UC affects the mucosal layer of the large bowel, and it involves invariably the rectum and may extend proximally to part or even to the entire colon, in an uninterrupted fashion (Judge and Lichtenstein, 2003). Depending upon the anatomic extent of involvement, patients can be classified as having proctitis (involvement limited to the rectum), left-sided colitis (involvement limited to the portion of the colon distal to the splenic flexure), or extensive colitis (Silverberg et al, 2005). The extent of UC influences not only the medical treatment (oral and/or topical therapy) (Stange et al, 2008), but also the schedule for colonic cancer surveillance, because the contribution of the disease extent at the time of diagnosis to the risk of malignancy has been confirmed (Katsanos et al, 2007).
Symptoms of UC depend upon the extent and severity of the disease, and usually include bloody diarrhea, rectal bleeding, rectal urgency, passage of pus, mucus or both, abdominal pain during bowel movements, weight loss, and fatigue. Systemic symptoms of malaise, anorexia, or fever are features of a severe attack (Friedman and Blumberg, 2008). In clinical practice, disease activity is typically described as mild (up to 4 bloody stools per day and no systemic toxicity), moderate (4–6 bloody stools per day and minimal toxicity), or severe (more than 6 stools per day and signs of toxicity, such as fever, tachycardia, anemia, increase in erythrocyte sedimentation rate) (Carter et al, 2004; Kornbluth and Sachar, 2004; Baumgart and Sandborn, 2007). Fulminant colitis is a rare and severe form of the disease, still lacking a formal definition, commonly referred to patients presenting extensive bleeding and anemia requiring blood transfusion, high fever, raised biochemical markers of inflammation, abdominal tenderness, and colonic dilation on plain abdominal film, a condition often leading to potentially fatal outcomes, such as toxic megacolon and colonic perforation (Sands, 2008).
With regard to disease behavior over the years, two cohort studies showed that, by 25 years, more than half of the patients with proctitis will progress to left-sided colitis and patients with more extensive disease will regress in approximately 75% of cases (Langholz et al, 1996). The most aggressive phase of the disease was frequently seen in the first 3 years after diagnosis (Langholz et al, 1994). In the first 3–7 years after diagnosis, 25% of patients were in remission, 18% experienced disease activity every year, whereas 57% had intermittently occurring relapses. After 10 years, the cumulative probability of colectomy was 24%. Reasons for procto-colectomy are mainly represented by severe colitis refractory to intensive treatment or rescue therapy (see below), massive bleeding, impending or toxic megacolon, non-severe chronic active disease despite therapy with immuno-suppressive and/or immuno-modulating agents, and dysplasia or cancer. Development of dysplasia or adenocarcinoma is associated with longstanding and extensive UC and insufficient suppression of chronic inflammation (Gupta et al, 2007; Viennot et al, 2009; Langholz, 2010). As far as concerns duration of disease, the reported cumulative probability of colorectal cancer (CRC) appears to be decreased, in the last years, from 8% to 18% after 20 and 30 years of disease (Eaden et al, 2001), to 2.5% and 7.6%, respectively (Rutter et al, 2006). In some recent studies, the risk of CRC, in patients with UC, has been reported to be comparable to that in the general population (Winther et al, 2004; Jess et al, 2006). This has been held to be due primarily to the more widespread use of surveillance colonoscopy, the more frequent use of chemo-prevention and the more frequent use of surgery in the UC treatment strategy. CRC occurs primarily in patients with extensive colitis or in those with a history of extensive colitis. These patients have a relative risk (RR) of CRC of 14.8, vs 2.8 in the case of left-sided colitis (population-based study; 12 000 person-years of mean follow-up). The risk of CRC is virtually inexistent in the case of proctitis and very low (RR = 1.7) when disease is limited to the portion of the colon distal to the splenic flexure (Ekbom et al, 1990). The association of persistent chronic inflammation and risk of CRC has long since been controversial; nevertheless, recent clinical and experimental data support its contribution to colon carcinogenesis (Viennot et al, 2009). Furthermore, features indicative of previous severe inflammation, such as pseudopolyps, and features indicative of chronically active colitis, such as a shortened or tubular colon and stricture formation, are all associated with a significant increase in the risk of CRC (Rutter et al, 2004).
Medical treatment with 5-aminosalicylates (5-ASA) has proved, in most studies, to prevent the onset of CRC (Velayos et al, 2005). Endoscopic surveillance is based upon the possibility to reveal the presence of dysplasia. Several questions still remain to be answered, such as, for instance, how dysplasia should be managed and how best to detect dysplasia in the flat mucosa. The relevance of the latter question emerges from the greater frequency of dysplasia in the flat mucosa, in IBD, compared to sporadic CRC. An analysis of the efficacy of surveillance strategies is difficult, on account of several unavoidable methodological limitations, especially the lack of control studies. However, some studies suggest that it reduces mortality from CRC in regularly monitored patients (Langholz, 2010). Overall, patients with UC have a normal life expectancy (Winther et al, 2003).
