commonl Peri-anal involvement Always Usually Usually Seldom Involves colon? Involves rectum? Seldom Commonly Involves terminal ileum Ulcerative Colitis Crohn's Disease
Comparisons of various factors in Crohn's disease and UC (Cont.) Higher than Crohn's Lower than ulcerative colitis Cancer risk? No consensus Generally regarded as an autoimmune disease Autoimmune disease Usually cured by removal of colon, can be followed by po uchitis Lower risk for smokers Often returns following removal of affected part Higher risk for smokers Surgical cure ? Smoking Crypt abscesses and cryptitis Can have granulomata Biopsy Seldom Commonly Fistulae, abnormal passageways between organs
Standard treatment for UC 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. Treatment
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. Current treatments have been effective for many patients with UC but have numerous limitations for patients with moderate to severe disease.
are the mainstay of UC pharmacotherapy for induction and maintenance of remission for patients with mild to moderate disease.
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-aminosalicyclic acid (5-ASA and mesalazine) was the therapeutically active compound 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.
Niraj Jani et al. Gastro Clin North America 2002, Katz S. J Clin Gastro 2002,
Corticosteroids It is often required for the one-third of patients who fail to respond to 5-ASAs, But it is not useful for maintenance of remission and carry significant undesirable side effects, as osteoporosis, glucose intolerance, and increased risk of infection.
Immunosupressive drugs It have a role in maintenance of remission in moderate to severe UC. Their relatively slow onset of action precludes their use during flares of the disease, and the use of these agents has been reported to potentially increase the risk of lymphoma in patients with IBD. It requires intense monitoring, and may cause irreversible nephrotoxicity, all of which limit its use to severe cases only.
Adverse effects : bone marrow , hepatitis, pancreatitis
Niraj Jani et al. Gastro Clin North America 2002, Katz S. J Clin Gastro 2002, Farrell RJ et al Lancet 2002, Chinyu Su et al, Gastro Clin North America 2002
Biological treatment It refers to the use of medication that is tailored to specifically target an immune or genetic mediator of disease. The, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy; many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms . (Infliximab ,Visilizumab)
Infliximab is known as a "chimeric monoclonal antibody" (the term "chimeric" refers to the use of both mouse (murine) and human components of the drug. The drug blocks the action of TNFα (tumor necrosis factor alpha) by binding to it and preventing it from signaling the receptors for TNFα on the surface of cells. TNFα is one of the key cytokines that triggers and sustains the inflammation respone.
Visilizumab is a humanized monoclonal antibody. It is being investigated for use as an immunosuppressive drug in patients with UC and Crohn's disease. Visilizumab binds to the CD3 receptor on certain activated T cells without effecting resting T cells. It is currently under clinical studies.
The α 4 7 integrin is a heterodimeric cell surface glycoprotein present on the surface of subsets of circulating memory CD4+ and CD8+T cells and most B cells. It has received particular attention in the context of mucosal immune responses because of its intimate involvement in lymphocyte recruitment to normal gastrointestinal (GI) mucosa and associated lymphoid tissue.
This agent inhibits the binding of α 4 7 integrin to its ligand, the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) which is highly expressed on GI mucosa-associaetd endothelium and high endothelial venules of mesenteric lymph nodes. Binding of integrin antagnosit to α 4 7 on lymphocytes disrupts lymphocyte migration into inflamed GI mucosa, thus providing a potential therapeutic option for patients with UC.
Surgery Failure of medical therapy leads to colectomy in (9% - 35%) of patients with UC within 5 years. Colectomy is considered to be an important adjunct treatment for refractory UC; however, colectomy with ileal pouch anal anastomosis (the standard surgical therapy) has many limitations and is associated with its own set of complications, including high stool frequency, female infertility, and a cumulative incidence of chronic pouchitis of 50% at 10 years.
Absolute indications for subtotal or total colectomy are:
perforation, with or without abscess formation
colonic carcinoma, for which total protocolectomy and lymph node dissection are required
Relative indications are as follow:
Severe acute colitis with or without toxic dilatation of the colon, with failure to respond to maximal therapy
Failure to medical management
Suspicion of cancer
Unlike Crohn's disease, UC 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. In rare cases the extra-intestinal manifestations of the disease may require removal of the colon.
Moderate High dose 5-ASA High dose maintenance Steroids Severe Extensive Colitis 5-ASA CsA AZA / 6-MP AZA/6-MP maintenance Colectomy Remission NO Remission NO Remissio n Remission Remission Failur e
Alternative treatments Smoking : Unlike Crohn's disease, UC has a lesser prevalence in smokers than non-smokers . Dietary modification : Dietary modification may reduce the symptoms of the disease. Lactose intolerance is noted in many ulcerative colitis patients. Those with suspicious symptoms should get a lactose breath hydrogen test.
Patients with abdominal cramping or diarrhea may find relief or a reduction in symptoms by avoiding fresh fruits and vegetables, caffeine, carbonated drinks and sorbitol-containing foods. Many dietary approaches have purported to treat UC, including the ElaineGottschall's specific carbohydrate diet and the "anti-fungal diet" (Holland/Kaufmann). The use of elemental and semi-elemental formula has been successful in pediatric patients
Bacterial recolonization Probiotics may have benefit. And promise for people with UC. Fecalbacteriotherapy involves the infusion of human probiotics through fecal enemas. It suggests that the cause of UC 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.
Intestinal parasites IBD 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 IBD.
Prognosis The outlook for recovery from a first attack of UC is very good. Mortality, which is about 5%, occurs almost exclusively in those who have a severe form of the disease involving the entire colon. The mortality is higher in patients over 60 years, approximately 17%, compared to 2% in patients between ages 20 and 59. Toxic megacolon has a mortality rate of about 20 percent. Death generally results from the complications of massive hemorrhage, systemic infections, pulmonary embolism, or associated cardiac disorders.