Crohn's disease

Crohn's disease is a disorder of unknown aetiology that is characterised pathologically by involvement of all bowel wall layers in a chronic inflammatory process with non-caseating granulomas. The granulomatous inflammation most frequently affects the terminal ileum but it may affect any part of the gastrointestinal tract and frequently affected areas are in discontinuity. There is a tendency to form fistulae. Epidemiology annual incidence in the UK is approximately 5/100,000. prevalence is 30-50 per 100,000. women more affected than men most commonly affected age group is between 15 and 35 years. There is also a second peak in the elderly. familial clustering and involves ulcerative colitis as well as Crohn's disease. more common in smokers than non-smokers (4:1). most common site of disease is the terminal ileum. Aetiology The cause of Crohn's disease is unknown. Several factors have been suggested: genetic - in up to 20% of patients with Crohn's disease there is another family member affected by Crohn's or ulcerative colitis. There is a weak association with HLA-DR1 and DRQ5 in California, USA smoking - increased risk of Crohn's infective organism - the following are suggestions, none are proven: o Mycobacterium paratuberculosis causes a granulomatous inflammation in the small intestine of cattle o persistence of measles virus; those born at the time of measles epidemics seem to be at higher risk diet - low intake of fibre from fruit and vegetables has been associated with the development of Crohn's immune mechanisms - may be a down-regulating of the normal mucosal immune response in Crohn's

Pathological features Macroscopically in Crohn's disease there may be a swollen, reddened and rubbery bowel with: skip lesions - discontinuous sites of pathology along the gastrointestinal tract cobblestone ulceration; a result of apthous ulceration progressing to oedema and nodular thickening

lead pipe thickening - thickened, stiff bowel narrowed lumen strictures 'rose-thorn' narrow-mouthed ulcers which lead to fistulae fistulae, often between adherent bowel and/or bladder, vagina, other abdominal organs or the abdominal wall mesenteric fat covering serosa enlarged mesenteric nodes

Microscopically, there is: non-caseating granulomas - not always present transmural inflammation and lymphocyte infiltration Crohn's disease may involve any part of the bowel from the mouth to the anus: the terminal ileum is involved in nearly 50% of cases jejunoileitis is also seen, but most ileal inflammation usually ends abruptly at the ileocaecal junction caecal and right colonic involvement is more common than lesions in the stomach and duodenum Clinical features This is a chronic, relapsing and remitting disease that has symptomatology dependent on the site of involvement of the GI tract. The commonest site at presentation is the terminal ileum and proximal colon. Various symptoms occur in most patients: abdominal pain weight loss diarrhoea Special note must be taken that: Crohn's disease may present with an acute onset of abdominal pain that may mimic acute appendicitis or yersinia ileitis. common features in active disease are lassitude, anorexia, malaise, and fever. in adolescents, a presentation with weight loss alone (without abdominal pain or diarrhoea) may be misdiagnosed as anorexia nervosa. Differential diagnosis The differential diagnosis of Crohn's disease includes: ulcerative colitis. In 10 to 20% of cases the two diseases cannot be differentiated. Distinguishing features include rectal involvement and bloody diarrhoea in UC, continuous disease pathology, but no strictures or fistulae. In UC there is a low plasma IL-6 in the active disease, and there is a stronger association with non-smokers. Also, UC patients are more often p-ANCA positive.

irritable bowel syndrome. This has no radiological abnormalities or weight loss. gastrointestinal malignancy. The most important cancers here are lymphoma, right colonic cancer and small bowel cancer. These patients might be expected to have night sweats and anaemia. Radiologically there may be a mass and metastases. ileal tuberculosis. This should be investigated for with a stool culture, and might be suspected in the immigrant population. Pathologically, after laparoscopic biopsy there will be caseating granulomas and mesenteric tubercules. anorexia nervosa coeliac disease - this will cause a malabsorptive picture chronic infection with Giardia, Yersinia and Campylobacter amyloidosis Behcet's disease Whipple's disease

