Ulcerative colitis is an idiopathic chronic inflammatory disease of the colon that follows a course of relapse and remission. In a small number of cases, ulcerative colitis is associated with extra-intestinal features. Disease extent can be divided into:

• Distal disease (left-sided colitis): colitis confined to the rectum (proctitis) or rectum and sigmoid colon (proctosigmoiditis).
• More extensive disease includes: left-sided colitis (up to the splenic flexure, 40% of patients), extensive colitis (up to the hepatic flexure) and pancolitis (affecting the whole colon, 20% of patients).
• 10% of patients may have involvement of the terminal ileum due to an incompetent ileocaecal valve.¹

It is sometimes difficult to distinguish between ulcerative colitis and isolated colonic Crohn's disease and such patients can be described as having indeterminate colitis.

Epidemiology¹

• American studies report an incidence of 10.4-12 per 100,000 population per year.
• A study in a general practice in Newcastle reported an annual incidence of 13. 9 per 100 000.²
• Peak incidence is between the ages of 15-25 with a smaller peak at 55-65, although any age may be affected.

Aetiology¹

• The aetiology is unknown. The consensus is it is a response to environmental triggers (infection, drugs, or other agents) in genetically susceptible individuals. The genetic component is not as strong in ulcerative colitis as it is in Crohn's disease. However, disease concordance in twins and positive family histories suggest a genetic element.
• There are marked differences between ethnic groups with some (such as Ashkenazi Jews) having a particularly high incidence.
• Some studies suggest that low birthweight children born to mothers with ulcerative colitis have a higher risk of developing the disease.
• Non-steroidal anti-inflammatory drugs (NSAIDs) may cause an episode of acute active disease in some patients with inflammatory bowel disease.
• There is a lower incidence of ulcerative colitis in patients who have had an appendicectomy: this appears to be an immune modulatory effect.
• Stress and milk consumption have both been associated with exacerbations.

Presentation^1,3

Symptoms

• The cardinal symptom is bloody diarrhoea.
• Associated symptoms include colicky abdominal pain, urgency, or tenesmus (a feeling of incomplete defecation with an inability or difficulty to empty the bowel at defecation).
• Disease limited to the rectum (proctitis) may present with constipation and rectal bleeding.
• There may be symptoms of systemic upset, including malaise, fever, weight loss and symptoms of extra-intestinal (joint, cutaneous and eye) manifestations.
• The presentation may mimic gastrointestinal infection and the history should include recent foreign travel in considering the possibility of an infective cause.
• Recent medication history is also important in considering other possible causes of the presenting gastrointestinal upset.

Signs

• Depending on disease severity, the patient may be clearly unwell, pale, febrile and dehydrated. He or she may have a tachycardia and hypotension.
• Abdominal examination may reveal tenderness, distension or palpable masses.
• If abdominal tenderness is associated with abdominal distension, then acute admission to hospital is required, as the patient could have toxic megacolon, which is potentially fatal. Other warning signs of potentially severe disease include tachycardia, fever and anaemia.

Extra-intestinal disease^1,3

Approximately 4% of patients will have extra-intestinal disease which may include:

• Related to the activity of colitis:
  • Erythema nodosum.
  • Aphthous ulcers.
  • Episcleritis.
  • Acute arthropathy affecting the large joints (e.g. wrists, hips, knees).
• Usually related to activity of colitis:
  • Pyoderma gangrenosum.
  • Anterior uveitis.
• Not related to activity of colitis:
  • Sacroiliitis.
  • Ankylosing spondylitis.
  • Primary sclerosing cholangitis.

Differential diagnosis¹

• The main differential is Crohn's disease which has very similar clinical features. The diagnosis is usually made from the biopsy result following a sigmoidoscopy or colonoscopy.
• Cathartic colon - this is due to prolonged use of laxatives. Radiologically, the appearances are similar to ulcerative colitis but there are important differences which help with diagnosis.
• Infective colitis (chronic schistosomiasis, amoebiasis, tuberculosis).
• Mild colitis may mimic irritable bowel syndrome.
• Other conditions which occasionally cause diagnostic difficulty include:
  • Ischaemic colitis.
  • Radiation colitis.
  • Bowel trauma.
  • Adenocarcinoma of colon.
  • Diverticulitis.
  • Polyposis syndromes.
  • Colonic polyps.
  • Rectal carcinoma.

