Clinical Review: Ulcerative colitis

Section 1: Epidemiology and aetiology
Ulcerative colitis (UC) and Crohn's disease are the two principal forms of inflammatory bowel disease (IBD).

UC is characterised by chronic colonic inflammation and, in contrast to Crohn's disease, the inflammation is almost always mucosal and continuous, extending from the rectum proximally and confined to the colon.

It is characterised histologically by distortion of crypt architecture and in active disease, the presence of neutrophilic infiltration, cryptitis and crypt abscesses. Medical treatment can control the disease, but 30% of patients will require surgery.

Epidemiology
The UK has one of the highest prevalences of UC in the world with 120-200 per 100,000 individuals being affected and an annual incidence of approximately 10 per 100,000, with an equal sex distribution.

Although the disease can present in any age group, the peak age of onset is between 30 to 40 years of age with a second smaller peak between 60 and 70 years of age.¹ The majority of affected individuals have mild or moderate UC.

Aetiology

The cause of UC is unknown; it may be a primary immune disorder in an individual who is genetically susceptible, or caused by an undetermined trigger which induces a marked inflammatory response. Evidence suggests mucosal inflammation is due to production of inflammatory cytokines, mediated via an excessive T-helper response.

This may be triggered by environmental factors although no dietary factor has been identified. NSAIDs may precipitate IBD, and smoking cessation increases the risk of UC, with ex-smokers 1.7 times more likely to develop UC than people who have never smoked.²

Other possible triggers include a number of bacteria, viruses and mucosal barrier dysfunction allowing luminal organisms to interact with immune cells leading to an immune response,³ for example following infective colitis.

Although no gene has been conclusively shown to cause UC, the higher frequency of UC amongst firstand second degree relatives supports a genetic predisposition, with 10-20% of affected patients having a first degree relative with IBD.

Classification

The Montreal classification⁴ has categorised the extent of UC into three subgroups:

• Ulcerative proctitis: involvement limited to the rectum (50 per cent at presentation).
• Left-sided UC (distal UC): involvement limited to a proportion of the colorectum distal to the splenic flexure (30 per cent at presentation).
• Extensive UC (pancolitis): involvement extends proximal to the splenic flexure (20 per cent at presentation).

The same group also proposed a classification system for the severity of UC:

• Clinical remission (S0): asymptomatic.
• Mild UC (S1): ≤four bowel movements daily, absence of any systemic illness and normal inflammatory markers (ESR).
• Moderate UC (S2): >four bowel movements daily but with minimal signs of systemic toxicity.
• Severe UC (S3): passage of ≥six bloody stools per day, pulse rate ≥90bpm, temperature ≥37.5 degrees, haemoglobin <10.5g/dl and ESR ≥30mm/h.

Section 2: Making the diagnosis
Patients may present as an emergency, or with chronic relapsing symptoms. A history of bloody diarrhoea, mucus secretion and frequency of defecation should alert physicians to the possibility of UC. However, it is worth remembering that patients may present with constipation limited to rectum (ulcerative proctitis).

Other symptoms include urgency, urge incontinence, tenesmus and colicky lower abdominal pain.

In patients with more extensive disease, systemic and extra-alimentary manifestations may also be present. These include fever, weight loss, malaise, anaemia, malnutrition, growth disturbances, arthropathy (including polyarthritis, ankylosing spondylitis and sacroiliitis - 20%, eye symptoms (uveitis, episcleritis), dermatological conditions (erythema nodosum, pyoderma gangrenosum) and hepatic manifestations (non-alcoholic fatty liver disease, primary sclerosing cholangitis and cholangiocarcinoma). Furthermore, there is an increase risk of mood disorders.

Although there is an increasing incidence of colorectal cancer with chronic UC, patients rarely present initially with primary cancer.

About 5-10% of patients will present acutely with signs of shock, such as tachycardia, and an acutely distended tender abdomen.⁵

Investigations
Patients with suspected UC should initially have blood tests including FBC, U&Es, CRP or ESR, LFTs, ferritin, vitamin B12 and folate.

There is currently no evidence to support routine testing for serological markers, such as perinuclear antineutrophil cytoplasmic antibodies and anti-Saccharomyces cerevisiae antibody, despite their association with IBD.

Stool samples should be sent for microscopy, culture and sensitivity to exclude an infective cause of IBD. Faecal calprotectin may be used to detect colonic inflammation.

The investigation of choice is colonoscopy to allow visualisation of the colon, combined with histopathological examination of mucosal biopsies. This may confirm the diagnosis and differentiate it from other causes of IBD. It also allows disease classification based on the extent of involvement.

Other investigations include barium enema, CT, MRI and capsule endoscopy. Plain radiographs are not routinely performed but are vital in acute presentations to exclude the complications of acute severe colitis, namely toxic megacolon or perforation.

