Ulcerative Colitis

Ulcerative colitis is chronic inflammation and ulceration of the lining of the colon and rectum, or, especially at the start of the condition, of the rectum alone. The cause of ulcerative colitis is unknown, but the condition is most common in young and middle-aged adults.

Symptoms

The main symptom of ulcerative colitis is bloody diarrhoea; the faeces may also contain mucus. In severe cases, the diarrhoea and bleeding are extensive, and there may be abdominal pain, fever, weight loss, and general malaise. The incidence of attacks varies considerably from person to person. Most commonly, the attacks occur at intervals of a few months. However, in some cases, there may be only a single episode.

Complications

Ulcerative colitis may lead to anaemia, due to blood loss. Other complications include a toxic form of megacolon (an abnormally enlarged colon), which may become life-threatening; rashes; mouth ulcers; arthritis; conjunctivitis (inflammation of the membrane covering the eyeball); and uveitis (inflammation of the iris or choroid of the eye). In addition, people whose entire colon has been affected for more than 10 years are at increased risk of developing cancer of the colon.

Diagnosis

Diagnosis is based on examination of the rectum and the lower colon or of the entire colon, or is made by a barium enema. During sigmoidoscopy or colonoscopy, a biopsy (removal of a tissue sample) may be performed. Samples of faeces may be taken for analysis in a laboratory to exclude the possibility of infection by bacteria or parasites. Blood tests may also be necessary. People who have suffered from ulcerative colitis for a number of years need periodic colonoscopy and biopsy to check for the development of cancer.

Treatment

In most cases, medical treatment effectively controls the disease by relieving symptoms and preventing complications from occurring. For ulcerative colitis occurring in the last part of the colon or the rectum, the drugs may be administered as suppositories. If the condition occurs higher up in the intestine, the drugs are taken orally. Aminosalicylate drugs, such as sulfasalazine (or the newer drugs mesalazine and olsalazine, which have fewer side effects), are used to treat acute attacks and maintain long-term freedom from symptoms.

Corticosteroid drugs are given to reduce inflammation during sudden flare-ups. Once the disease is under control, immunosuppressant drugs may be used to prevent relapses. Colectomy (surgical removal of the colon) may be required for a severe attack that fails to respond to other treatments, for those with complications such as toxic megacolon, or to avoid colonic cancer in those people who are at high risk. This operation usually produces a dramatic improvement in health, although the person is usually left with an ileostomy (an opening in the surface of the abdomen through which faeces are passed.il - technical

Essentials

Ulcerative colitis is a chronic inflammatory disease of the colon that always affects the rectum, extends proximally to a variable extent, and is characterized by a relapsing and remitting course. In mild disease the mucosa is hyperaemic and granular; punctate ulcers appear in more severe disease, and these may then enlarge and extend deeply. Infiltration with acute and chronic inflammatory cells is largely confined to the mucosa, with histological features of chronicity, e.g. distorted crypt architecture, important in clinical distinction from other causes of colitis, e.g. infective.

The cause of ulcerative colitis is unknown: genetic factors are involved although not all the relevant genes are yet identified. A dysregulated immune response to luminal antigen may be important.

Clinical features and investigation

Typical presentation of mild or moderate disease is with a gradual onset of symptoms including diarrhoea, rectal bleeding, the passage of mucus, and—less frequently—abdominal pain; such patients usually look well and exhibit few abnormal physical signs.

Severe disease is characterized by anorexia, nausea, weight loss, and severe diarrhoea (>6 motions daily) that becomes a slurry of faecal material, pus, and blood. The patient is likely to look unwell with fever, tachycardia, and other signs of volume depletion, and the abdomen is often distended and tympanitic, with reduced bowel sounds and marked colonic tenderness.

Extraintestinal manifestations may be related to activity of the colitis (e.g. aphthous ulceration of the mouth, erythema nodosum, peripheral arthropathy, pyoderma gangrenosum) or not (e.g. anterior uveitis, sacroiliitis, primary sclerosing cholangitis). Local colonic complications of acute disease include acute dilatation and perforation, and complications of longstanding disease include carcinoma (7–15% risk after 20 years).

Diagnosis is usually made of the basis of exclusion of infective colitis by stool culture and the finding of typical diffuse sigmoidoscopic appearances in the rectum. All patients with a severe attack require a plain abdominal radiograph, primarily to exclude acute dilatation. Active disease is often accompanied by a neutrophil leucocytosis, thrombocytosis, and a rise in inflammatory markers.

Management

For active disease treatment depends on severity, but initial therapy is usually as follows: (1) proctitis—a 5-aminosalicylic acid drug, given by mouth and concurrently as a suppository; (2) mildly active disease (≤4 motions/day)—oral prednisolone (20 mg daily), together with topical steroids or 5-aminosalicylic acid (or both); (3) moderately active disease (>4 motions/day, but not systemically ill) – as for mild disease, but with prednisolone 40 mg daily; (4) severe disease (>6 bowel motions/day, with blood; systemically ill) – resuscitation/intravenous fluids; hydrocortisone, 100 mg intravenously every 6 h and 100 mg as a rectal drip twice daily; those who deteriorate during the first few days of intravenous treatment, or who have not made a substantial improvement after 3–4 days, need either ‘rescue’ therapy with ciclosporin or infliximab, or colectomy. Patients with chronic active disease that prevents steroid withdrawal are treated with immunosuppressants, azathioprine and ciclosporin being most widely used.

In the long term, drugs containing 5-aminosalicylic acid (e.g. sulphasalazine, mesalazine) reduce the relapse rate and are able to maintain remission over many years. Patients with extensive longstanding disease require regular colonoscopic surveillance, with prophylactic colectomy usually advised if biopsies reveal dysplasia.

Indications for surgery include (1) severe inflammation unresponsive to medical therapy; (2) acute complications (perforation, dilatation); (3) chronic active disease; and (4) prevention of cancer. Restorative proctocolectomy with ileoanal reservoir/pouch is the procedure of choice in specialist centres, provided the anal sphincter is intact.

Introduction

Ulcerative colitis is a chronic inflammatory disease of the colon, of unknown cause. It always affects the rectum and extends proximally to involve the colon to a variable extent. It is characterized by a relapsing and remitting course.

The disease was first described in 1859 by Samuel Wilks, a physician at Guy’s Hospital, who recognized that ‘simple, idiopathic colitis’ could be distinguished from other forms of colitis, mainly bacterial dysentery. It took many years for the concept to be accepted, but finally, in 1931, Sir Arthur Hurst was able to give a complete description of the disease including the sigmoidoscopic appearances. Nevertheless, he still considered the disease to be primarily infective, even though its chronic nature might be induced secondarily by other factors.

Epidemiology

Ulcerative colitis is a worldwide disease, although it may be difficult to diagnose in areas where infective colitis is prevalent. Accurate figures for incidence and prevalence are not universally available, but the disease is now recognized in most countries. Table 1 lists data for high-incidence areas and also shows that there have been no trends to suggest the disease is becoming more common, which is in contrast to Crohn’s disease. Low-incidence areas include Asia, Japan and South America, where the incidence rates are at least tenfold less than in those Western countries with a high prevalence, although this is increasing, which may to some extent reflect better diagnostic awareness.

The age of onset peaks between 20 and 40 years, but the disease may present at all ages from the first few months of life to the eighties. Some series show a secondary peak of onset in the 60- to 70-year-old age group, but this has not been a universal finding. Earlier series suggested a predominance of the disease in women, but more recently there has been little difference between the sexes.