Investigations Investigations in Crohn's disease are aimed at: making the diagnosis. Investigations to establish the diagnosis of suspected Crohn's disease include: o sigmoidoscopy and rectal biopsy o small bowel radiology: indicated if there are symptoms suggestive of small bowel involvement - diarrhoea, pain and weight loss. Crohn's colitis should be excluded by a subsequent barium enema. o barium enema: this is often more readily available than a colonoscopy. If positive, then small bowel radiology may be indicated to exclude other disease sites. o bloods: anaemia is common - generally iron deficiency anaemia, rarely B12 or folate deficiency ESR and platelet count are usually raised, albumin is usually lowered o stool examination: Cl difficile toxin assay, pathogens o biopsy: granulomata are characteristic o colonoscopy: assessment of strictures, colonic polyps, allow biopsy of terminal ileum, or multiple biopsies if a barium enema was equivocal. o laparotomy: often necessary to distinguish a Crohn's stricture from other causes of strictures, e.g. malignancy. Particularly relevant to the ileal form. monitoring disease activity. o clinical - active disease may present with anorexia, malaise, fever, weight loss and tachycardia. o blood tests - raised ESR, CRP or platelet count, or a low albumin or anaemia, occur in active disease. However, a normal

ESR and CRP do not imply inactive disease. o radiology - ulcers, fistulae, or disease at a new site on barium studies indicate activity. o endoscopy - ulcers. o ultrasound - may reveal thickened bowel loops, an inflammatory mass or abscess. Imaging o plain abdominal radiograph should be carried out - there may be signs of sacro-ileitis and skip lesions, although the latter are hard to see on the plain film. o small bowel contrast study there may be strictures, fistulae and ulceration - rose thorn ulcers - and cobblestone mucosal surfaces. Kantor's string sign - luminal narrowing of the ileum may be present, with clinical features of partial obstruction. o large bowel enema may demonstrate discontinuous skip lesions with normal bowel between, a ragged luminal outline due to ulceration, and loss of haustration. Other features may include rose thorn ulcers and pseudo-diverticulae caused by fibrotic stricturing. o CT scanning may show an inflammatory mass or an abscess. o labelled white cell scan may also be helpful in the demonstration of the extent of inflammation if barium radiology is equivocal. o ultrasound is useful in detection of abscesses. o radionucleotide scanning may be useful in detection of areas of disease activity. o MRI is the procedure of choice for the investigation of complex perianal disease. o in children the bone age may be two or more years less than the chronological age. endoscopy: both upper and lower GI endoscopy. o the disease is not continuous o the rectum is not always involved (50%) o fissures are often seen o skip lesions, cobblestone appearance of mucosa, and strictures are often present histology: full thickness inflammation, non-caseating granulomata, fissuring, ulceration, erosions.

Diagnosis Diagnosis of Crohn's disease is based on clinical, radiological and pathological evidence of the disease. It involves a careful history of chronic, remitting disease - the problems may take months or years to clinically manifest, barium studies of small and large bowel showing narrowing - Kantor's string sign of the terminal ileum - and skip lesions, stool culture, sigmoidoscopy and rectal biopsy, and colonoscopy with multiple biopsy. Crohn's disease confined to the colon may be difficult to discriminate from ulcerative colitis.