The diagnosis of UC relies upon a combination of medical history, endoscopic findings, histological features on multiple colonic biopsies, and negative stool tests for infectious agents. Endoscopic findings include loss of normal vascular pattern, erythematous and granulous appearance of the mucosa, mucosal friability, and ulceration. Histological lesions affect primarily the mucosa and show a continuous pattern. Histological changes in the mucosa of active disease include ulcerations, crypt abscesses, loss of globet cells, and infiltration of lymphocytes and granulocytes (Stange et al, 2008). Quiescent disease may show only architectural distortion of the mucosal crypts. These features may help in ‘delayed’ (i.e. once the acute episode is overcome) differential diagnosis with bacterial acute colitis, that results, as a rule, in complete restitution ad integrum. Stool specimens should be cultured for common pathogens including specific assays for Clostridium difficilis toxin A and B, Campylobacter spp and Escherichia coli 0157:H7 (Stange et al, 2008).
Crohn’s disease involves the ileum and large bowel in more than 90% of patients, but it can affect any part of the GI tract from the mouth to the anus.
Unlike UC, anatomical lesions are discontinuous and chronic inflammation is transmural (Judge and Lichtenstein, 2003). At diagnosis, the disease involves the terminal ileum in 47% of patients, the large bowel in 28%, the small and large bowel in 21%, and the upper GI tract in 3% (Louis et al, 2001). Perianal disease and, in particular, perianal fistulas are often associated with CD localized elsewhere. It is more often associated with colonic disease involving the rectum, followed by colonic disease with rectal sparing and by ileocolonic disease. The lowest frequency of perianal disease occurs in patients with isolated ileal disease (Hellers et al, 1980). Perianal disease often precedes, or appears simultaneously with, intestinal symptoms (Hellers et al, 1980; Schwartz et al, 2002). The cumulative frequency of perianal fistulas occurrence appears to increase with the duration of disease (12% at 1 year, 26% at 20 years) (Hellers et al, 1980).
The Vienna classification recognizes distinct clinical phenotypes of CD with respect to disease location and development of parietal (strictures) or extra-parietal (fistulas or abscesses or both) complications, the occurrence of which are, respectively, referred to as stricturing and penetrating behavior (Gasche et al, 2000).
Although the anatomical involvement of CD is fairly stable over time, the behavior of the disease varies substantially with time. In a French study, behavior was classified, at the diagnosis, as non-stricturing and non-penetrating in 70% of patients, stricturing in 17%, and penetrating in 13% of patients. After 10 years of follow-up, there was a change from non-stricturing non-penetrating to either stricturing, in 27%, or penetrating disease, in 29%, of patients (Louis et al, 2001).
Symptoms of CD are heterogeneous and vary depending upon the location, behavior, and severity of disease, as well as the presence of extra-intestinal manifestations, but usually include diarrhea for more than 6 weeks, abdominal pain, and weight loss. These symptoms should give rise to the suspicion of CD, especially in young patients. Systemic symptoms of malaise, anorexia, or fever are also common (Stange et al, 2006). Although in clinical trials, clinical or endoscopic disease activity can be measured with a variety of disease activity indices (Sandborn et al, 2002), in clinical practice, disease activity is typically described as mild (ambulatory patients able to tolerate oral alimentation without manifestations of obstruction, dehydration, fever, abdominal mass or tenderness, or >10% weight loss), moderate (treatment for mild disease ineffective, more prominent symptoms of abdominal pain and tenderness, intermittent nausea and vomiting without overt obstruction, >10% weight loss or significant anemia), and severe disease (persisting symptoms despite intensive treatment, persistent vomiting, evidence of intestinal obstruction or abscess, rebound tenderness, BMI <18 kg−2) (Stange et al, 2006; Baumgart and Sandborn, 2007). The clinical course is typically chronic intermittent with periods of clinical activity and remission. It has been reported that 1 year after diagnosis, 10–30% of patients with CD have a relapse or exacerbation of disease, 15–25% experience low disease activity, and 50–65% are in remission. Long-term follow-up (10–15 years) showed that the majority of patients (up to 73%) experienced a chronic intermittent course of the disease, 10% experienced prolonged remission, while 20% showed a chronic course with continuous activity (Munkholm et al, 1995; Loftus et al, 2002). During the course of the disease, as a consequence of transmural inflammation, local complications such as strictures, fistulas with bladder and vagina, intra-abdominal abscesses, may occur and, in many cases, may require surgery. Because of the frequent occurrence of local complications and/or the presence of a chronic course of the disease with continuous activity not responding to medical treatment, the majority of patients with CD require surgery with time (Munkholm et al, 1993, 1995; Louis et al, 2001; Schwartz et al, 2002; Carter et al, 2004). After 20 years, most patients with CD have been operated on at least once (Cosnes et al, 2002). Following surgical resection, recurrence of CD is virtually inevitable (Rutgeerts et al, 1990). Risk factors for recurrence of CD after surgery include penetrating/fistulizing disease behavior, young age, short duration of disease before surgery, ileocolonic disease and cigarette smoking (Langholz, 2010). The latter is an accepted risk for a more severe disease course, in terms of both clinical activity and need of either first or further intestinal surgery (Papay et al, 2010).