Table 1 Incidence of ulcerative colitis
  Period of study Incidence (per 105)
USA
Minnesota 1935–64 7.2
Baltimore 1960–63 4.6
UK
Oxford 1951–60 6.5
Wales 1968–77 7.2
Aberdeen 1967–76 11.3
Denmark
Copenhagen 1962–78 8.1
1981–88 9.5
Netherlands
Leiden 1979–83 6.8
Sweden
Stockholm County 1975–79 4.3
Israel
Tel-Aviv 1961–70 3.6

Both in the United States of America and South Africa (Cape Town), Jews are more prone to ulcerative colitis than non-Jews by a factor of 3 or 4. Within Israel, Ashkenazi Jews have a higher incidence than Sephardim, but it is still less than the incidence in Jews in the United States of America or, indeed, than the European incidence. This suggests that environmental factors may be involved in addition to genetic factors. However, the differences in incidence between urban as opposed to rural communities or between different socio-economic groups have been slight and inconstant.

Aetiology

The cause(s) of ulcerative colitis remains unknown. The main hypotheses that have been proposed include genetic predisposition, infection, allergy to dietary components, immune responses to bacterial or self-antigens, an abnormality in epithelial cell integrity, and the psychosomatic theory. There are virtually no data to support a primary role for psychosomatic factors in the aetiology of the disease, although they may play a secondary role in determining the pattern of symptoms and must always be considered when managing individual patients.

Genetic factors

The familial incidence of ulcerative colitis has long been recognized, with 10 to 20% of patients likely to have at least one other family member affected either with ulcerative colitis or with Crohn’s disease. Most of the familial association is within first-degree relatives. Within a multiply affected family there is a high degree of concordance for disease characteristics (e.g. extent, severity, presence of extraintestinal manifestations). Familial incidence may, of course, reflect that family members are often exposed to common environmental factors. However, the higher concordance in monozygotic twins than in dizygotic twins provides strong evidence that genetic factors play a role in determining disease susceptibility. Nevertheless, the concordance rates for ulcerative colitis in monozygotic twins is still quite low at 6 to 12%, suggesting that the genetic component of an individuals risk of developing the disease is much less than it is for Crohn’s disease, where concordance rates for identical twins is 35 to 45%.

The mode of inheritance is unknown, but as with Crohn’s disease, multiple genes are probably involved in determining disease susceptibility and its behaviour. Studies of multiply affected families, using microsatellite technology, have demonstrated linkage to chromosome 12 and, less strongly, to chromosomes 3 and 7. These susceptibility loci are shared by patients with Crohn’s disease, although some evidence suggests that the locus on chromosome 12 contains two separate genes, one for ulcerative colitis and a second for Crohn’s disease. Large genome-wide association studies are defining genomic regions of interest more accurately and hence aid the detection of the relevant genes. In most studies, ulcerative colitis is more strongly linked to chromosome 6p (the HLA region) than is Crohn’s disease. Study of individual HLA alleles has shown that possession of HLA DRI03 is likely to be associated with severe disease. In Japan and in the Jewish population of California the disease is associated with HLA DRI502 (an allele of DR2 common in these populations but very uncommon in Europeans).

The occurrence of extraintestinal manifestations also appears to be related to genetic make-up. For example, patients who develop a reactive, large-joint arthropathy in association with active disease are likely to possess the HLA DR103 allele (35%), compared with patients who do not (8%) or healthy controls (3%). In contrast, the small-joint, seronegative arthropathy is associated with HLA B44 (77%) and MICA-8 (98%). Nevertheless, it is not possible to be sure on the basis of present knowledge whether these associations are biologically meaningful, or whether they represent linkage disequilibrium with a nearby gene.

Infection

No specific infective organism has been consistently isolated from patients with ulcerative colitis. However, the recognition that the strains of Escherichia coli in the normal colon are continually changing has led to the concept that patients may carry strains which, by releasing enzymes or other toxic products, might damage the mucosa. The demonstration that, even in remission, patients with ulcerative colitis are more likely than control subjects to harbour E. coli expressing adhesins is a particularly interesting observation, as these may allow the bacteria to adhere readily to the epithelium. The role of sulphate-reducing bacteria is also of interest as these organisms are found more commonly in those with colitis. They reduce sulphate to sulphide which, in turn, inhibits butyrate oxidation in epithelial cells. Several investigators have demonstrated reduced activity of butyrate dehydrogenase within colitic epithelium, even in remission, raising the possibility that luminal bacteria may have a deleterious effect on epithelial cell metabolism and, hence, integrity. Studies of the luminal microbiota using ribosomal RNA analysis have not only shown that the human colon contains at least 500 species of bacteria, less than one-half having been identified by culture, but that changes occur in patients with ulcerative colitis, although these do not appear to be consistent from one patient to another. Evidence is accumulating that disease susceptibility may be mediated by host genetic factors affecting adaptive immunity, innate immunity, and autophagy (a normal intracellular process for degrading organelles but also involved in antigen presentation and bacterial degradation), although this is admittedly stronger for Crohn’s disease than for ulcerative colitis.

Food allergy

The early suggestions of allergic responses to milk proteins, eggs, and other dietary proteins have not been substantiated as an aetiological factor. Milk-free diets may be beneficial in a few patients, but it is not clear whether this results from an associated hypolactasia, an immunological response, or some other mechanism. The failure of ulcerative colitis to respond either to avoidance of oral food by intravenous nutrition, or to colonic isolation by means of a split ileostomy, are further pointers that dietary factors play little part.

Other environmental factors

As well as infection and diet, smoking and the use of oral contraceptives may influence disease. Many studies have now shown that ulcerative colitis is more common in non-smokers than smokers, with a relative risk of 2 to 6. Ex-smokers have a particularly high incidence, and this is highest for former heavy smokers compared with light smokers. Women taking oral contraceptives may have a slightly increased risk of the disease, but this association is weak and loses significance when the data are corrected for smoking habits and social class. Minor infections, paracetamol, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been implicated, especially as triggers for a relapse, but the data are inconclusive, which largely reflects small sample sizes.

Immunopathogenesis

The intense infiltration of the inflamed mucosa with plasma cells, B and T lymphocytes, and macrophages suggests immunological activity. It is not known whether activation of both humoral and cellular immune mechanisms merely reflects increased antigenic absorption through an abnormal epithelium, a response to a specific aetiological agent, or an underlying defect in mucosal immunoregulation. The inability to down-regulate an immune response to luminal antigen is a hypothesis that is supported by some of the genetic data, as well as by experiments using animal models of colitis. A wide variety of immune-manipulated mouse models have shown that these animals develop colitis when grown in a specific pathogen-free environment, but that colitis does not develop in animals reared in germ-free environments until they are given oral bacteria. Interestingly, some strains of mice are more susceptible than others, which clearly indicates a genetic susceptibility to exogenous antigen, hence a dysregulated response to luminal antigen may underlie much of the pathogenesis of ulcerative colitis.

There is an increase in plasma cells synthesizing all three of the major immunoglobulin isotypes: IgA, IgG, and IgM. However, the largest proportional increase is in IgG-producing cells, and this is predominantly of the IgGl and IgG3 subclasses, in contrast to Crohn’s disease where an IgG2 response is predominant. IgG1 and IgG3 are synthesized in response to protein antigen and are effective in fixing complement. Complement activation is known to occur in active colitis, probably as a result of the formation of antigen–antibody complexes, and is likely to be one of the principal effector mechanisms in establishing the inflammatory lesion. Some of the increased mucosal IgG synthesized is known to have antibody specificity for bacterial and epithelial antigens. As antibody to epithelial antigens, especially a 40-kDa protein, is a feature of ulcerative colitis, rather than Crohn’s disease, it is possible that autoimmunity plays a part in ulcerative colitis. This concept is strengthened by the association with other autoimmune disorders and with circulating antibodies to neutrophils (pANCA), neither of which is associated with Crohn’s disease. Nevertheless, whether anticolon antibodies or pANCA have a pathogenetic role is still uncertain.

