© Springer International Publishing Switzerland 2015
Daniel J. Stein and Reza Shaker (eds.)Inflammatory Bowel Disease10.1007/978-3-319-14072-8_77. What Happens If I Do Nothing for My Ulcerative Colitis? The Natural History of Untreated Ulcerative Colitis
(1)
Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA
Keywords
Ulcerative colitisColon cancerColectomyDiarrheaHospitalizationQuality of lifeColorectal cancerSuggested Response to the Patient
Ulcerative colitis is a chronic, lifelong, inflammatory disease where the body’s immune system (the system that normally fights infection) is attacking your colon which causes ulcers and bleeding from the lining of the colon. Symptoms typically occur in periods of attacks we call flares and can last from months to years at a time. These flares are different for every patient and can be characterized by abdominal pain, diarrhea, bloody diarrhea, nausea, vomiting, and/or weight loss. This leads to loss of quality of life, frequent doctor’s visits, and hospitalizations, and some patients require removal of the colon due to worsening of the disease. Most patients have up to two flares in a 5-year period, but this will be very different for every patient. For many patients who go untreated, ulcerative colitis tends to get progressively worse over time. Flares tend to get more frequent and more severe, putting patients at risk for hospitalizations and even surgery to remove the colon (colectomy). Additionally, if left untreated, UC can put patients at a higher risk of developing colon cancer over time.
Once the diagnosis has been made, early treatment is recommended to decrease how often these flares occur and decrease the severity of each flare. Due to the development of newer medical treatments, the possibility of disease worsening is lesser today than it was a few decades ago. These treatments have also reduced the need for colon removal (colectomy) and possibly decreased the risk of colon cancer. It is important to understand that UC is a lifelong diagnosis and that medical therapy cannot cure ulcerative colitis, but it is very good at controlling the disease.
Brief Review of the Literature
Ulcerative colitis (UC) is a chronic inflammatory disease characterized by recurrent episodes of acute flares followed by periods of remission. Earlier population-based studies have revealed that without treatment, these patients have a higher risk of colorectal cancer and increased mortality [1], although this risk has decreased over the decades owing to successful immunosuppressive and biologic medical therapies [2–7]. An untreated disease pathology has the potential for extension throughout the colon leading to systemic symptoms which may require a colectomy.
Disease Course in Relation to Disease Extent
UC is classified, based on disease extent, into ulcerative proctitis, left-sided colitis, and extensive colitis. The Montreal classification includes disease extent, symptom severity (number of bowel movements per day), and signs of systemic involvement (ESR, temperature, hemoglobin) [8]. Identification of disease severity and extent serves as a useful prognostic indicator. Ulcerative proctitis is the most frequent form at diagnosis (30–60 %), and left-sided colitis (10–40 %) and extensive colitis (10–35 %) are less frequent [9–15]. The risk of proximal progression is estimated to be around 10–20 % at 5 years and up to 30 % at 10 years [9, 16].
Disease extent is a major factor predicting the progression of disease which can signify increase in disease activity with worsening outcomes. Patients with ulcerative proctitis were shown to progress to extensive colitis at the rate of 14 % over 10 years after diagnosis. A higher rate of progression was seen in patients with left-sided colitis at 28 % in the IBSEN Norwegian cohort [7]. Young age at diagnosis and primary sclerosing cholangitis were strong and independent predictors of proximal progression in a prospective study of 420 patients [17]. The median time of progression from proctitis or left-sided colitis to extensive colitis in this study was 5.25 years.
Expected Frequency of Disease Flare-Ups
Most UC patients have at least two flare-ups in 5 years but less than 1 yearly flare-up [10]. About half of the patients in the IBSEN Norwegian cohort experienced the most severe flare-up at diagnosis, and one third of the patients had subsequent flare-ups of similar severity [13]. Younger patients at diagnosis had a trend towards higher relapse rate. In fact, patients diagnosed over the age of 50 years had a significantly lower relapse rate and colectomy rate. These findings were also corroborated in the EC IBD multicenter study [7, 18, 19].
Long-Term Complications
Disease progression in ulcerative colitis can lead to benign colonic strictures due to hypertrophy and irreversible contraction of muscularis mucosae that is eventually detached from the submucosal layer [20]. These strictures become problematic in that it is difficult to completely rule out an occult malignancy within these strictures, often leading to surgery. Also, there is a reduction in the number of neuroglial cells leading to dysmotility, and persistent diarrhea in spite of mucosal healing seen on endoscopy, and reduced rectal accommodation leading to fecal urgency and incontinence, when the anorectal compartment is involved [21]. These changes may persist even after mucosal healing is achieved, which is thought to play a role in continued symptoms in some patients without active mucosal inflammation.