Investigations^1,4

The diagnosis should be made on the basis of clinical suspicion supported by appropriate macroscopic findings on sigmoidoscopy or colonoscopy, typical histological findings on biopsy and negative stool examinations for infectious agents.

• Initial investigations include:
  • FBC, renal function and electrolytes, LFTs, ESR and CRP.
  • Low magnesium and serum albumin levels are sometimes found in ulcerative colitis.
  • Stool culture, including ova, cysts and parasites and also Clostridium difficile toxin.
  • Serological markers have been developed to differentiate ulcerative colitis from Crohn's disease. p-ANCA is more commonly associated with ulcerative colitis, whilst ASCA is more commonly associated with Crohn's.
• Abdominal imaging: essential in the initial assessment of patients with suspected ulcerative colitis, to exclude toxic dilatation and perforation. May also help to assess disease extent or identify proximal constipation. In milder forms, ultrasound, CT, MRI and radionuclide scanning may all be contributory.
• Sigmoidoscopy and rectal biopsy: for all patients presenting with diarrhoea, rigid sigmoidoscopy should be performed unless there are immediate plans to perform flexible sigmoidoscopy.
• Colonoscopy:
  • This is usually preferable to flexible sigmoidoscopy, because the extent of disease can be assessed but, in moderate-to-severe disease there is a higher risk of bowel perforation and flexible sigmoidoscopy is safer.
  • The extent of the disease is defined as the proximal margin of macroscopic inflammation, because this is most clearly related to the risk of complications, including dilatation and cancer.
  • It is advisable that patients with ulcerative colitis should have a colonoscopy after 8-10 years to re-evaluate disease extent.

Disease severity in ulcerative colitis^1,3

Management depends on disease activity and extent:

• Mild:
  • Fewer than four stools daily, with or without blood.
  • No systemic disturbance.
  • Normal ESR and CRP.
• Moderate: four to six stools a day with minimal systemic disturbance.
• Severe: more than six stools a day containing blood and evidence of systemic disturbance (fever, tachycardia, anaemia, or hypoalbuminaemia).

Disease activity can be evaluated using a simple clinical activity index, such as the Walmsley Index. Similar tools exist for paediatric patients (e.g. the Pediatric Ulcerative Colitis Activity Index).⁵

Indications for urgent hospital referral¹

• Patients with severe colitis should be admitted to hospital for assessment and treatment.
• Patients with moderate disease, who fail to respond to steroids within two weeks, should be admitted to hospital.
• Patients who respond partially to treatment should be seen urgently in the outpatient department and treated for refractory colitis.

Management^1,3,6

• Topical management is appropriate for some patients with active disease. This is usually the case for those with proctitis and often the case if the disease extends into the sigmoid.
• For those with more extensive disease, oral or parenteral therapy are the mainstays of treatment, although some of these patients may get additional benefit from topical therapy.
• Leukophoresis (extracorporeal removal of leukocytes from the blood) may be beneficial in carefully selected patients with ulcerative colitis. It is available in specialised centres as part of research trials.^7,8 A recent meta-analysis found that leukophoresis was more efficacious than conventional pharmacotherapy in improving response and remission rate.⁹
• Beware antimotility drugs (e.g. codeine, loperamide) and antispasmodic drugs, which may precipitate paralytic ileus and megacolon in active ulcerative colitis.