The main subsets of T cells (CD4+, CD8+) are present in increased numbers in the inflamed mucosa, but their proportions do not change significantly. Several lines of evidence suggest that the T cells are activated and release a variety of cytokines. Whether there is a failure of T cells to either up-regulate or down-regulate the mucosal immune response has not been clearly shown. However, data suggest that there may indeed be a failure to induce suppression to specific antigens, which could lead to some of the immunological overactivity that is observed in this disease. Intraepithelial T lymphocytes isolated from colons resected for severe ulcerative colitis also fail to suppress T-cell proliferative responses to specific antigens, a property that is not due to the increased numbers of intraepithelial T lymphocytes using γδ T-cell receptors.

As well as T-cell activation, there is also a marked increase in the population of activated macrophages, which not only release inflammatory mediators (reactive oxygen metabolites, leukotrienes, platelet-activating factor) but serine proteases, metalloproteinases, and cytokines. The release of interleukin 1 (IL-1), IL-6, and tumour necrosis factor (TNF) will not only lead to tissue damage but will initiate an acute-phase response, down-regulate albumin synthesis, and induce fever. Release of interferon-γ from activated T cells induces HLA class II molecules on colonic epithelial cells, which are then able to present antigen to the adjacent CD4+ lymphocytes and activate CD8+ intraepithelial T lymphocytes. Changes in epithelial permeability induced by interferon-γ and inflammatory mediators, endothelial damage by a wide variety of cytokines and mediators leading to local ischaemia, and stimulation of collagen synthesis by transforming growth factor β (TGFβ), IL-1 and IL-6, may all contribute to the inflammatory process.

Pathology

Macroscopic features

Ulcerative colitis always involves the rectum, but in about 40% of patients the disease is limited to the rectum and sigmoid. In adults, only about 20% will have the whole colon involved, although this proportion rises to about 50% in children. In mild disease, the mucosa is hyperaemic and granular, but small punctate ulcers appear as the disease becomes more severe, which may then enlarge and extend deeply into the lamina propria. The ulceration may be linear along the line of the taeniae coli, and the mucosa can become intensely haemorrhagic. Inflammatory polyps (pseudopolyps) may develop in patients with longstanding disease: these are usually found in the colon and rarely in the rectum, are of no significance, and have no malignant potential. In some patients they may regress over time.

When the disease goes into remission, the colonic appearances may return to normal, but—especially in patients who have had recurrent attacks—the mucosa becomes atrophic and featureless. There is often narrowing and shortening of the bowel. Fibrous strictures complicating long-standing chronic disease are extremely rare.

If an acute dilatation occurs in a patient with severe disease, the bowel becomes thin and congested. There is usually severe ulceration, with only small islands of mucosa remaining, and the bowel may perforate.

Microscopic features

The inflammation of ulcerative colitis is largely confined to the mucosa. The lamina propria becomes oedematous, with dilated and congested capillaries, and extravasation of red blood cells. There is a cellular infiltrate of acute and chronic inflammatory cells: neutrophils, lymphocytes, plasma cells, macrophages, mast cells, and eosinophils.

The neutrophils invade the epithelium, usually in the crypts, giving rise to a cryptitis and eventually to a crypt abscess. The triggers for this migration of neutrophils are unknown, but chemotactic peptides of colonic bacteria (e.g. formyl methionyl leucyl phenylalanine) as well as IL-8, leukotriene B4, platelet-activating factor, and activated complement are potential candidates.

Damage to the crypts leads to increased epithelial cell turnover and discharge of mucus from goblet cells. With increasing inflammation, the surface epithelial cells become flattened and irregular, and eventually ulcerate. Deep ulcers may extend into the lamina propria, leading to inflammatory changes in the submucosa that may be accompanied by an acute dilatation or perforation.

Many of the acute changes of ulcerative colitis are nonspecific and may also be seen in infective colitis. However, the diagnosis of ulcerative colitis can be made with some accuracy (>80% probability) if features of a chronic inflammatory process are present. These include distorted crypt architecture, crypt atrophy, basal lymphoid aggregates, and a chronic inflammatory infiltrate.

Histological appearances may return to normal once the disease has gone into remission, but there is frequently evidence of bifid or shortened crypts, hyperplasia of the muscularis mucosae, neuronal hypertrophy, and Paneth-cell metaplasia at the base of the crypts.

Clinical features

Patients usually present with a gradual onset of symptoms, often intermittent, but becoming progressively more severe. Occasionally, ulcerative colitis can present much more rapidly and may mimic an infective colitis. Indeed, some patients begin with a documented infection such as campylobacter or salmonella colitis, but continue to have symptoms that ultimately lead to the correct diagnosis.

The principal symptoms include diarrhoea, rectal bleeding, the passage of mucus, and—less frequently—abdominal pain. When the inflammation is confined to the rectum (proctitis), patients often pass fresh blood, which is usually mixed with the stool but can be streaked on the surface. These patients often complain of constipation rather than diarrhoea and, on clinical symptoms alone, may be mistakenly diagnosed as suffering from haemorrhoids. When the inflammation extends beyond the rectum, there is usually diarrhoea with the passage of partly altered blood. The diarrhoea is often accompanied by urgency and tenesmus, and patients can be incontinent. Nocturnal diarrhoea is a common symptom in the presence of severe inflammation. When severe ulcerative colitis affects most or all of the colon, patients are usually anorexic, nauseated, and have lost weight. They usually have severe diarrhoea (>6 motions daily) that becomes a slurry of faecal material, pus, and blood that resembles anchovy sauce—indeed, some patients may fail to recognize that they are passing blood. Patients may also complain of malaise, lassitude, and symptoms referable to chronic iron deficiency or to some of the extraintestinal manifestations, especially recurrent aphthous ulcers of the mouth.

On examination, patients with mild or moderate attacks usually look well and exhibit few abnormal physical signs. Weight should always be recorded and, for children and adolescents, both height and weight should be noted on growth charts. Abdominal examination may reveal a tender colon but is often normal. Bowel sounds are normal and rectal examination is also normal, apart from revealing blood in some cases.

Patients with a severe attack may also look deceptively well, with tachycardia or a tender colon sometimes the only abnormal signs. However, many of these patients are obviously ill, with fever, salt and water depletion, anaemia, and evidence of weight loss. There may be oral candidiasis, aphthous ulceration, signs of iron deficiency, and finger clubbing. The skin changes of hypoalbuminaemia and dependent oedema may occur. The abdomen is often distended and tympanitic, with reduced bowel sounds and marked colonic tenderness.

Minor perianal disease, such as a fissure, may occur in patients with an active ulcerative colitis, but this is never as severe as is seen in patients with Crohn’s disease.

Assessment of disease severity

This can be done clinically, by grading the degree of inflammation seen endoscopically or histologically, and by using laboratory tests of inflammatory activity. Many activity indices have been devised for the purpose of clinical trials, but these are rarely used in day-to-day practice apart from the following simple guide.

Clinical grading

  1. 1 Mild—there are fewer than four stools daily, with or without blood, with no systemic disturbance and a normal erythrocyte sedimentation rate
  2. 2 Moderate—this is between mild and severe
  3. 3 Severe—there are at least six stools daily, with bleeding, and evidence of systemic illness as shown by fever, tachycardia, a falling haemoglobin, hypoalbuminaemia, and raised erythrocyte sedimentation rate and C-reactive protein (CRP).

Laboratory markers of inflammation

Active disease is often accompanied by a neutrophil leucocytosis, thrombocytosis, and a rise in acute-phase proteins (e.g. CRP) and in erythrocyte sedimentation rate (ESR). There may also be a fall in haemoglobin and albumin levels. These inflammatory markers are useful when measured serially during the course of treatment as an indicator of disease activity. However, if corticosteroids are used, the white cell count can no longer be used as a marker of disease activity because it will often rise in response to the steroids. Patients with a proctitis rarely have a rise in CRP unless the inflammation is particularly severe.