Complications/Associations The complications of Crohn's disease are best considered as local or general; the general complications include some of the extraintestinal manifestations of Crohn's disease. Local complications Possible local complications of Crohn's disease include: intestinal obstruction haemorrhage perforation with abscess stricture formation; common perianal abscess fistula fistulae to the bowel, bladder, vagina increased risk of malignancy but less than that of ulcerative colitis. General complications Common complications include: weight loss anaemia arthritis - large joints erythema nodosum ocular problems - conjunctivitis, episcleritis, iritis sacroiliitis - this is unrelated to HLA B27 gall stones, especially of the cholesterol type Less common: liver complications - primary sclerosing cholangitis, fatty liver, nonspecific hepatitis, pericholangitis. ankylosing spondylitis - related to HLA B27 pyoderma gangrenosum carcinoma of the bile ducts and primary sclerosing cholangitis - much less common than in ulcerative colitis renal complications - ureteric stricture, stones, right hydronephrosis, nephropathy (oxalate, amyloid). nutritional deficiency - osteomalacia, weakness (potassium, magnesium, vitamin D), lassitude (vitamin B12, folate, iron), rashes (zinc, niacin), alteration of taste (zinc). systemic amyloidosis - more common in Crohn's than UC reduced fertility Management There is no medical or surgical cure for Crohn's disease. If the symptoms are due to inflammation then they generally respond to medical measures. Surgical intervention is usually required when symptoms are due to strictures.

Medical management The medical management of Crohn's disease is difficult. The general management principles are outlined in management of inflammatory bowel disease. aminosalicylates corticosteroids - used in acute disease steroid-sparing agents metronidazole cholestyramine elemental diet anti-TNF-alpha agents There is clear evidence that stopping smoking reduces the risk of recurrence Surgical management Surgical intervention is limited in Crohn's disease because: the whole alimentary tract may be affected from mouth to anus the disease is often active at more than one site Consequently, there is a high incidence of postoperative complications following surgery, and a concept of minimal surgical intervention has thus been reached. Indications for surgery in Crohn's disease include: persistent ill-health with intractable disease despite medical management retardation of physical and sexual development in children intestinal obstruction that does not respond to medical therapy toxic dilatation of the colon perforation, external fistula or abscess formation periureteric inflammation causing ureteric obstruction suspicion of carcinomatous change Types pf operations ideally resection with primary reanastomosis bypass obstruction, e.g. duodenum stricturoplasty in patients at risk of developing short bowel syndrome extensive colonic involvement may require panproctocolectomy There is a 30-50% recurrence rate mostly at the neoterminal ileum; however, patients are still palliated well and not all require reoperation. Surgical procedures should be covered with corticosteroids.

Prognosis most patients have a chronic intermittent disease course, while 13%

have an unremitting disease course and 10% have a prolonged remission less than half require corticosteroids at any point during any given year, approximately 10% are treated with corticosteroids and 30% are treated with 5-aminosalicylates up to 57% of patients require at least one surgical resection about one tenth of patients have prolonged remission nearly 75% of patients have a chronic intermittent course, and about one eighth have an unremitting course if the patient has both small and large bowel disease then about 70% will require surgical intervention. The atypical form of Crohn's is an acute ileitis. This, unlike other forms of Crohn's, does not recur and may represent a completely different disease. The excess mortality in patients with Crohn's disease is approximately double that of the general population. This is due to the complications of active disease.

Ulcerative Colitis
Ulcerative colitis is a chronic disease of unknown aetiology in which a part or the whole of the mucosa of the large bowel becomes diffusely inflamed and may ulcerate, as a result of which the patient suffers from diarrhoea which may be bloody. It is characterised by exacerbations and remissions. The highest incidence of this disease is in adulthood, although it may occur in childhood. The cause of ulcerative colitis is unknown but genetic, immunological, dietary, and psychological factors have all been implicated. Epidemiology This condition may occur at any time from early childhood to late adulthood. There is an annual incidence of 5-8/100,000 in most communities of Celtic and Anglo-Saxon origin in north-western Europe, North America and New Zealand. The prevalence of symptomatic disease in north-western Europe is 70-150/100,000. This disease is very uncommon in Asia and Africa. As in Crohn's disease, familial clustering may be seen. Pathological features Ulcerative colitis primarily affects the mucosa and the submucosa, with inflammatory cell infiltrate, crypt abscess and ulcer formation. Goblet cells are few in number and frequently depleted of mucus. Redundant mucosa between ulcers form pseudopolyps, and the mucosa is friable and bleeding easily on contact. There are no skip lesions. The rectosigmoid is most commonly involved with 50% of patients having total colonic involvement. Chronic disease causes shortening and thickening of the bowel wall with haustral loss. Clinical features Ulcerative colitis may be fulminant, chronic, or relapsing. The patient may present dehydrated and/or toxic. Symptoms include: number of stools may vary from 1 or 2 to 20 or 30 per day diarrhoea, sometimes bloody; mild abdominal pain in the left iliac fossa; fever; weight loss if this condition occurs in infancy or childhood, then the presentation may be