Drug treatments^1,3

• Aminosalicylates:
  • Mesalazine - 5-aminosalicylic acid (5-ASA) - is now the treatment of choice for induction and maintenance of remission of mild-to-moderate ulcerative colitis.¹⁰ Oral mesalazine is less effective than oral corticosteroids and so should be used as sole treatment only in mild attacks. Topical mesalazine is probably slightly more effective than topical corticosteroids.
  • Oral mesalazine is mostly used to maintain remission. Mesalazine also seems to help reduce the risk of colorectal cancer.
  • Modified once-daily mesalazine preparations and a multi-matrix oral formulation are now available for patients who have compliance problems.^11,12
  • The newer 5-ASA preparations olsalazine and balsalazide are inferior to sulfasalazine in maintenance therapy but have fewer adverse effects. Sulfasalazine has a higher incidence of side-effects compared with newer 5-ASA drugs but selected patients, e.g. those with a reactive arthropathy, may benefit.
  • Olsalazine has a higher incidence of diarrhoea in pancolitis and is best for patients with left-sided disease, or intolerance of other 5-ASAs.
• Corticosteroids:
  • Corticosteroids are used to induce remission in relapses of ulcerative colitis. They have no role in maintenance therapy.
  • Corticosteroids may be applied topically (suppositories, liquid or foam enemas), orally or intravenously (IV).
• Thiopurines:
  • Azathioprine and its active metabolite 6-mercaptopurine may be used when:
    • Patients are intolerant to corticosteroids.
    • Patients need two or more corticosteroid courses in a calendar year.
    • Disease relapses when the dose of prednisolone is less than 15 mg a day.
    • If disease relapses within six weeks of stopping steroids.
  • Azathioprine seems to be effective for at least five years and increasing the duration of treatment will keep patients in remission for longer.
• Ciclosporin:
  • This is an effective salvage therapy for patients with severe refractory colitis and it has a rapid onset of action.
  • It reduces the colectomy rate by 50% in the short term but its use is controversial because of toxicity (drug-associated mortality is about 3%) and the long-term failure rate.
• Infliximab:
  • Infliximab is effective in inducing clinical remission in patients with moderate-to-severe ulcerative colitis, whose disease is refractory to conventional treatment using corticosteroids and/or immunosuppressive agents.¹³
  • Infliximab is recommended as an option for the treatment of acute exacerbations of severely active ulcerative colitis only in patients in whom ciclosporin is contra-indicated or clinically inappropriate.¹⁴
  • Infliximab is not recommended for the treatment of subacute manifestations of moderately to severely active ulcerative colitis.¹⁵
• Stool bulking agents:
  • In left-sided disease, distal transit is rapid but proximal transit is slowed, which can result in proximal constipation.
  • Relief of proximal constipation by stool bulking agents or laxatives may help to induce remission in proctitis.

Active ulcerative colitis

• Suppositories for disease to the rectosigmoid junction and foam or liquid enemas for more proximal left-sided disease.
• In mild-to-moderate disease, topical mesalazine combined with oral mesalazine, olsalazine, or balsalazide daily, are effective first-line therapy. Topical mesalazine alone or oral mesalazine alone are effective but less effective than combination therapy. Topical corticosteroids are less effective than topical mesalazine and should be reserved as second-line therapy for patients who are intolerant of topical mesalazine.
• Proximal constipation with distal active colitis should be treated with stool bulking agents or laxatives. Antidiarrhoeal agents should be avoided, as they do not reduce stool frequency in colitis and increase the risk of toxic megacolon.
• Oral corticosteroids are indicated in mild disease that fails to respond to topical treatment and mesalazine, in moderate disease (e.g. patients with bloody diarrhoea), or when a prompt response is required. Patients should be treated with oral prednisolone 40 mg daily (or equivalent), with topical agents used as adjunctive therapy. Prednisolone should be reduced gradually according to severity and patient response, generally over a period of eight weeks.
• Patients with chronic active steroid-dependent disease should be treated with azathioprine or mercaptopurine.
• Ciclosporin may be effective for severe, steroid-refractory colitis.