Faecal calprotectin, which is released from neutrophils and therefore a marker of acute inflammation even in the absence of symptoms, has recently been identified as a sensitive marker of disease activity. It may be useful in differential diagnosis (e.g. an elevated faecal calprotectin value in a patient previously diagnosed as having an irritable bowel syndrome indicates the need to reconsider the diagnosis), and it may also be useful to monitor the response to therapy and to screen asymptomatic relatives who are concerned about familial risk.

Investigation and diagnosis

The diagnosis of ulcerative colitis is made on the basis of the history, the absence of faecal pathogens, and the endoscopic and histological appearances of the colon.

Stool cultures

Stool cultures should be set up for all patients presenting for the first time and, ideally, for all those presenting with a relapse of established disease. Special culture conditions are required for campylobacter, yersinia, gonococci, and Clostridium difficile. The possibility of an infection with E. coli 0157 must also be considered, especially in patients in whom bleeding and abdominal pain are predominant symptoms. An infective colitis with opportunistic organisms in patients with immunodeficiency syndromes has become much more common and has to be remembered in the differential diagnosis.

Sigmoidoscopy and colonoscopy

Sigmoidoscopy is safe, even in patients with a severe attack, and not only confirms rectal inflammation but also allows a biopsy specimen to be taken and an assessment of severity to be obtained. Although some centres use colonoscopy in severe attacks, this is rarely necessary for diagnosis, for assessment of severity, or for determining management. It is best avoided in the acute stage. The earliest signs of colitis on sigmoidoscopy are blurring of the vascular pattern associated with hyperaemia and oedema, leading to blunting of the valves of Houston. With increasing severity, the mucosa becomes granular and then friable. With severe inflammation, the mucosa shows spontaneous bleeding and ulceration. These changes begin in the rectum, they are diffuse, and extend proximally to affect a variable length of the colon. Severe attacks of the disease can be associated with relative rectal sparing. The reason for this is not known, but the finding can be wrongly used to diagnose Crohn’s disease of the colon. Pseudopolyps (inflammatory polyps) often occur in patients with long-standing disease, but tend to be in the colon rather than the rectum: they have no malignant potential and may even regress over many years if the disease remains in remission.

Colonoscopy with multiple biopsies is useful for assessing the extent of disease and is mandatory for patients with a colonic stricture. It is also required for cancer surveillance (see later). Preparation of the colon should follow the normal methods, with osmotic purgation being the most satisfactory. However, a more gentle approach is needed if colonoscopy is done in the presence of severe inflammation, but this is rarely indicated.

Biopsy specimens must be taken at sigmoidoscopy or colonoscopy, preferably with small, cupped forceps. Histological assessment contributes to grading severity as well as the differential diagnosis.

Imaging

All patients with a severe attack must have a plain abdominal radiograph. Not only does this exclude a dilated colon, but it may provide prognostic information (mucosal islands, distended small-bowel loops) and demonstrate the extent of the disease. An abnormal haustral pattern, thickening of the bowel wall, and mucosal oedema can be detected on a plain film. As an inflamed colon does not hold faecal material, the presence of faecal matter in the ascending or transverse colon will indicate that the inflammation is distal.

Barium radiography has largely been superseded by colonoscopy and is virtually never indicated in a severe attack, but—if required—a single-contrast study in an unprepared colon with barium entering the colon at low pressure should be used. In less severe disease, a double-contrast barium enema can be safely given, but the colon must not be overdistended and the procedure must be stopped if the patient complains of pain.

Other laboratory data

These are required for assessing severity, as discussed above, and to document haematological or biochemical complications.

Iron deficiency is common as a result of chronic iron loss; this can be exacerbated by a severe attack, in which 0.5 g of elemental iron can be lost. Thus, a hypochromic, microcytic anaemia is frequently present. A neutrophil leucocytosis, thrombocytosis, eosinophilia, or monocytosis may also be present and are indicators of active inflammation.

Biochemical abnormalities are rare in mild or moderate attacks, but hypokalaemia, hypoalbuminaemia, and a rise in gammaglobulin frequently accompany a severe attack. Minor elevations of the aspartate transaminase or alkaline phosphatase are also frequently seen in patients with a severe attack, but they return to normal when the disease goes into remission. They probably reflect a fatty liver, together with the effects of toxaemia or poor nutrition. Persistent elevation, especially of alkaline phosphatase, may indicate underlying chronic liver disease and needs further investigation (see below). Serum immunoglobulins rarely exceed the upper limit of normal during a relapse, but usually fall as remission occurs.

Differential diagnosis

Symptoms of gradual onset

If the patient has a history of slow onset of symptoms, including blood and mucus, and has diffuse inflammation on sigmoidoscopy, the diagnosis of ulcerative colitis is highly probable. The major differential diagnosis is Crohn’s disease (see this article Crohn's disease). If clinical, radiological, endoscopic, and histological information is considered together, less than 10% of patients fall into the category of indeterminate colitis, a term originally used to describe an uncertain colitis based on the examination of a colectomy specimen and therefore inappropriate when only biopsy specimens are available, hence the recommended term is ‘colitis, not yet classified’.

Collagenous colitis usually has only a mild inflammation on colonoscopy and is diagnosed on the basis of a thickened subepithelial collagen band (wider than 15 µm) seen in a rectal biopsy specimen. Microscopic or lymphocytic colitis has a normal endoscopic appearance but shows a diffuse infiltration of the lamina propria with lymphocytes and eosinophils on histological examination. Although ischaemic colitis classically occurs around the splenic flexure, it may occur in the rectum, especially in older people, and can be diagnosed histologically. Radiation damage to the rectum may occur, especially in men who have had radiotherapy to the prostate.

Rarely, a drug-induced colitis may occur. The drugs that have been implicated include NSAIDs, gold, penicillamine, and 5-aminosalicylic acid. This last drug may cause considerable diagnostic confusion in patients who already have ulcerative colitis. An antibiotic history must be taken, but a pseudomembranous colitis secondary to C. difficile can occur in the absence of antibiotic usage, especially in older people.

Symptoms of acute onset

For those patients presenting with a much more acute history, infective forms of colitis must be excluded by stool culture. A sudden onset of symptoms, the predominance of abdominal pain, the ingestion of potentially infected food (chicken, shellfish), and evidence of diarrhoeal disease in contacts are obvious pointers to an infection. Sigmoidoscopic appearances are usually very similar to ulcerative colitis, but a rectal biopsy can be very useful in distinguishing an infective from a more chronic ulcerative colitis. The presence of a chronic inflammatory infiltrate, architectural disturbances of the glands, and basal lymphoid aggregates favour ulcerative colitis. The common organisms causing an infective colitis are salmonella, shigella, and campylobacter. Yersinial infections may also cause colitis and can pursue a chronic course over many months before resolving. Special culture conditions may isolate the organism from stool, but a rising titre of serum antibody is often the more reliable method of identifying the infection. E. coli 0157 is a recognized cause of an acute colitis, especially in institutions, and massive bleeding is often a characteristic feature. Children may develop a haemolytic uraemic syndrome. Diagnosis is difficult because most laboratories are not equipped either to detect this strain of E. coli or to measure specific antibody. For patients who have travelled in endemic areas, amoebic and schistosomal colitis must be considered; stool examination and histological demonstration of amoebas or schistosomal ova in rectal biopsy specimens make the diagnosis.

Other causes of infective colitis can occur in immunosuppressed patients and include cytomegalovirus, herpes simplex, and Mycobacterium avium intracellulare. Although these organisms usually cause fairly characteristic sigmoidoscopic appearances, they can be associated with a more diffuse pattern of inflammation. Other sexually transmitted causes of proctitis (gonorrhoea, chlamydia, lymphogranuloma) do not usually cause diarrhoea and, especially with gonorrhoea, are associated with the passage of watery pus.

Other considerations

Ulcerative colitis also has to be differentiated from irritable bowel syndrome, colonic polyps or carcinoma, diverticular disease, solitary rectal ulcer syndrome, and factitious diarrhoea. Sigmoidoscopy usually clarifies the diagnosis, but if the ulceration of the solitary rectal ulcer syndrome becomes circumferential, this can be mistaken for ulcerative colitis. A biopsy specimen showing strands of smooth muscle radiating up into the lamina propria between the glands is characteristic of the solitary ulcer syndrome.