of failure to thrive or failure to progress normally into puberty in fulminating disease the presentation may be of abdominal distension, catastrophic diarrhoea, fever and collapse

Signs may be as follows: pallor, dehydration, mouth ulcers, abdominal tenderness. Associated conditions include: erythema nodosum pyoderma gangrenosum uveitis arthritis Severity The severity of ulcerative colitis can be assessed on the basis of: bowel frequency - less than four motions per day is considered mild, more than six is severe. rectal bleeding temperature - patients with mild disease are apyrexial, those with severe disease may be higher than 37.8 C. haemoglobin of less than 10.5 is considered severe, greater than 11 is mild ESR of less than 30mm per hour is mild, greater than this is severe tachycardia is related to severity low albumin - below 30g per litre implies severe disease Differential diagnosis The differential diagnosis is influenced by the presentation, a principal factor being the age. Crohn's disease infective colitis is often a cause of one episode of colitis which is mislabelled as ulcerative colitis e.g. salmonellosis, shigellosis, Campylobacter, amoebiasis. In the immunosuppressed patient then one must consider opportunistic infections e.g. cytomegalovirus, herpes virus, Cryptosporidium, Mycobacterium avium intracellulare. colonic carcinoma, adenoma - diagnosed on endoscopy, particularly important in the elderly diverticulitis - not in childhood irritable bowel disease, which would tend to occur in the young, and has early morning explosiveness, not tending to be bothered at night. ischaemic colitis - these patients may have a history of vascular disease with sudden onset of pain, and thumb printing on plain abdominal radiography or barium enema. It does not occur in childhood. post-radiation colitis, the diagnosis of which is based on the history Investigations FBC - anaemia due to blood loss; leukocytosis ESR - increased; correlates with active disease CRP - raised; but less so than in Crohn's disease biochemistry - in active disease, biochemical abnormalities may include hypokalaemia, hyponatraemia, hypomagnesaemia, hypocalcaemia, and hyoalbuminaemia. Abnormal LFTs due to associated chronic active hepatitis increased ALT - or sclerosing cholangitis - increased alkaline phosphatase ANCA - found in HLA-DR2 associated form of ulcerative colitis

Radiology: plain abdominal x-ray - excludes toxic dilatation, which is more than 5.5 cm in diameter in adults barium enema: o diagnosis of extent and severity of the disease o procedure is contraindicated in those patients at risk of a toxic dilatation rectal biopsy - taken at sigmoidoscopy colonoscopy - this is contraindicated in those patients at risk of toxic dilatation. Allows multiple biopsies to be taken throughout the colon and delineation of the extent and activity of the disease white cell scan - allows imaging in severe disease molecular biology - a high intensity of CD44v6 and v3 epitope expression on crypt epithelial cells in patients with UC has been noted. This observation may have diagnostic potential in distinguishing UC from Crohn's