Because of the multiple surgical resections and/or to the extensive inflammatory involvement of the intestine, progressive structural damage to the bowel can occur, with intestinal function becoming irreversibly lost (D’Haens, 2010). Manifestations of loss of function include bile-salt diarrhea, steatorrhea, vitamin and mineral deficiencies, anemia, short bowel syndrome with dehydration and malnutrition, and, in case of dysfunction of internal mechanisms, loss of continence (Judge and Lichtenstein, 2003).
In CD patients with colonic involvement, an overall RR of CRC of 2.5% was estimated, whereas such risk in patients without colonic involvement was similar to that in the general population (Canavan et al, 2007). Patients with small intestinal CD are at increased risk of small bowel adenocarcinoma, with a reported pooled RR of 31.2 compared with the general population (Canavan et al, 2006). Although this difference is highly significant, the real risk is low because small bowel adenocarcinoma is a rare cancer and accounts for <5% of all GI cancers (Langholz, 2010). No single evaluation can establish the diagnosis of CD. Instead, the diagnosis is made on the basis of clinical history and physical examination, together with objective findings from endoscopic, radiological, laboratory, and histological studies. When CD is suspected, hematological tests, such as complete blood count, C-reactive protein (CRP), erythrocyte sedimentation rate, routine stool examination and fecal calproctectin measurement (when available), should be performed (Stange et al, 2006; Benevento et al, 2010). The value of routine stool examination, in patients with suspected CD or exacerbations of disease, arises both from the need to rule out enteric infections and to definitely exclude C difficilis colitis that, in its recurrent form, may mimic CD (Thomas et al, 2003; Thielman and Guerrant, 2004). Ileo-colonoscopy and biopsies from the terminal ileum, as well as from each colonic segment to look for microscopic evidence of CD, are first-line procedures to establish the diagnosis. The most useful endoscopic features of CD include skip lesions, cobblestone mucosa, and ulcerations with clear margins, usually surrounded by normal mucosa. Focal (discontinuous) chronic (lymphocytes and plasma cells) inflammation and patchy chronic inflammation, focal crypt irregularity (discontinuous crypt distortion), and granulomas (not related to crypt injury) are the generally accepted microscopic features that allow a diagnosis of CD (Stange et al, 2006). Interestingly, recent studies have reported that non-invasive procedures, such as abdominal and pelvic US, provide support to the clinical suspicion (Benevento et al, 2010); thus, in the presence of an experienced operator, abdominal US may precede ileo-colonoscopy that will be performed if the findings obtained by laboratory and US tests support the suspicion of CD. Once endoscopic and histological findings confirm the diagnosis of CD, then the location, extent of inflammatory lesions, and the presence of complications should be carefully assessed (Stange et al, 2006). To this end, the patient should undergo an imaging study of the bowel to define extent, severity, and type of disease (inflammatory vs fibrotic vs penetrating), as well as to exclude the presence of septic complications (abscesses) of CD. Several instrumental techniques are used to investigate the small intestine including fluoroscopic examinations [small bowel follow through (SBFT, a non-intubation study), and small bowel enema, (SBE, intubation study)], trans-abdominal US, and magnetic resonance (MR) – or computed tomography (CT)-enteroclysis (intubation study) or enterography (non-intubation study). SBE is gradually being replaced by other techniques. Major pitfalls are the high dose of radiation, the poor capacity, compared with other techniques, of quantifying the degree of inflammation of the bowel wall and the poor acceptance rate of patients. It is still considered relatively reliable for evaluating strictures and internal fistulas, before surgery (Angriman et al, 2008). Compared with SBE, SBFT has similar sensitivity and specificity and is associated with less radiation exposure, is less expensive and less time-consuming (Bernstein et al, 1997). Furthermore, mucosal detail is usually better identified with SBFT.
Regardless of performance, the current preference for one technique with respect to another often depends largely on institutional standards, availability of local expertise and individual experience. CT scan or MRI should be preferred to traditional techniques, however, when an abscess or additional pathological findings are suspected (Gore et al, 1996; Gasche et al, 1999; Rieber et al, 2000, 2002; Potthast et al, 2002; Rohr et al, 2002; Stange et al, 2006; Benevento et al, 2010).