Extraintestinal manifestations

The extraintestinal manifestations of ulcerative colitis are listed in Bullet list 1 (below).

Skin

An erythematous, macular skin rash, sometimes photosensitive, that used to be common in patients with ulcerative colitis was a hypersensitivity rash to sulphasalazine (related to the sulphapyridine moiety). However, this is now rarely seen because most patients are maintained on other formulations of 5-aminosalicylic acid which do not contain the sulphonamide. Urticaria can rarely occur in association with mesalazine.

Bullet list 1 Extraintestinal manifestations of ulcerative colitis

Related to activity of colitis
  • ◆ Aphthous ulceration of the mouth
  • ◆ Fatty liver
  • ◆ Erythema nodosum
  • ◆ Peripheral arthropathy
  • ◆ Episleritis
  • ◆ Pyoderma gangrenosum
Usually unrelated to activity of colitis
  • ◆ Anterior uveitis
  • ◆ Unrelated to colitis
  • ◆ Sacroiliitis
  • ◆ Ankylosing spondylitis
  • ◆ Primary sclerosing cholangitis
  • ◆ Cholangiocarcinoma

Erythema nodosum occurs in about 2 to 4% of patients and is mostly associated with active disease. The lesions occur most commonly on the anterior aspect of the lower legs. Pyoderma gangrenosum is rare (1–2%) and is usually seen in patients with active disease, but occasionally persists despite inactive colitis. The lesions usually begin as sterile pustules, usually on the limbs, which break down as they enlarge and finally coalesce. Ulceration leads to necrosis and the lesions become surrounded by black, necrotic tissue. Treatment of the colitis is usually followed by regression of the skin lesions, but pyoderma can be very resistant to therapy and may only respond following colectomy, but it can persist even then. Recently, anti-TNF monoclonal antibodies (e.g. infliximab, adalimumab, certolizumab) have been shown to be very useful in treating refractory pyoderma, including peristomal lesions in patients who have an ileostomy: following an induction regimen, maintenance administration is usually necessary to keep the pyoderma in remission.

Mouth

Crops of aphthous ulcers are common in patients with active disease. A sore tongue and angular stomatitis often accompany chronic iron deficiency.

Eyes

Episcleritis or anterior uveitis occur in 5 to 8% of patients. Local corticosteroids and treatment of active colitis usually lead to resolution.

Joints

An acute arthropathy occurs in 10 to 15% of patients with active disease. It affects the larger joints (knees, hips, ankles, wrists, elbows) and is usually asymmetrical. It is a non-erosive condition and settles as the colitis goes into remission. A less common joint complication is a symmetrical small-joint polyarthropathy, which is seronegative and is unrelated to the activity of the colitis.

Low back pain is a common symptom and usually due to sacroiliitis, which can be seen by plain radiology in 12 to 15% of patients and in 30 to 35% by MRI. It is unrelated to the activity of the colitis, is not strongly associated with HLA B27, and rarely progresses to ankylosing spondylitis. The latter disease occurs in only 1 to 2% of patients, with 60% of these having the HLA B27 phenotype. There is a 2:1 ratio in favour of males with this complication. The spondylitis may present before the colitis becomes apparent or may follow the intestinal symptoms. Its natural history is independent to that of the colitis and should be treated with physiotherapy, hydrotherapy, and—if necessary—NSAIDs. However, these drugs can occasionally worsen the colitis and should therefore be used cautiously. Anti-TNF antibodies are highly effective in relieving the pain of either sacroiliitis or ankylosing spondylitis.

Liver disease

Patients with severe attacks of ulcerative colitis often have minor elevations of alkaline phosphatase or transaminases. The cause of these enzyme rises is probably multifactorial, including malnutrition, sepsis, and a fatty liver, which occurs in up to 60% of patients undergoing urgent colectomy. The liver enzymes return to normal when remission is achieved, but there may be persistent abnormalities in liver enzymes in about 3% of patients, usually a rise in alkaline phosphatase. The overwhelming majority of these patients will have primary sclerosing cholangitis when the bile duct is visualized by endoscopic cholangiography. Histologically, liver biopsy specimens show evidence of chronic liver disease, but the spectrum of appearances ranges from those of an autoimmune hepatitis to the classic picture of concentric periductular fibrosis with obliteration of bile ducts.

Many patients with ulcerative colitis and sclerosing cholangitis remain well for many years. The colitis is often very mild, though frequently affecting the whole colon, but the liver disease is progressive and ultimately leads to portal hypertension and liver failure. Sclerosing cholangitis is a premalignant condition and explains the well-recognized association between ulcerative colitis and cholangiocarcinoma. Furthermore, there is a high incidence of colorectal cancer, especially of the right colon, in these patients. Colonoscopic surveillance is mandatory. The mild nature of the colonic inflammation despite extensive disease, the frequently observed rectal sparing, and the right-sided cancers have called into question whether the colonic disease is really the same as ulcerative colitis. At the present time there is no clear answer, but the possibility that primary sclerosing cholangitis (PSC)-colitis might be a distinct entity should be remembered when posing questions about pathogenesis.

Rare associations

Pericarditis with or without an effusion has been described in association with an acute attack of colitis, but a true association is not yet proven. Autoimmune haemolytic anaemia has been reported in ulcerative colitis and may recur when the colonic disease becomes active. Amyloid rarely occurs in ulcerative colitis; it is much more likely to be associated with Crohn’s disease. A rapidly progressing bronchiectasis has also been described in some patients with ulcerative colitis.

Medical management

The main principles of therapy for the treatment of ulcerative colitis are to control active disease rapidly, to maintain remission, to select patients for whom surgery is appropriate, and to ensure as good a quality of life as possible. Patient education about their disease is essential, and all patients should be given the opportunity to subscribe to patient self-help groups such as the National Association for Colitis and Crohn’s Disease (in the United Kingdom) or the Crohn’s and Colitis Foundation of America.

Treatment of active disease

The most effective drugs for controlling active disease are the corticosteroids, which may be given systemically, topically, or in combination. Drugs containing 5-aminosalicylic acid (sulphasalazine, olsalazine, balsalazide, mesalazine) are often used to treat a mild colitis, but prednisolone has been shown to be more effective and to control symptoms more rapidly, which make it the drug of choice. The dosage and route of administration are largely governed by disease severity. Once active inflammation has been controlled and remission obtained, the corticosteroids should be tailed off because they are ineffective as maintenance therapy and prolonged use puts the patient at risk of long-term side effects such as osteoporosis.

Proctitis

Proctitis refers to disease limited to the rectum: in practice it refers to inflammation that does not extend beyond the limits of a rigid sigmoidoscope. It can be remarkably difficult to treat. Initial therapy is usually a 5-aminosalicylic acid drug by mouth in combination with topical therapy. The latter can be a corticosteroid or 5-aminosalicylic acid in the form of a suppository, with the latter shown by metaanalysis of clinical trials to be more effective and therefore the drug of choice. If a good response is not obtained, then a 5-aminosalicylic acid suppository in the morning and a steroid one in the evening can produce a better response than either alone. For patients who do not respond, oral prednisolone may be given. Some have sufficiently severe proctitis to warrant intravenous steroids, and occasionally colectomy may be necessary.

Many patients with refractory proctitis develop a severe proximal constipation, which can cause considerable abdominal discomfort, bloating, and nausea. Relief of the constipation, usually by gentle osmotic purgation, will often give considerable symptomatic benefit, and it may also be associated with a marked improvement in the inflammation. Some patients appear to be refractory because foam or enema preparations are used: changing to a suppository allows a much higher concentration of drug in the rectum and is frequently associated with improvement in symptoms.

