UC typically presents in the third or fourth decade of life. Clinical presentation is based on disease location and severity. Severity is classified as mild, severe or fulminant with moderate disease between mild and severe (Table 15.2). Diarrhoea, usually bloody with cramping typically awakening the patient from sleep, signifies mucosal inflammation. Mild disease may be accompanied by frequent diarrhoea but is not associated with significant life impairment. Moderate disease, between mild and severe, typically leads to significant symptoms including profound diarrhoea (usually bloody), dehydration, fatigue and weight loss. This may progress to severe disease, which may require hospitalisation. Fulminant disease is most severe often requiring intensive care or surgery.

Table 15.2 Determination of severity in ulcerative colitis

UC may be associated with extraintestinal manifestations in some patients (Table 15.3) which may be associated with disease activity (Fig 15.1). Those not associated with disease activity may run a clinical course independent of the disease and persist after colectomy.

Table 15.3 Common extraintestinal manifestation of inflammatory bowel disease

Figure 15.1 Pyodermagangrenosum on the lower leg.

Disease extent and location

UC can be divided into three groups based on the disease location: proctitis or proctosigmoiditis (continuous involvement, from the anus, of the rectum or rectosigmoid); left-sided colitis (continuous involvement up to the splenic flexure); and pancolitis (continuous involvement extending proximal to the splenic flexure). Patients with more extensive disease have a worse prognosis. Proximal progression is common. Approximately half the patients with proctitis and two-thirds of patients with left-sided colitis will progress to a more proximal involvement aover time.

Frequent low-volume bowel movements, urgency, rectal bleeding and tenesmus alone suggest proctitis. However, patients with or without these symptoms may also present with prostration, fever, tachycardia, dehydration and complications of blood loss, suggesting more severe disease or more extensive bowel involvement. Advanced cases may present with massive abdominal distention because of megacolon. In fulminant colitis, severe diarrhoea and high C-reactive protein despite intensive treatment predict eventual colectomy. Fortunately, the presentation of fulminant colitis is relatively uncommon.

Differential diagnosis

The presenting clinical features of ulcerative colitis are non-specific, especially among patients without a prior history. Acute colitis secondary to infection and ischaemia are important considerations depending on the patient and are of particular importance in elderly patients. A history of previous episodes is important but distinguishing a flare of UC from an infectious colitis is not possible on clinical grounds alone. Crohn’s disease that is confined to the colon may be difficult to distinguish from UC, but may present with rectal sparing and skip lesions.

Diagnosis

Among patients without a prior history of ulcerative colitis, presenting features are non-specific so that additional diagnostic testing is required. Diagnosis is confirmed by clinical features, endoscopic and histological findings as well as stool examination to exclude acute colitis. Infection, ischaemia, non-steroidal anti-inflammatory medication-induced colitis, diverticular colitis and Crohn’s disease are important considerations.

Stool studies

Infectious colitis may present independently or result in a flare of existing UC. Exclusion of enteric infection is paramount since these infections can mimic clinical and endoscopic features of active UC. Specific stool studies to exclude common enteric pathogens such as Shigella spp., Campylobacter spp., Yersinia spp., Entamoeba spp. and enterohaemorrhagic Escherichia coli are essential. Stool studies may be negative even in the presence of infection and it is very important that the clinician understand what is routinely tested for in his or her facility when stool culture, ova and parasite analysis are ordered. Exclusion of C. difficile infection among patients with UC is very important. While commonly associated with prior antibiotic use, hospitalisation or residence at a long-term care facility, patients with IBD are at a higher risk for this infection even in the absence of these usual risk factors. Stool C. difficile toxin should be requested on all patients with IBD presenting with symptoms of a flare.

Stool biomarkers

Reliable stool biomarkers to predict disease activity, recurrence or likelihood of relapse in IBD would avoid invasive endoscopy and/or radiation exposure. Calprotectin, a biomarker that can easily be detected in stool, has been shown to be a sensitive and specific marker of relapse in UC but not CD. Faecal lactoferrin is elevated in active IBD and may increase prior to IBD relapse. Unfortunately, while results are encouraging, data on biomarkers are limited. More information is needed before they can be reliably used in clinical practice.