Severe ulcerative colitis

• Patients who have failed to respond to maximal oral treatment with a combination of mesalazine and/or steroids with or without topical therapy, or those who present with severe disease, should be admitted for intensive IV therapy.
• Monitoring of pulse rate, stool frequency, CRP and plain abdominal radiograph help identify those who need colectomy.
• Acute-onset ulcerative colitis is sometimes difficult to distinguish from infective colitis but treatment with corticosteroids should not be delayed until stool microbiology results are available.
• Subcutaneous heparin to reduce the risk of thromboembolism.
• Nutritional support (by enteral or parenteral route) if the patient is malnourished.
• IV corticosteroids (hydrocortisone 400 mg/day or methylprednisolone 60 mg/day). There is no benefit from IV steroids beyond 7-10 days.
• Ciclosporin or infliximab may be useful to induce remission in steroid-resistant cases.
• Withdrawal of anticholinergic drugs, antidiarrhoeal agents, NSAID and opioid drugs, as continuing them risks colonic dilatation.
• Continuation of aminosalicylates once oral intake resumes, although these have not been studied in severe disease.
• Topical therapy (corticosteroids or mesalazine) if tolerated and retained, although there have been limited studies in acute severe disease.
• IV antibiotics only if infection is considered, or immediately before surgery.
• Objective re-evaluation on the third day of intensive treatment. A stool frequency of more than eight per day or CRP greater than 45 mg/L at three days predicts the need for surgery in 85% of cases. Consideration of colectomy or IV ciclosporin if there is no improvement during the first three days.
• Following induction of remission, oral ciclosporin for 3-6 months is appropriate.

Maintenance of remission

• Lifelong maintenance therapy is generally recommended for all patients, especially those with left-sided or extensive disease and those with distal disease who relapse more than once a year.
• Options include aminosalicylates, 6-mercaptopurine or azathioprine, Infliximab is also sometimes used.
• Remission is helped by the use of probiotics.
• Stopping medication may be appropriate for patients with distal disease who have been in remission for two years but there is evidence that maintenance therapy reduces the risk of colorectal cancer.

Surgical¹⁶

• Providing the condition is stable, the procedure of choice is ileal pouch-anal anastomosis (IPAA).
• In acute fulminant ulcerative colitis, subtotal colectomy leaving a long rectal stump is preferred. Removal of the rectum with creation of an IPAA can be performed at a later stage if anal continence is desired.
• Indications for colectomy:
  • Toxic megacolon; surgery should be performed within 24 hours unless the condition resolves.
  • Severe ulcerative colitis that fails to respond to corticosteroid therapy within 7 to 10 days.
  • Chronic persisting colitis in a non-acute setting on the grounds of poor therapeutic response and poor quality of life.
  • High-grade dysplasia or cancer.

Complications

• Colorectal cancer: the British Society of Gastroenterology recommends an initial colonoscopy ten years after diagnosis of ulcerative colitis, to assess severity. A risk assessment includes severity of disease, family history, presence of polyps and development of complications such as primary sclerosing cholangitis. Patients are then offered a colonoscopy at one, three or five years depending on their level of risk.¹⁷ The evidence base for this regime is not robust and the National Institute for Health and Clinical Excellence (NICE) recommends further research in this area.¹⁸
• Pouchitis: up to 45% of patients who undergo ileal pouch surgery for ulcerative colitis suffer from pouchitis. Metronidazole or ciprofloxacin for two weeks is the first- line therapy. Mesalazine or corticosteroids may be used in acute pouchitis if antibiotics are ineffective. Long-term, low-dose metronidazole or ciprofloxacin are potentially effective for chronic pouchitis.
• Post-ileal pouch-anal anastomosis (IPAA) complications include leakage and pelvic abscess.
• Toxic megacolon is a rare complication that can be triggered by hypokalaemia, opiates, anticholinergics and barium enemas. The colon becomes acutely dilated and patients are severely ill. IV fluids, IV steroids, antibiotics and IV ciclosporin are the mainstay of conservative treatment but total colectomy may be required.
• Management of extra-intestinal manifestations: those that are associated with active intestinal disease largely respond to therapy aimed at controlling disease activity, whereas those that occur whether disease is inactive or quiescent, run a course independent of therapy for intestinal disease.
• Osteoporosis: this is common, although the absolute fracture risk, contribution of steroids and role of prophylaxis remain a subject for debate.¹⁹
• Psychosocial and sexual problems may arise.²⁰

Prognosis¹

• With modern medical and surgical management, the disease now has a slight excess of mortality in the first two years after diagnosis but little subsequent difference from the normal population.
• However, a severe attack of ulcerative colitis is still a potentially life-threatening illness. Mortality is increased in the elderly and in those with complications (e.g. anaemia or sepsis).
• Toxic megacolon and colonic cancer are the most common causes of death.
• About 50% of patients with ulcerative colitis have a relapse in any year. An appreciable minority has frequently relapsing or chronic, continuous disease and, overall, 20-30% of patients with pancolitis require colectomy.
• After the first year, approximately 90% of patients are fully capable of work, although ulcerative colitis causes significant employment problems for a minority.