Diagnosis Careful history and examination is, of course, very important for the diagnosis of ulcerative colitis. The hallmark is bloody diarrhoea with mucus, usually of gradual onset, but it can be abrupt. The diagnosis of ulcerative colitis is based on: exclusion of other causes of diarrhoea like bacillary or amoebic dysentry colonoscopy and biopsy - histological characteristics, and endoscopic features differentiation from Crohn's disease - this may be very difficult: o ANCA positivity associated with forms of ulcerative colitis o increased expression of CD44v6 and CD44v3 variants in the colonic mucosa of patients with ulcerative colitis has been described and may have diagnostic potential in differentiating ulcerative colitis and Crohn's disease. There is absence of CD44v6 expression from normal colonic mucosa, but CD44v6 and CD44v3 have been identified in colorectal tumours. Management There have been massive improvements in the management of ulcerative colitis in the past 40 or 50 years, as evidenced by the death rates in severe attacks: before 1952, 45% now, 1 to 2 % The management has been improved by: corticosteroids better understanding of fluid balance and electrolytes in severely ill patients better understanding of indicators of severity of the disease Surgical management Surgery is required in 20% of patients with ulcerative colitis. The quality of life after surgery is excellent and a colectomy eliminates the need for continuous medical therapy and the need for cancer surveillance. Most extraintestinal symptoms of UC will resolve after a colectomy. The exceptions to this are sclerosing cholangitis and arthritis. Note also that

growth retardation is reversed if a colectomy is performed before puberty. Indications With ulcerative colitis, emergency surgery is indicated for: haemorrhage perforation toxic megacolon severe flares which have failed course of high dose steroids, complete bowel rest and intravenous feeding development of colonic carcinoma Elective surgery is indicated for: intractable symptoms long-standing active disease which increases the risk of carcinoma Principles of surgery Removal of the entire large bowel, by definition, is curative in ulcerative colitis. Alternatives include a panproctocolectomy and terminal ileostomy, and total colectomy and ileo-rectal anastomosis. panproctocolectomy and terminal ileostomy: o the whole colon is removed from the caecum to the anus o this procedure necessitates the construction of a permanent ileostomy total colectomy and ileo-rectal anastomosis: o in this procedure the colon is removed but the rectal stump is left in situ. o the terminal ileum may be re-anastomosed to it, either at the initial operation or as a secondary procedure. o it is possible to fashion the terminal ileum into a pouch - Park's pouch - to form a reservoir above the rectal stump. There is a risk recurrence of disease in the rectal stump. Thus the rectal mucosa is first stripped and the pouch anastomosed to the dentate line.

Cancer surveillance in Ulcerative Colitis There is an increased risk of developing colorectal carcinoma in patients with UC. The risk of development of cancer is dependent on the duration and the extent of the disease. If the patient has a pancolitis then: after 10 years risk is 1 after 20 years risk is 13% after 30 years risk is 34% It is conjectured that neoplasms are preceded by initially mild and later severe dysplasia of the colonic epithelium. Surveillance in the form of colonoscopy with multiple biopsies every 18-24 months is designed to identify such premalignant changes.

Complications/Associations Local complications of ulcerative colitis include: haemorrhage malnutrition electrolyte imbalance toxic megacolon stricture formation - rare fistula formation - rare perforation increased risk of malignancy - lymphoma, carcinoma General: weight loss anaemia hypoproteinaemia arthropathy - tends to affect large weight-bearing joints liver associations: o primary sclerosing cholangitis o fatty liver o non-specific hepatitis o pericholangitis o chronic active hepatitis o bile duct carcinoma sacro-iliitis and ankylosing spondylitis pyoderma gangrenosum erythema nodosum anterior uveitis episcleritis carcinoma of the bile ducts - rare Note that gallstones are associated with Crohn's disease but not ulcerative colitis. Prognosis a colectomy is curative

70% of patients with untreated UC relapse annually there is a 1% risk of the development of colonic cancer if someone has the disease for 10 years; in most UK centres, patients with extensive UC of 10 years' duration are offered colonoscopy every 1-2 years in an effort to prevent colonic cancer by taking multiple biopsies to look for mucosal dysplasia and to offer colectomy if appropriate, or to detect cancer at a curable stage there is a substantial variation in severity, extent and responsiveness, together with extra-intestinal and multiple intestinal manifestations life-expectancy is similar to that of the general population patients with well-controlled distal UC can be followed up routinely in primary care (will require a blood count and liver function test every 6-12 months, and referral for colonoscopy at 8-10 years to reassess disease extent)