Haematology and biochemistry

Haematological measurements may vary based on the severity and duration of the colitis. Patients with mild colitis may have minimal abnormalities whereas patients with more severe disease may have a leukocytosis related to inflammation and anaemia due to blood loss. Anaemia may be more pronounced and associated with frank iron deficiency with longer duration of illness. Thrombocytosis may also be present due to inflammation or iron deficiency. Albumin may be low due to severe disease or malnutrition. C-reactive protein or sedimentation rate may be elevated. Electrolyte imbalance and prerenal azotemia may occur secondary to dehydration. Alkaline phosphatase may be elevated if primary sclerosing cholangitis is present or as a result of drug toxicity.

Radiology

Plain abdominal x-rays should be performed to exclude toxic megacolon and perforation among severely ill patients. Computed tomography (CT) scanning may be considered if there is concern of other aetiologies such as Crohn’s disease. CT of the abdomen may reveal colonic thickening and provide additional information as to the extent of the disease. Barium enema is rarely performed because of the widespread use of sigmoidoscopy and colonoscopy (Fig 15.2).

Figure 15.2 Left-sided colitis on barium enema.

Sigmoidoscopy, colonoscopy and biopsy

Endoscopic visualisation with biopsy is essential for all patients with suspected UC and is often necessary to document disease activity for a suspected flare. Disease activity, if present, should be visible in the rectum and may extend more proximally. Rectal sparing or segmental colitis raises the possibility of infection, ischaemia, Crohn’s disease or other aetiology. Biopsies confirm the presence of chronic colitis and exclude acute colitis as seen with infection. Among patients with colitis refractory to therapy, especially if they are receiving corticosteroid or immunosuppressive therapy, cytomegalovirus should be excluded by biopsy with special studies. Severely ill patients may undergo an unprepped flexible sigmoidoscopy whereas patients with mild to moderate disease are often prepped for colonoscopy. There is usually little value in performing a complete colonoscopy on patients with active UC and it may be dangerous. However, prepping for colonoscopy, if possible, will allow for better visualisation above the sigmoid colon, especially if findings are not typical for UC or it is important to determine extent of disease for therapy. Flexible sigmoidoscopy with biopsy is often sufficient for those with established disease to confirm disease activity. Among patients with long-standing quiescent disease proximal to the rectum, colonoscopy with biopsies is routinely performed for dysplasia surveillance.

Pathology

Ulcerative colitis results from chronic inflammation confined to the mucosal layer of the colon. Inflammation is continuous and may involve only the rectum or may spread more proximally. Confusion with CD occurs when patients with UC have a discrete area of inflammation in the caecum (a ‘caecal patch’), or those with a flare of pancolitis have an inflamed terminal ileum (‘backwash ileitis’). Both of these presentations are consistent with ulcerative colitis.

Treatment

Treatment goals for UC are induction and maintenance of remission and are based on disease extent, clinical severity and previous medication history.

Mild to moderate disease

Oral mesalamine

The best option for patients with mild to moderate UC is mesalamine (5-aminosalicylate), orally or rectally. Response rates vary because of differences in dose, disease activity and definitions of outcomes but about two-thirds will respond. Sulfasalazine, the first of this class, is both an inexpensive and effective medication. It remains essentially unchanged until it reaches the colon where it is cleaved into the active moiety 5-aminosalicylate and sulfapyridine by bacteria. Sulfapyridine (a sulfa antibiotic) is responsible for most of the observed toxicity that includes allergic reaction or renal toxicity (Box 15.2). The remaining mesalamine formulations differ on their mechanism and site of drug delivery. Newer preparations release in the colon, require fewer tablets and can be dosed once or twice daily to improve compliance. These medications are well tolerated. Headache is the most common adverse effect and, rarely, renal toxicity occurs. A baseline serum creatinine should be determined prior to starting therapy. Pancreatitis has also been described with sulfasalazine due to its sulfa moiety but also with mesalamine, although the likelihood with mesalamine is extremely low.