Mildly active disease

Patients who have no more than four motions daily on average, with inflammation extending beyond the limits of the rigid sigmoidoscope, should be given 20 mg of oral prednisolone daily, together with topical steroids or 5-aminosalicylic acid (or both). Treatment should be given for at least 4 weeks, before being tailed off over the subsequent 3 to 4 weeks. Clinical trials have shown that oral 5-aminosalicylic acid formulations are more effective than placebo in treating active disease, especially in high doses. However, corticosteroids achieve remission more quickly and in a higher proportion than 5-aminosalicylic acid drugs.

Moderately active disease

Patients who have, on average, more than four bowel motions daily but who are not systemically ill should be given 40 mg of prednisolone by mouth daily. Giving larger doses (such as 60 mg daily) provides only a marginally better effect but increases the frequency of side effects quite considerably. The dose is reduced to 20 mg daily over 2 to 3 weeks and the regimen then follows that described for mild disease.

Severe disease

This is defined as an attack in which the patient has more than six bowel motions daily, with blood, and who is systemically ill as shown by tachycardia, fever, and anaemia. The colon is usually tender on palpation. These patients should be admitted to hospital and assessed by both physician and surgeon. Fluid and electrolyte losses are replaced intravenously, and blood transfusion should be given if the haemoglobin is less than 10 g/dl. Patients are given intravenous corticosteroids (such as 100 mg of hydrocortisone, 6-hourly) together with a twice daily rectal drip of hydrocortisone (100 mg in 100 ml water).

Parenteral nutrition is indicated for those who are malnourished, but intravenous saline and dextrose–saline are sufficient for most, together with potassium supplements. Most patients with a severe attack prefer to have only clear fluids by mouth during the first 24 h. Thereafter, there is no evidence that a light diet has any adverse effect on the disease, but many clinicians will leave the patient on only clear fluids for the first few days. Prophylactic heparin should be given, either unfractionated or low molecular weight, since thomboembolism is still a cause of death in these patients: this is safe and only very rarely associated with massive haemorrhage.

Provided the patient is improving, treatment is continued for 5 to 7 days. At this time, a good response is one in which the patient feels well, there is no fever or tachycardia, the colon is not tender on abdominal palpation, and the diarrhoea has largely settled, usually to less than four motions daily, with the stools rarely formed, but without macroscopic bleeding. These patients can then go on to oral prednisolone (e.g. 40 mg daily), a retention enema, an oral 5-aminosalicylic acid drug, and a light diet. By contrast, those who deteriorate during the first few days of intravenous treatment, or who have not made a substantial improvement after 3 to 4 days, need further treatment: simply continuing intravenous therapy for more than 7 to 10 days is rarely beneficial, and surgery is usually required. Indeed, it is now clear that patients who, after 3 days of intravenous steroid therapy, still have marked diarrhoea (>8 stools/24 h) or 4 to 6 stools daily with a CRP of more than 45 mg/litre, have a very high chance (85%) of requiring urgent surgery. For this group of patients, proceeding directly to urgent surgery may be appropriate if they have had difficult, refractory colitis prior to the current admission, but ‘rescue’ therapy with either ciclosporin or infliximab should be considered for those having their first attack of colitis, or for patients whose previous history of colitis has always been associated with good quality of life.

Rescue therapies

Ciclosporin will induce remission in 60 to 80% of patients not responding to intravenous steroids. This should be added after 3 to 5 days of steroid therapy. It is usually given intravenously, a dose of 2 mg/kg being as effective as 4 mg/kg (although an oral formulation may be just as effective), and most patients respond very quickly (3 to 4 days), hence—for those in whom surgery becomes necessary—a decision about colectomy can be made after a week or so of treatment. Those who do respond to drug therapy can be converted to oral treatment with decreasing doses of prednisolone. Practice varies between continuing oral ciclosporin for some months, changing to azathioprine, or using the two in combination. No controlled trial data are yet available to provide evidence-based guidelines. However, it is important to recognize that ciclosporin is not a cure, and 50% of those responding will have further relapses of their ulcerative colitis and require colectomy within 5 years. For those who do ultimately come to surgery, the initial response to ciclosporin provides time for educating patients about their disease, the implications of life with a colectomy (with or without an ileoanal pouch), and the long-term prognosis. This is particularly important for young patients, especially if it is their first attack. The use of ciclosporin in the manner and dosage (low with respect to its usage in organ transplantation) described above has not been associated with major side effects, although prolonged use of high-dose steroids and ciclosporin can be associated with pneumocystis pneumonia. Blood pressure and renal function need to be closely monitored.

A small trial of intravenous infliximab has recently been published from Sweden, in which patients not responding to intravenous steroids after 5 to 10 days were randomized to receive infliximab (5 mg/kg) or placebo while continuing the steroid. The colectomy rate in the infliximab group was significantly less than in the placebo group. This trial, together with a number of small open-label studies, have shown that 65 to 80% of patients not responding to steroid therapy can be saved from colectomy during the index admission by infliximab. This is a very similar proportion to that achieved with ciclosporin, and the long-term outlook is similar, with about 50% coming to colectomy during subsequent follow-up. Whether maintenance infusions every 8 weeks will reduce the long-term colectomy rate remains to be established.

Whether ciclosporin or infliximab is used as rescue therapy is largely a matter for physician preference. In the absence of a direct comparison in the setting of a formal randomized, double-dummy trial, both drugs seem to be associated with very similar outcomes. Side-effect profiles are clearly different, but whether in the long-term infliximab is safer than ciclsporin is not known. What should be avoided is using these drugs sequentially if there is no response to one: a small series from Mount Sinai Hospital in New York showed that no therapeutic benefit is gained by so doing, whether ciclosporin was given first followed by infliximab, or vice versa, and there was high morbidity and even mortality in those who had both drugs in addition to prolonged intravenous corticosteroids.

Approximately 15–25% of patients with a severe attack will require an urgent colectomy regardless of medical therapy given. These patients can often be identified early on, using clinical and radiological features that have been shown to have prognostic significance, namely the passage of more than nine stools daily, a pulse rate greater than 100/min, or a temperature greater than 38 °C during the first 24 h of treatment. A serum albumin level of less than 30 g/litre during the first few days or the failure of acute-phase proteins such as the serum CRP to fall are also poor prognostic signs. Seventy-five per cent of patients showing mucosal islands in the colon or having more than three loops of distended small bowel on a plain abdominal radiograph will come to urgent surgery. These findings, based on retrospective studies, have been confirmed by prospective series. If rescue therapy is to be used, it should be introduced (as discussed above) on day 4 of steroid therapy so that a decision about the need for surgery can still be made within 10 days of admission. This approach minimizes the risks of patients developing opportunistic infections (e.g. pneumocystis, cytomegalovirus), of becoming malnourished, and of postoperative complications.

Chronic active disease

Some patients repeatedly relapse when they come off corticosteroids or receive a daily dose of less than 10 to 15 mg of prednisolone. Immunosuppression therapy with azathioprine or 6-mercaptopurine is often beneficial in this group. In the United Kingdom, azathioprine is the drug that is most used, in doses of 2.0 or 2.5 mg/kg, and may allow the prednisolone to be withdrawn. It usually takes 4 to 6 weeks before an effect is seen, and the drug is then continued for several months. Although few long-term sequelae have been encountered, most clinicians do not usually continue therapy for more than 18 to 24 months.

Oral ciclosporin (5 mg/kg) has also been used for chronic active disease, but no formal clinical trials have been made. High-dose prednisolone (40 mg) given on alternate days is another approach that may be useful. However, if the patient’s lifestyle is impaired by chronic disabling symptoms or by the side effects of treatment, surgical management should be considered. Recently, two trials have reported favourably on the use of infliximab in patients refractory to medical therapy: following infusions at 0, 2, and 6 weeks about 60% had a response, but only about 20% went into prolonged remission.