Document references

1. Basson M et al; Ulcerative Colitis, Medscape, May 2011
2. Umanskiy K, Fichera A; Health related quality of life in inflammatory bowel disease: the impact of World J Gastroenterol. 2010 Oct 28;16(40):5024-34. [abstract]
3. Ulcerative Colitis, Prodigy (June 2010)
4. Khan AN et al; Ulcerative Colitis Imaging, Medscape, Jul 2011
5. Turner D, Seow CH, Greenberg GR, et al; A systematic prospective comparison of noninvasive disease activity indices in Clin Gastroenterol Hepatol. 2009 Oct;7(10):1081-8. Epub 2009 Jul 1. [abstract]
6. Guidelines for the management of inflammatory bowel disease in adults, British Society of Gastroenterology (2011)
7. Leukapheresis for inflammatory bowel disease, NICE Interventional Procedure Guideline (2005)
8. Habermalz B, Sauerland S; Clinical Effectiveness of Selective Granulocyte, Monocyte Adsorptive Apheresis Dig Dis Sci. 2009 Jun 11. [abstract]
9. Zhu M, Xu X, Nie F, et al; The efficacy and safety of selective leukocytapheresis in the treatment of Int J Colorectal Dis. 2011 Aug;26(8):999-1007. Epub 2011 Apr 8. [abstract]
10. Oliveira L, Cohen RD; Maintaining remission in ulcerative colitis - role of once daily extended-release Drug Des Devel Ther. 2011 Feb 27;5:111-6. [abstract]
11. British National Formulary
12. Yang LP, McCormack PL; MMX(R) Mesalazine: a review of its use in the management of mild to moderate Drugs. 2011 Jan 22;71(2):221-35. doi: 10.2165/11205870-000000000-00000. [abstract]
13. Hoentjen F, Sakuraba A, Hanauer S; Update on the management of ulcerative colitis. Curr Gastroenterol Rep. 2011 Oct;13(5):475-85. [abstract]
14. Ulcerative colitis (acute exacerbations) - infliximab, NICE Technology Appraisal Guidance (December 2008); Infliximab for the treatment of acute exacerbations of ulcerative colitis
15. Colitis (ulcerative) - infliximab, NICE Technology Appraisal Guidance (April 2008); Infliximab for the sub-acute manifestations of ulcerative colitis
16. Adkins E et al; Surgical Treatment of Ulcerative Colitis, Medscape, Mar 2011
17. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups, British Society of Gastroenterology (May 2010 update from 2002)
18. Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn's disease or adenomas, NICE Clinical Guideline (March 2011)
19. Guidelines for Osteoporosis in Inflammatory Bowel Disease and Coeliac Disease, British Society of Gastroenterology (2007)
20. Ochsenkuhn T, D'Haens G; Current misunderstandings in the management of ulcerative colitis. Gut. 2011 Sep;60(9):1294-9. Epub 2011 Apr 19. [abstract]

Internet and further reading

• British Society of Gastroenterology
• Crohn's and Colitis UK
• Primary Care Society for Gastroenterology
• British Colostomy Association
• Sexual and Reproductive Health for Individuals with Inflammatory Bowel Disease, Faculty of Sexual and Reproductive Healthcare (2009)
• Service standards for the healthcare of people who have Inflammatory Bowel Disease, British Society of Paediatric Gastroenterology Hepatology and Nutrition (2009)
• Williams C, Panaccione R, Ghosh S, et al; Optimizing clinical use of mesalazine (5-aminosalicylic acid) in inflammatory Therap Adv Gastroenterol. 2011 Jul;4(4):237-48. [abstract]