Box 15.2 Side effects of sulfasalazine ^∗

Dose-related: slow acetylators

• Nausea, vomiting, anorexia (most common)

• Headache (common)

• Diarrhoea

• Macrocytosis (folate deficiency)

• Haemolysis (Heinz body)

• Proteinuria, haematuria

Non-dose-related

• Skin rash (and Stevens-Johnson syndrome)

• Agranulocytosis, aplastic anaemia

• Reversible male infertility (oligospermia, dysspermia)

• Hepatitis

• Pancreatitis

• Fibrosing alveolitis

• Vasculitis, lupus

^∗ Start at one 500 mg table, twice daily on the first day after meals, then increase by two tablets every second day until the patient is taking the full amount (typically, 1 g four times a day in acute disease; and 1 g twice a day for prophylaxis). Usually efficacious within 2–4 weeks (in 40–80% of patients) A blood count and urinalysis should be performed before starting therapy and then regularly during the first 3 months of treatment, and thereafter every 6 months. Supplement with folate, 1 mg/day orally. The drug may also be of specific benefit for the arthropathy in ankylosis spondylitis associated with inflammatory bowel disease.

Mesalamine is not useful in moderate to severe UC and in mild to moderate disease is often administered at too low a dose. In appropriate doses all are probably equally effective. Sulfasalazine is relatively inexpensive and once or twice daily preparations will enhance compliance. Olsalazine should be avoided if possible, because it can cause secretory diarrhoea. Common preparations with the usual doses to induce and maintain remission are outlined in Table 15.4.

Table 15.4 Oral mesalamine preparations for induction and maintenance of remission in mild to moderate ulcerative colitis

	Optimal daily dose for remission (g)
Drug	Induction	Maintenance
Oral mesalamine
Sulfasalazine	4–6	2–4
Eudragit S coated	3.6–4.8	2.4–3.6
Ethylcellulose coated	3–4	2–3
Balsalazide	6.75	3–4.5
Topical mesalamine
Mesalamine suppository	0.5–1 twice daily	1 daily
Mesalamine enema	4 nightly	4 nightly or every other night

From Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults. Am J Gastroenterol 2010; 105:501–523.

Topical preparations

The most underutilised group of mesalamine medications are the topical rectal preparations. These are effective for symptoms of urgency, pain and tenesmus. In distal colitis they are more effective than oral preparations and a combination of oral and topical mesalamine enema improves overall efficacy. Patients with proctitis (disease limited to the last 15 cm of the colon) benefit from mesalamine suppositories, 1000 mg once or twice daily, while mesalamine enema therapy (4 g at bedtime) is useful for treatment of disease up to the splenic flexure. For patients who cannot hold a whole enema, start with half of the preparation, which will also be beneficial, and work up to a full enema daily. Oral corticosteroids are rarely required for disease confined to the rectosigmoid region.

Hydrocortisone enema may be added in the morning if the patient has not responded to rectal mesalamine after a period of 2–3 weeks. Rectal corticosteroids are helpful in resistant cases but mesalamine enemas are more effective as first-line therapy. After response, wean the topical steroids and maintain rectal and topical mesalamine. If after several weeks response is maintained, try to taper topical mesalamine but it may be required indefinitely. Oral mesalamine should be continued as maintenance therapy to prevent relapse.

Moderate to severe colitis

In cases of moderate to severe UC systemic corticosteroids or infliximab are the best options.

Maintenance of remission

Mesalamine

Mesalamine is the best treatment to maintain remission in cases of mild to moderate colitis where remission was induced by one of these medications. It may also maintain remission on selected patients whose remission was induced by corticosteroids and who were not taking mesalamine or were taking too low a dose of these medications. Maintenance dosing for various preparations in outlined in Table 15.4.

Azathioprine or 6-mercaptopurine

Azathioprine or 6-mercaptopurine should be considered for patients with moderate to severe colitis who require corticosteroids to induce remission but who cannot be successfully weaned from these medications despite concurrent treatment with mesalamine.

Azathioprine (2–2.5mg/kg) and 6–mercaptopurine (1–1.5mg/kg) are equally effective in 60–70% of patients in maintaining remission and allowing corticosteroid tapering but are slow to act, requiring 3–4 months or more to take effect. Clinical and haematological monitoring by experienced clinicians is necessary. Pancreatitis, hepatitis and severe leukopenia are important adverse events. Pancreatitis and hepatitis are idiosyncratic whereas leukopenia is dose dependent (Box 15.3).