Maintenance of remission

Salicylate drugs

Sulphasalazine and its active moiety, 5-aminosalicylic acid, reduce the relapse rate by about fourfold and are able to maintain the disease in remission when given over many years. Thus, provided they are well tolerated, they should be given indefinitely. For sulphasalazine, the optimal dose to obtain good therapeutic efficacy with the least side effects is 2 g daily. Common side effects are nausea, anorexia, and headache: these are dose related and caused by the sulphapyridine component. Other side effects, which are also usually due to the sulphonamide but are not dose related, include hypersensitivity skin rashes, male infertility, agranulocytosis, and Heinz-body haemolytic anaemia. Overall, 10 to 15% of patients are unable to take the drug, although the nausea and headache can often be overcome by starting at a low dose and gradually increasing.

Sulphasalazine is an unusual drug in that it is poorly absorbed in the stomach and small intestine. When it reaches the colon, the azo-bond linking the 5-aminosalicylic acid and sulphapyridine moieties is split by bacterial azoreductases. The sulphapyridine is absorbed, metabolized in the liver, and excreted in the urine. The majority of the 5-aminosalicylic acid (c.70%) is poorly absorbed and excreted in the faeces. As it is the 5-aminosalicylic acid that is the active compound, several drugs are now available that present 5-aminosalicylic acid to the colon without the sulphapyridine that causes most of the side effects of sulphasalazine. The 5-aminosalicylic acid cannot simply be given by mouth as it is rapidly absorbed. Thus, it is either given as a delayed-release formulation (the mesalazine group) or as a prodrug (olsalazine, balsalazide). Table 2 lists these and details their characteristics.

Table 2 The salicylate drugs

 

  Characteristics
Mesalazine preparations
Enteric coated  
Asacol Coated with Eudragit, S 5-ASA released at pH 7.0
Claversal, Salofalk Coated with Eudragit, L 5-ASA released at pH 6.5
Controlled release  
Pentasa Tablets comprise 5-ASA granules coated with ethyl cellulose; released with time at pH >6.5
Mezavant (Lialda in USA) Mesalazine in multimatrix formulation
Prodrugs
Sulphasalazine 5-ASA linked to sulphapyridine by an azo bond which is split by colonic bacteria
Olsalazine Two molecules of 5-ASA linked with an azo bond
Balsalazide 5-ASA lined to an amino acid by an azo bond

5-ASA, 5-aminosalicylic acid.

Which drug containing 5-aminosalicylic acid should be prescribed as maintenance therapy for ulcerative colitis? Sulphasalazine is well tolerated by 85% or so of patients, is cheap, and serious side effects (such as Stevens–Johnson syndrome, agranulocytosis, and pancreatitis) are very rare. The newer drugs are more expensive than sulphasalazine, but they have equal therapeutic efficacy and are now the drugs of choice. In general they are associated with fewer side effects, but occasional patients develop typical salicylate reactions (rhinitis, urticaria, and colitis). About 10 to 12% of patients will develop loose stools when given olsalazine: this gradually settles if treatment is continued, but about 5% will develop severe watery diarrhoea that usually necessitates stopping the drug. The risk of diarrhoea can be minimized by taking the drug with food. Progressive renal failure due to chronic interstitial nephritis is a recognized complication, mostly associated with the delayed-release forms of mesalazine, and all patients taking this require regular monitoring of their serum creatinine (eGFR), with renal consultation in the event that this deteriorates. Sulphasalazine is still a useful drug for those patients with joint symptoms as it often benefits those while maintaining the colonic disease in remission.

Diet

Patients with recurrent, severe disease are slightly prone to hypolactasia, and a lactose-free diet may be beneficial. Individual patients may be intolerant of dairy products, wheat, eggs, and other dietary constituents, but most patients should have a normal, well-balanced diet.

Surgical management

The indications for surgery are:

  1. 1 severe inflammation unresponsive to medical therapy
  2. 2 acute complications-perforation, dilatation
  3. 3 for chronic active disease
  4. 4 to prevent cancer

The choice of operation is partly determined by the expertise available and the activity of the disease. When surgery is performed for a severe attack, a one-stage proctocolectomy with a Brooke ileostomy has been shown to be a safe and effective procedure. The major problems with the operation are poor healing of the perineal wound, adhesion obstruction, and ileostomy dysfunction. Sexual dysfunction in males rarely occurs if a perimuscular excision of the rectum is made. However, with the advent of restorative proctocolectomy with the formation of an ileoanal reservoir or pouch, many surgeons will do only a colectomy in the acute stage. The rectal stump is either oversewn (which is not recommended as it often leaks, with abscess formation), or brought out as a mucous fistula either in the lower end of the wound or in the left iliac fossa. This allows histological examination of the whole colon to exclude Crohn’s disease. The rectum is excised and the pouch formed some months later when nutrition has been restored and the patient is not taking corticosteroids or immunosuppressive drugs.

Restorative proctocolectomy with ileoanal reservoir/pouch

Restorative proctocolectomy has become the procedure of choice in specialist centres, provided the anal sphincter is intact, hence this operation is not advised over the age of 65 years. The two-limb (J) pouch is now the favoured design, with most surgeons preserving the anal transitional zone by anastomosing the pouch 1 to 2 cm above the dentate line. This allows for a stapled anastomosis, which shortens the operation and is associated with better continence than a mucosectomy that inevitably requires anal dilatation by retractors. If the operation is being carried out for high-grade dysplasia or cancer, most surgeons will perform a mucosectomy and hand-sew the pouch to the dentate line.

Most patients who undergo a pouch operation have excellent function, with less than 10% having any leakage, which is usually limited to night-time soiling. Nevertheless, all patients should be advised to wear a pad at first after a pouch procedure. The pouch usually requires emptying 6 to 12 times daily within the first few weeks of functioning, and loperamide is usually needed. Adaptation occurs during the first few months, and by the end of a year the emptying frequency is around four to six times daily, but without urgency. Good function persists in the long term (>10 years). Complications of the pouch, once the immediate surgery is over, include anal stenosis, adhesion obstruction and pouchitis, at least one attack of which occurs in 40 to 50% of patients during the first 5 years, consisting of diarrhoea with blood and evidence of inflammation on endoscopy. It usually responds to antibiotics such as metronidazole or ciprofloxacin, but occasionally requires topical treatment with corticosteroids or 5-aminosalicylic acid. Refractory pouchitis can be a severe management problem: the use of probiotic preparations can maintain some of these patients in remission, but others may require immunosuppressives, infliximab or even removal of the pouch.

The causes of pouchitis are heterogeneous and include ischaemia, infection with a recognized pathogen (such as campylobacter), and poor emptying, but most pouchitis attacks are unexplained. Poor emptying can be recognized by isotopic scanning using a radiolabelled artificial stool and usually responds to regular catheterization of the pouch. Idiopathic pouchitis is particularly interesting in so far as it is only seen in patients who have previously had ulcerative colitis, and rarely if ever in patients who have a pouch for other reasons. After the formation of a pouch, for whatever indication, the ileal mucosa undergoes colonic metaplasia. The triggers for this are unknown but almost certainly involve luminal stasis. Thus, whatever factors first render individuals susceptible to developing ulcerative colitis also seem to render them susceptible to developing acute inflammation in ileal mucosa that has undergone colonic metaplasia.

With increasing use of restorative proctocolectomy, there is increasing recognition that there is often a reduced fecundability in female patients. This problem should be discussed with the patient before the procedure is performed and, in some centres, ova are harvested and frozen in case of subsequent infertility. Male patients should also be counselled with regard to subsequent impotence, although this is a rare occurrence given good surgical technique.

Some patients have poor pouch function which is not due to pouchitis. Some will have cuffitis or prepouch ileitis to account for symptoms, but others have poor function due to noninflammatory causes. These include dietary intolerance, motility disorders, bacterial overgrowth in the small intestine, and a concomitant irritable bowel syndrome.