Risk of Colectomy
Colectomy is a curative procedure for patients with ulcerative colitis and significantly improves general health, but dealing with an ostomy or J pouch can be debilitating for some patients. About 50 % of the colectomies performed for UC are done emergently [22]. Colectomy has not been shown to increase mortality, but a delay in surgery has been shown to increase postoperative complications and mortality [23]. The rates of colectomy have declined over the years, and two separate studies showed this decline in 1-year colectomy rate in UC patients from 9 % in 1962–1987 to 6 % in 2003–2005. This decline is most likely due to the increasing use of azathioprine/6-mercaptopurine across these time periods [24, 25]. In the recent EC IBD study, average colectomy rate in UC patients was at 8.7 % after 10-year follow-up. The difference in colectomy rates between northern (10.4 %) and southern centers (3.9 %) in this study suggests that the disease process might be more pronounced in patients living in cooler and more sterile areas [2, 12]. Patients with extensive UC and severe refractory disease constitute more than 90 % of the colectomies. Consistent with the prior knowledge that in most cases, severe disease flares might be seen earlier in the course of the disease, about two thirds of the colectomies occurred in the first 2 years after diagnosis [12, 13]. Extensive colitis at diagnosis is an independent predictor of colectomy up to 10 years after diagnosis, based on the IBSEN study [7, 26]. Extensive colitis patients have a fourfold higher risk of colectomy compared to those with ulcerative proctitis [26]. However, in this same cohort, patients with proximal extension were shown to have a tendency towards higher rate of colectomy when compared to patients with extensive colitis at diagnosis [7]. Overall, younger patients (<30 years old), extensive colitis, ESR > 30 mm/h, and corticosteroid requirement at diagnosis were associated with a 15 times higher risk of colectomy [2].
The presence of systemic symptoms such as weight loss and fever in addition to extensive colitis at diagnosis further increased the risk of colectomy. These factors however did not influence the risk of relapse, suggesting that severe disease might be associated with more drastic outcomes [27]. The minor fraction of patients with extensive colitis and systemic symptoms at diagnosis, that were able to avoid colectomy through timely response to medical therapies, have lesser risk of relapses when compared to patients lacking systemic symptoms, based on the IBSEN and Copenhagen cohort studies [7, 27, 28]. Endoscopic findings in these patients also corroborate the epidemiologic findings with increased mucosal healing at 1 year in patients with extensive colitis and systemic symptoms that showed good response to medical treatment [28].
Colorectal Cancer
Colonic mucosal inflammation and associated stress from reactive oxygen species can lead to genetic alterations and carcinogenesis [29]. According to a Belgian national registry study, 73 % of the UC patients developed colorectal cancer (CRC) only in areas of colitis [30]. Follow-up of unselected patients from population-based cohorts showed a cumulative CRC incidence of 0.4 and 1.1 % after 10 and 20 years, respectively [31]. The overall risk of CRC in UC patients was comparable to the background risk of CRC in the general population, in a meta-regression analysis of the same study [2, 31]. Cumulative CRC incidence was greater in other studies, up to 10–20 %, by the second and third decades of the disease process, but this was mainly noted in pancolitis patients seen at referral centers. A higher incidence of CRC was seen in UC patients with long duration of disease, coexistent primary sclerosing cholangitis (PSC), and young age at diagnosis, although the Belgian study showed that older age at diagnosis was an independent risk factor for CRC and these patients had early cancer within 8 years from diagnosis [2, 30, 31]. Extensive colitis, male sex, and young age at diagnosis were the factors that were associated with increased mortality in UC patients with CRC. The incidence of CRC in UC patients has declined over time periods with only a third of the relative risk present in 1999–2008 compared to 1979–1988 [31], most likely due to successful use of biologics and immunomodulatory therapies. The IBSEN study also corraborates the existing evidence that CRC does not significantly increase the mortality risk in UC patients compared to the general population [2]. Presently, the prognosis is similar in UC patients compared to the general population with a 5-year survival of approximately 50 % [32]. 5-aminosalicylic acid (5-ASA) agents have been shown to reduce the incidence of CRC in a meta-analysis of 1,932 UC patients [33]. Due to the decreasing incidence of CRC in UC patients, the role of 5-ASA agents for chemoprevention may be less important than previously thought. For UC patients with coexistent PSC, where there is a significantly increased risk of CRC, ursodeoxycholic acid (UDCA) has shown some promise by reducing the levels of secondary bile acids which serve as carcinogens leading to increased risk of CRC, especially in the right colon [34]. But recent 2010 guidelines have advocated against the use of UDCA for chemoprevention based on prospective evaluation of patients who had a higher incidence of dysplasia and colorectal cancer after receiving high dose UDCA [35].
Screening for colorectal cancer in UC patients is recommended at 8–10 years for patients with pancolitis and at 15 years for patients with left-sided colitis. No surveillance is required for patients with ulcerative proctitis, and further surveillance can be based on risk factors [36–40]. The Belgian national registry study reported that time to CRC incidence was independently affected by age of IBD onset in addition to IBD duration with older age of diagnosis of IBD predisposing a shorter interval to CRC onset [30]. The high number of patients who were diagnosed with CRC concurrently with UC in this study probably indicates a need for a more stringent surveillance approach in older patients at diagnosis. For patients with UC and PSC, the risk of CRC or dysplasia is threefold higher than for patients with UC alone [30]. In this patient group, the cumulative incidence rates were 33 and 40 % after 20 and 30 years after UC diagnosis, respectively [41]. For UC patients with coexistent PSC, annual surveillance colonoscopy is required from diagnosis [38, 42]. In patients newly diagnosed with PSC, a colonoscopy is recommended to diagnose coexistent UC [42]. Further, UC patients with a first-degree relative with history of CRC have a two- to threefold increased risk of CRC, and if the first-degree relative had CRC before the age of 50 years, the risk is ninefold compared to patients with no significant family history [43]. Chromoendoscopy was found to be superior to conventional colonoscopy with random biopsies in detecting dysplastic lesions [44]. Confocal laser endomicroscopy has a 2.5 times increased detection rate of dysplastic lesions compared to chromoendoscopy and has a 4.75-fold higher detection rate compared to conventional colonoscopy with random biopsies [45, 46].
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