Once ingested, azathioprine is rapidly converted to 6-mercaptopurine. The main competing pathways for the metabolism of 6-mercaptopurine are conversion to 6-thioguanine (6-TG), the active therapeutic moiety, and 6-methylmercaptopurine(6-MMP), an inactive excretion product associated with liver toxicity (Fig 15.3). Elevated 6-TG results in immunosuppression and leukopenia and levels may correlate with efficacy, but this is controversial. The enzyme responsible for conversion to 6-MMP is thiopurine methyltransferase (TPMT). Its activity is genetically determined and can be normal, intermediate or absent. Patients with normal TPMT (88%) can start either medication at the target dose, 2–2.5 mg/kg azathioprine or 1–1.5 mg/kg 6-mercaptopurine. Those with an intermediate TPMT level (11%) are usually started on half this dose while those unable to metabolise the drug (0.3%) should not receive it. Diminished capacity of TPMT results in elevated 6-TG and subsequent toxicity manifested by profound leukopenia. Assays for TPMT, 6-TG and 6-MMP assist in the proper use of these medications.

Figure 15.3 The metabolism of azathioprine (AZA) and 6-mercaptpurine (6MP). Enzymes: TPMT = thiopurine methyltransferase; XO = xanthene oxidase. Metabolities: 6TUA = 6-thiouric acid; 6TGN = 6-thioguanine; 6MMP = 6-methylmercaptopurine; HPRT = hypoxanthine-guanine phosporibosyl transferase.

From Swaminath A, Kornbluth A. Optimizing drug therapy in inflammatory bowel disease. Curr Gastro Rep 2007; 9:513–520.

Infliximab

For patients whose remission is achieved with infliximab, this agent should be continued indefinitely. Despite high initial response rates, up to one-third or more of patients will lose response over time. For these patients medical options are limited and colectomy should be considered.

Nicotine

Nicotine as an adjunctive therapy may be useful in patients who developed UC after smoking, but it is generally ineffective. Methotrexate has no proven benefit, but might be helpful if a patient refuses colectomy. Antibiotics can be helpful in severe colitis to guard against bacteraemia and as a prophylactic measure for possible surgery, but have no role in the treatment of the underlying UC.

Complications

Fortunately, complications related to severe colitis are rare. The most important are toxic megacolon leading to colonic perforation and massive gastrointestinal bleeding. Toxic megacolon results from the dilation of a severely inflamed colon leading to abdominal distention. Patients may present with severe pain, peritoneal signs (if perforation is present) and fever. Diarrhoea may decrease significantly as the colon loses its ability to function. Dilation of the colon is confirmed by abdominal x-ray and the condition is treated by intravenous antibiotics and prohibiting oral intake. For patients with evidence of perforation, surgery is necessary. Massive gastrointestinal bleeding is treated with supportive care and treatment directed at the colitis. Uncontrolled bleeding may require colectomy. Complications of ulcerative colitis can also be related to extraintestinal manifestations as outlined previously, and to therapies such as corticosteroids and immunomodulators.

Colorectal neoplasia

Ulcerative colitis patients are keeping their colons longer as a result of better medical therapies. Patients with UC are at risk for colorectal cancer based on the anatomic extent and the duration of their disease. The risk is highest in patients with pancolitis beginning after 8–10 years of disease, then increases nearly 1% every year thereafter. Risk is also present with left-sided colitis, lagging behind pancolitis by about 5–10 years. The risk with proctitis is probably no greater than the general population but progression to the proximal colon may occur.

Earlier age at onset of colitis (under 15 years old) and primary sclerosing cholangitis are independently associated with higher colorectal cancer risk. Disease activity does not correlate with colorectal cancer risk. This is extremely important because many patients will have long durable remissions so that the risk of loss to follow-up becomes higher. Patients in remission may be lured into a false sense of security about their disease with disastrous consequences.

The methods to avoid development of colorectal cancer include prophylactic colectomy and surveillance colonoscopy. Surveillance colonoscopy is preferred but colectomy should be considered for patients with longstanding disease especially if their disease is refractory or requires immunosuppressive therapy. Decisions must be individualised based on patient preference with understanding of the risks and benefits of each strategy. Patients with pancolitis and disease longer than 8–10 years should have surveillance colonoscopy yearly or every other year. Patients with left-sided disease follow a similar schedule but some begin surveillance later. In patients with UC who have primary sclerosing cholangitis, surveillance should begin at diagnosis, given the risk of earlier cancer.