Local complications and their treatments

Perianal lesions

Minor lesions such as fissures, perianal abscesses, or haemorrhoids may occur in patients with ulcerative colitis, but extensive lesions such as fistulas are exceptional and suggest Crohn’s disease. Treatment of fissures involves treatment of active inflammation. Surgical treatment should be avoided wherever possible and, if necessary, should be conservative.

Massive haemorrhage

This rarely occurs in association with severe attacks. Intravenous corticosteroids and blood transfusion usually allow the bleeding to stop. However, urgent colectomy must be considered if patients have already received six or more units of blood and are still bleeding.

Perforation

This is the most dangerous of the local complications and carries appreciable mortality. In patients receiving corticosteroids, the physical signs of peritonitis may not be obvious, and malaise, tachycardia, and reduced or absent bowel sounds may be the only clinical features. Plain abdominal films usually show free intraabdominal gas. It may complicate an acute dilatation but can occur in its absence. Management consists of immediate intravenous fluid, electrolytes, antibiotics and hydrocortisone, with urgent colectomy performed within 24 h as soon as the patient has been resuscitated. The mortality of a perforation is as high as 16%, even in specialist centres.

Acute dilatation

This is defined as a transverse colon with a diameter of greater than 5.0 to 6.0 cm, with loss of haustration seen on a plain radiograph in a patient with a severe attack of ulcerative colitis. It occurs in about 5% of severe attacks and can be precipitated by hypokalaemia or the administration of opiates. Abdominal signs are often minimal, but the patient is usually obtunded, the bowel sounds are reduced, and the abdomen may become distended. Medical therapy with intravenous steroids is given as usual if the colon is already dilated on presentation of a severe attack: about 50% will settle on medical therapy alone, but urgent surgery is required for those who continue to deteriorate or do not improve within 24 h. Colectomy should be performed if the colon dilates during the course of treating a severe attack.

Strictures

These occur very rarely in patients with long-standing ulcerative colitis with a shortened, narrow colon. Colonoscopy with multiple biopsies must be performed as there should be a high index of suspicion for carcinoma.

Pseudopolyps

These are common and may be filiform, sessile, or may form bridges. They can occur throughout the colon but often spare the rectum. They are not premalignant and may occasionally regress.

Colonic carcinoma

The risk of cancer is mainly in patients who have had extensive disease for more than 10 years, especially if they have had recurrent attacks. The most recent series studying primary cohorts suggest that the cumulative risk for patients with extensive disease is about 7 to 15% at 20 years, with very little risk up to 15 years of disease.

Carcinoma is usually, but not always, preceded by dysplasia. This can be detected histologically and has led to colonoscopic surveillance programmes for patients with longstanding ulcerative colitis affecting most or all of the colon. Provided no dysplasia is found (at least 30 biopsies around the colon are recommended), the examination is repeated every 1 to 3 years. If high-grade dysplasia is present, prophylactic colectomy is usually considered. For low-grade dysplasia, repeat colonoscopy within a few months is usually advised, but there are increasing reports of cancers occurring in association with low-grade dysplasia, hence colectomy is increasingly being recommended whenever dysplasia is recognized, regardless of grade. As large numbers of colonoscopies are involved in a surveillance programme, the question of cost benefit has been raised. However, two recent studies have shown that patients have a worse outcome with respect to cancer if they are not in a surveillance programme. The recent introduction of chromoendoscopy has allowed targeted biopsy of suspicious areas, which not only allows a high pick-up rate of dysplasia but also reduces the number of biopsies that need to be taken, a saving that partly off-sets the increased time of the procedure. In a few specialist centres, confocal laser endoscopy provides an even more sensitive way of detecting epithelial dysplasia.

Course and prognosis

Most patients with ulcerative colitis have intermittent attacks of the disease, but the duration of remission between attacks can vary from a few weeks to many years. About 10 to 15% of patients will have a chronic continuous course and rarely achieve a full remission for any appreciable time. A few (5–10%) will have a severe first attack requiring urgent surgery, but fewer—if any—have one attack only and never relapse.

Patients with extensive or total disease are much more likely to have a severe attack within 1 year of diagnosis than patients with distal disease and are therefore at greater risk of colectomy. However, a year from diagnosis the risk of colectomy is similar in all groups, with a cumulative rate of about 1% per year. Patients with disease limited to the rectum are a special group in so far as most of them continue to have very limited involvement, with only about 30% developing more extensive disease in the 20 years after diagnosis.

Despite having a chronic relapsing disease, 90% or so of patients are able to work, with very few days of sick leave each year. Nevertheless, quality of life can be impaired in many patients. During active inflammation, lassitude, discomfort, and urgency of defecation are the major symptoms that limit everyday activities. Sexual and marital problems are not uncommon, but may be no more frequent than that seen in other populations of patients with acute-on-chronic illnesses. Most of these problems disappear during remission, although fear of relapse and the need for continuing treatment and medical supervision can cause considerable anxiety. Many patients will alter their lifestyle with respect to daily activity, travel, and diet, but with prompt treatment of active disease and supportive medical care, most are able to have a normal life for most of the time. The development of patient self-help groups (such as the National Association for Colitis and Crohn’s Disease in the United Kingdom) has been of tremendous value in providing education and an environment in which patients can regain their confidence and overcome the problem of isolation, an important and common factor in patients with an uncommon and socially unpleasant disease.

There has been a dramatic fall in the mortality rates for ulcerative colitis since the introduction of corticosteroids in the 1950s and improvement in the management of severe attacks. The mortality rate for a severe attack, including urgent surgery, should now be less than 2%. In the longer term, mortality differs hardly at all from that expected in a matched healthy population, a fact which the majority of life assurance companies fail to recognize.

Ulcerative colitis in particular groups of patients

Pregnancy

Women with ulcerative colitis have normal fertility and are not at increased risk of having a spontaneous abortion, and there is no evidence that pregnancy is a risk factor for relapse. If they do become pregnant, the chance of having a normal baby is the same as for healthy women. Furthermore, there is no good evidence that corticosteroids, drugs containing 5-aminosalicylic acid, or azathioprine are harmful. Maintenance treatment should be continued throughout pregnancy and, if a relapse does occur, it should be treated aggressively with corticosteroids to obtain a rapid remission. There is now a cohort of women who have conceived while receiving infliximab, and no adverse outcomes have been seen although the drug is not recommended either during pregnancy or in women wanting to conceive. Methotrexate is totally contraindicated if conception is possible, as it is known to be teratogenic.

Childhood

Ulcerative colitis is less common in children than in adults and, for the United Kingdom, the prevalence is about 6 to 7 per 100 000. Nevertheless, it can present within the first few weeks of life, although the mean age of presentation is about 10 years. The symptoms are those of diarrhoea, rectal bleeding, abdominal pain, and failure to thrive. There may be delayed growth, but this is more commonly a feature of childhood Crohn’s disease. The proportion of children with a total colitis is about 50%, which is higher than in adults, and probably accounts for the higher rate of colectomy reported in most series.

Treatment follows the same principles as for adults, although dosages are adjusted for the child’s weight. In addition, great attention must be made to nutrition to allow for adequate growth. For children requiring repeated courses of corticosteroids, an alternate-day regimen usually controls the disease activity but prevents growth retardation. If colectomy becomes necessary, a restorative proctocolectomy should be done.

Further reading

Allan RN, et al. (eds) (1996). Inflammatory bowel diseases, 3rd edition. Churchill Livingstone, Edinburgh.

Anderson CA, et al. (2009). Investigation of Crohn’s disease risk loci in ulcerative colitis further defines their molecular relationships. Gastroenterology, 136, 523–9.

Jewell DP, et al. (ed) (2006). Challenges in inflammatory bowel disease, 2nd editon. WileyBlackwell, Oxford.

Sartor RB, Sandborn WJ (2004). Kirsner’s inflammatory bowel disease, 6th edition. WB Saunders, Philadelphia, PA.