Section 3: Managing the condition
Collaborative management by gastroenterologists, surgeons, nurses, stoma therapists and nutritionists includes anti- inflammatories, nutritional and psychological support, symptomatic relief and surgery.

The extent and severity of the disease guides treatment.

Distal disease
Distal colon and rectal disease is managed medically, aiming to initially induce remission with steroids and then maintain remission with 5-aminosalicylic acid (5-ASA) agents. Topical prednisolone suppositories or enemas may be used.

Extensive disease
Prednisolone is used to induce remission, with 5-ASAs to control symptoms.

Steroid-sparing agents (azathioprine) are used for steroid-dependent patients or those unresponsive to steroids. A high protein and calorie diet with elemental supplementation is recommended.

Codeine phosphate and loperamide are used for diarrhoea.

Acute severe colitis
Initial medical management includes bed rest, fluid and electrolyte correction, transfusion and a high protein/calorie diet or total parenteral nutrition.

PPIs or H2 blockers are recommended. High-dose prednisolone is administered, with ciclosporin inducing remission in 50% of patients unresponsive to steroids, but with a high early relapse rate. If ciclosporin is contraindicated, infliximab can be considered as an alternative agent,⁶ although it is not recommended for routine use.

Surgery
Surgery plays a major role in acute severe UC when medical treatment has failed, or for complications, including toxic megacolon, perforation or bleeding. Early indicators of surgery are presentations within the first year of diagnosis, high-frequency bloody stools, low albumin, anaemia, weight loss and the number and severity of previous episodes.

Perforation carries a 40% mortality risk, falling to 2-8% if surgery occurs prior to perforation. Therefore patients are reviewed daily by gastroenterologists and surgeons, and surgery is offered with any deterioration or plateau in condition.

Thirty per cent of UC patients eventually undergo surgery,⁷ either in the acute setting or electively for failed medical treatment, steroid dependency, recurrent exacerbations, severe symptoms, extra-intestinal manifestations, growth retardation in children and malignant transformation.

Surgery is regarded as curative, but patients are at risk of infective and cardiovascular complications.⁸ Surgery consists of a total colectomy with four options of dealing with subsequent defecation: colectomy with ileostomy; colectomy and ileorectal anastomosis; proctocolectomy and permanent ileostomy; or restorative proctocolectomy and ileal reservoir (pouch).

The operation depends on the clinical condition, comorbidities, sex and age. The function of a pouch is to avoid a permanent ileostomy and is offered to younger patients as sphincters have to be adequate to avoid incontinence. Pouch surgery is associated with complications in 20-50% of cases, including pelvic sepsis, poor function, pouchitis and a 50% reduction in female fertility.

New developments
Given the benefits of infliximab, other biologic therapies, such as adhesion molecule inhibitors, auto-CD3 antibodies (visilizumab) and anti-interleukin-2 receptor antibodies (daclizumab), are all being reviewed.⁹ Probiotics and Escherichia coli Nissle 1917 have been shown to maintain remission in UC,¹⁰ including chronic pouchitis.

Section 4: Prognosis
There is a small increase in mortality in patients with UC compared with the general population, particularly in the elderly. Early reports had suggested that the hazard ratios for death is greatest in the first few years of the disease but more recent data suggest this risk has shifted to patients with more than a five-year history of UC.¹¹ This may be attributed to better management in the acute phase of the disease.

Follow up
About 30% of patients are regularly reviewed in outpatient departments.⁵ All UC patients are at an increased risk of developing colonic carcinoma and should therefore undergo screening colonoscopy.

The use of NSAIDs can trigger or worsen UC so patients should be advised to use paracetamol or opioid-based analgesia.

Patients wishing to conceive should be advised to do so during remission and continue their remission medications.Once pregnant, such patients should be jointly managed by a gastroenterologist and an obstetrician.

Cancer risk
There is a significant risk of developing colorectal cancer in chronic UC. At 10 years, the risk is 2%, rising to 8% at 20 years and 18% at 30 years.

Therefore such patients must undergo colonoscopic screening commencing 10 years from the onset of symptoms.

In addition to chronicity of symptoms current guidelines stratify risk based on extent of disease, activity, family history, previous polyps of areas of dysplasia and presence of primary sclerosing cholangitis. High-risk patients are scoped annually, intermediate-risk patients every three years and low-risk patients every five years.

During colonoscopy, systematically positioned random biopsies may be taken, or abnormal areas can be targeted with chromoscopy.

Section 5: Case study
John Smith, a 33-year-old accountant, visited his GP complaining of fresh rectal bleeding. Although John did open his bowels several times a day, he did not volunteer this information and as haemorrhoids were present on examination, this was considered the cause of his bleeding and dietary advice was given.

Several months later, John visited A&E as he had a further episode of rectal bleeding and abdominal pains.