Colorectal cancers in UC can be flat and missed by colonoscopy. The goal of surveillance is to detect microscopic dysplasia, which can be associated with either a missed cancer in the existing colon or the development of later cancer. Patients with high grade dysplasia, a dysplasia associated mass or cancer should have a colectomy. Low grade dysplasia, confirmed by an experienced pathologist, initially thought to be more benign, may be associated with synchronous cancer not evident on colonoscopy. The management of low grade dysplasia is patient specific but colectomy should be considered.

A controversial area in UC cancer surveillance is the meaning of an adenomatous polyp. As patients keep their colons longer, the likelihood of finding sporadic (non-UC associated) polyp increases. Since these polyps by nature are dysplastic, should a patient with long-standing disease undergo colectomy if one is found? This depends of the age of the patient, the duration of the UC, the characteristics of the polyp and whether the area around the polyp is dysplastic. Patients who are older and have no dysplasia around the polyp can be probably treated by simple polypectomy whereas younger patients should be considered for colectomy.

Surgical treatment

UC can be cured by colectomy and in many cases the patient’s overall quality of life improved. Colectomy is indicated for treatment failures, development of acute complications from active disease, chronic complications such as dysplasia, carcinoma and recurrent haemorrhage, or growth retardation in children (Box 15.4). The surgical procedure of choice is the ileal pouch anal canal anastomosis (IPAA). First the colon is completely removed and a ‘J’-shaped ileal pouch constructed with anastomosis to the anal canal. A diverting loop ileostomy is created to allow the anastomosis to heal. The ileostomy is closed 2 months later. Although this surgery is becoming more common, results are still dependent on the surgeon’s experience. Pouch failure rates vary but are generally under 10%. Most patients can expect to have about five bowel movements a day and one nocturnal bowel movement after IPAA. This can be much higher when the patient has refractory pre-existing diarrhoea-predominant irritable bowel syndrome (IBS). These patients might be better off with a standard ileostomy.

Pouchitis

Pouchitis is an important complication of IPAA manifesting with urgency, tenesmus, faecal incontinence, cramping, malaise and fever. Its cause is unknown and diagnosis is confirmed by pouchoscopy. About half of patients will develop acute pouchitis over time, with about 10–15% developing severe chronic pouchitis refractory to therapy and requiring pouch excision. Crohn’s disease or ischaemia of the pouch is possible, but most cases are idiopathic.

Most patients respond to antibiotics such as metronidazole, ciprofloxacin or amoxicillin/clavulanic acid, given in a short course (10–14 days) or in chronic cases as prolonged suppressive therapy. Topical mesalamine or corticosteroids and short-chain fatty acid enemas have had some success. Oral probiotics may prevent recurrence.

Crohn’s Disease

Aetiology

Crohn’s disease (CD) is a chronic idiopathic inflammatory bowel disease affecting primarily young adults. While, like UC, family history is the most important risk factor, only about 10% of patients overall have an affected family member. It tends to occur within families and is more common in individuals of Jewish ethnicity. Unlike UC, where cigarette smoking is protective, in CD it results in an earlier age at diagnosis and a worse disease course.

Clinical presentation

Crohn’s disease is a heterogeneous disorder with clinical presentation, prognosis and response to therapy is based on age at diagnosis, site of involvement and behaviour (Table 15.4). Younger age at diagnosis is associated with a worse prognosis. CD may be associated with extraintestinal manifestations in some patients (Table 15.5), which may be associated with disease activity. Those not associated with disease activity may run a clinical course independent of the disease and persist after treatment.

Table 15.5 The Montreal classification of Crohn’s disease

Age at diagnosis	A1 below 16 years
	A2 between 17 and 40 years
	A3 above 40 years
Location	L1 ileal
	L2 colonic
	L3 ileocolonic
	L4 isolated upper disease^∗
Behaviour	B1 non-stricturing, non-penetrating
	B2 stricturing
	B3 penetrating
Perianal disease	Present or absent

∗ Isolated upper disease is a modifier that can be added to other locations when concomitant upper disease is present.

From Satsangi J, Silverberg MS, Vermeire S, et al. The Montreal classification of inflammatory bowel disease: controversies, consensus and implications. Gut 2006; 55:749–753.