Irritable bowel syndrome
Although he had lost some weight this was attributed to his new healthier, high-fibre diet, and he was given a diagnosis of irritable bowel syndrome which was exacerbating his haemorrhoids.

Several months later, he re-presented to his GP feeling lethargic with worsening abdominal pains, frequency of stools and painful joints. Initial blood tests revealed anaemia with mildly elevated inflammatory markers.

His GP organised a flexible sigmoidoscopy which revealed marked proctitis, with mucosal biopsies confirming UC.

Following a full colonoscopy he was managed by a gastroenterologist and his GP with oral mesalazine and occasional prednisolone enemas.

Over the next year, he had three acute exacerbations requiring oral prednisolone and two hospital admissions.

During the last admission his symptoms were not adequately managed with medical management and he developed toxic megacolon requiring an emergency subtotal colectomy and end ileostomy.

This was complicated by a pelvic collection requiring percutaneous drainage and a prolonged course of antibiotics.

He was discharged from hospital three weeks later with instructions to follow a high-calorie and protein diet.

Ileal pouch formation
Six months later, he had returned to his ideal weight and underwent an elective restorative ileal pouch formation and subsequent reversal of his ileostomy.

However, shortly after the closure of his ileostomy he developed urgency and frequency of liquid stool and subsequent endoscopy and biopsies confirmed pouchitis.

This was managed with 5-ASA and antibiotics for several months but eventually he opted for pouch excision and a permanent end ileostomy from which he made a full recovery.

Section 6: Evidence base
Clinical trials

• Rutgeerts P, Sandborn WJ, Feagan BG et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Eng J Med 2005; 353 (23): 2462-76.

The ACT 1 and ACT 2 (Acute UC Treatment) trials evaluated the use of infliximab in UC. They showed a clinically significant response in patients treated with infliximab compared with those on placebo.

• Jakobovits SL, Jewell DP, Travis S. Infliximab for the treatment of UC: outcomes in Oxford from 2000 to 2006. Aliment Pharmacol Ther 2007; 25: 1055-60.

Just over half the patients treated with infliximab required colectomy at a median of 140 days after the first infusion. Of those avoiding colectomy, only 17 per cent sustained a steroid-free remission.

Guidelines

• The British Society of Gastroenterology recently published an update of the Guidelines for the management of inflammatory bowel disease in adults.⁵
• The British Society of Paediatric Gastroenterology, Hepatology and Nutrition12 published Guidelines for IBD management in children.
• NICE. Infliximab for acute exacerbations of ulcerative colitis. TA163, London, NICE, 2008.
• NICE. Infliximab for subacute manifestations of ulcerative colitis. TA140, London, NICE, 2008.
• NICE. Colonoscopic surveillance for prevention of colorectal cancer in people with ulcerative colitis, Crohn's disease or adenoma. CG118, London, NICE, 2011.

Key text

• Nicholls RJ, Tekkis PP. Ulcerative Colitis. In: Philips RKS. Colorectal surgery: A companion to specialist surgical practice (fourth edition). Elsevier Health Sciences.

Online

• A clear and comprehensive information sheet for patients and families. www.bsg.org.uk/patients/patients/general/ulcerative-colitis.html
• Crohn's and Colitis UK provide patient information sheets. www.nacc.org.uk/content/services/infoSheets.asp
• Patient-centred website on all aspects of UC with links to support groups for patients. www.ulcerativecolitis.org.uk

Click here to take a test on this article and claim a certificate on MIMS Learning

References
1. Cosnes J, Gower-Rousseau C, Seksik P et al. Gastroenterology 2011; 140(6): 1785-94.

2. Hanauer SB. Inflamm Bowel Dis 2006; 12: S3-S9.

3. Kucharzik T, Masser C, Lugering A et al. Inflamm Bowel Dis 2006; 12: 1068-83.

4. Satsangi J, Silverberg MS, Vermeire S et al. Gut 2006; 55: 749-53.

5. Mowat C, Cole A, Windsor A et al. Gut 2011; 60: 571-607.

6. NICE. Infliximab for acute exacerbations of ulcerative colitis. TA163. London, NICE, 2008.

7. Bernstein C, Fried M, Krabshuis J et al. Inflamm Bowel Dis 2010; 16: 112-24.

8. Winther K, Jess T, Langholz E et al. Gastroenterology 2003; 125: 1576-82.

9. D'Haens G, Daperno M. Curr Gastroenterol Rep 2006; 8: 506-12.

10. Schultz M. Inflamm Bowel Dis 2008; 14: 1012e18.

11. Card T, Hubbard R, Logan R. Gastroenterology 2003; 125: 1583-90.

12. Sandhu B, Fell J, Beattie R et al. J Pediatr Gastroenterol Nutr 2010; 50(1): S1-S13.

Visit the GP Curriculum Centre for hundreds of articles linked to key topics in the RCGP curriculum