CROHNS DISEASE (REGIONAL ENTERITIS)
CD became widely recognised following the report in 1932 by Crohn, Ginzburg and Oppenheimer describing young adults with a chronic inflammatory disease of the ileum. It can affect any part of the gastrointestinal tract from the lips to the anal margin, but ileocolonic disease is the most common presentation.Epidemiology
It is most common in North America and northern Europe with an incidence of 5 per 100 000. This has increased over the last 30 years but is now thought to be levelling off. Prevalence rates as high as 56 per 100 000 have been reported in the UK. Over the last four decades, there seems to have been a rise in the incidence , which cannot be accounted for by increased diagnosis. It is slightly more common in women than in men, but is most commonly diagnosed in young patients between the ages of 25 and 40 years. There does, however, seem to be a second peak of incidence around the age of 70 years. Migration seems to increase the risk of developing CD as seen from the increased risk in migrant communities compared with their native countries.Figure 65.24 Ileostomy formation. Suturing the free extremity of the proximal ileum to the skin edges after eversion to form a spout (after Brooke).
Aetiology
Although CD has some features suggesting chronic infection, no causative organism has ever been found; similarities between CD and tuberculosis have focused attention on mycobacteria. Studies have found DNA of Mycobacterium paratuberculosis in the intestines of 60% of patients with CD as opposed to 10% of control subjects. However, no immunology reaction has been detected against this organism, and anti-tuberculosis treatment has no effect. Focal ischaemia has also been postulated as a causative factor, possibly originating from a vasculitis arising through an immunological process. A wide variety of foods has now been implicated, but none conclusively. Smoking increases the risk threefold, which is contrary to the protective effect seen in UC.Genetic factors are thought to play a part. About 10% of patients have a first-degree relative with the disease, and concordance has been shown to approach 50% in monozygotic twins. Inheritance is thought to involve multiple genes with low penetrance. The NOD2/CARD15 gene has excited some interest recently. Certain variants of this gene have been shown to have strong associations with CD.
There is an association with ankylosing spondylitis. As with UC, it is now believed that CD can predispose to cancer, although the incidence of malignant change is not nearly as high as in UC and is most manifest in the ileum.
Pathogenesis
As in UC, there is thought to be an increased permeability of the mucous membrane. This leads to increased passage of antigens, which are thought to induce a cell-mediated inflammatory response. This results in the release of cytokines, such as interleukin-2 and tumour necrosis factor, which coordinate local and systemic responses. In CD, there is thought to be a defect in suppressor T cells, which usually act to prevent escalation of the inflammatory process.Pathology
Ileal disease is the most common, accounting for 60% of cases; 30% of cases are limited to the large intestine, and the remainder are in patients with ileal disease alone or more proximal small bowel involvement. Anal lesions are common. CD of the mouth, oesophagus, stomach and duodenum is uncommon. Resection specimens show a fibrotic thickening of the intestinal wall with a narrow lumen (Fig. 65.26). There is usually dilated gut just proximal to the stricture and, in the strictured area, there are deep mucosal ulcerations with linear or snake-like patterns. Oedema in the mucosa between the ulcers gives rise to a cobblestone appearance. The transmural inflammation leads to adhesions, inflammatory masses with mesenteric abscesses and fistulae into adjacent organs. The serosa is usually opaque, there is thickening in the mesentery, and mesenteric lymph nodes are enlarged. The condition is discontinuous, with inflamed areas separated from normal intestine, so called skip lesions. Under the microscope, there are focal areas of chronic inflammation involving all layers of the intestinal wall. There are non-caseating giant cell granulomas, but these are only found in 60% of patients. They are most common in anorectal disease. The earliest mucosal lesions are discrete aphthous ulcers. Recent studies have also shown multifocal arterial occlusions in the muscularis propria.Figure 65.26 Crohns disease of the ileocaecal region showing typical thickening of the wall of the terminal ileum with narrowing of the lumen (courtesy of Dr B. Warren, John Radcliffe Hospital, Oxford, UK).
Clinical features
Presentation depends upon the area of involvement.Acute Crohns disease
Acute CD occurs in only 5% of cases. Symptoms and signs resemble those of acute appendicitis, but there is usually diarrhoea preceding the attack. Rarely, there could be a free perforation of the small intestine, resulting in a local or diffuse peritonitis. Acute colitis with or without toxic megacolon can occur in CD but is less common than in UC.
Chronic Crohns disease
There is often a history of mild diarrhoea extending over many months, occurring in bouts accompanied by intestinal colic. Patients may complain of pain, particularly in the right iliac fossa, and a tender mass may be palpable. Intermittent fevers, secondary anaemia and weight loss are common. A perianal abscess or fissure may be the first presenting feature of CD; the cause is often an infected anal crypt associated with concomitant diarrhea but, as the disease becomes chronic, specific fistulae resulting from the CD itself can develop. After months of repeated attacks with acute inflammation, the affected area of intestine begins to narrow with fibrosis, causing obstructive symptoms. Children developing the illness before puberty may have retarded growth and sexual development. With progression of the disease, adhesions and transmural fissuring, intra-abdominal abscesses and fistula tracts can develop.Enteroenteric fistulae can occur into adjacent small bowel loops or the pelvic colon, and enterovesical fistulae may cause repeated urinary tract infections and pneumaturia.
Enterocutaneous fistulae rarely occur spontaneously and usually follow previous surgery.
Anal disease
In the presence of active disease, the perianal skin appears bluish. Superficial ulcers with undermined edges are relatively painless and can heal with bridging of epithelium. Deep cavitating ulcers are usually found in the upper anal canal; they can be painful and cause perianal abscesses and fistulae, discharging around the anus and sometimes forwards into the genitalia. The most distressing feature of anal disease is sepsis from secondary abscesses and perianal fistulae. Remarkably, the rectal mucosa is often spared and may feel normal on rectal examination. If it is involved, however, it will feel thickened, nodular and irregular.Investigation
LaboratoryA full blood count needs to be performed to exclude anaemia. There is usually a fall in albumin, magnesium, zinc and selenium, especially in active disease. Protein levels that correspond to disease activity include C-reactive protein and orosomucoid.
Endoscopy
Sigmoidoscopic examination may be normal or show minimal involvement. However, ulceration in the anal canal will be readily seen.As a result of the discontinuous nature of CD, there will be areas of normal colon or rectum. In between these, there are areas of inflamed mucosa that are irregular and ulcerated, with a mucopurulent exudate. The earliest appearances are aphthoidlike ulcers surrounded by a rim of erythematous mucosa. These become larger and deeper with increasing severity of disease. In colonic CD, there may be stricturing, and it is important to exclude malignancy in these sites (Fig. 65.27). At the ileocolic anastomosis of a patient having had previous ileocaecal resection, recurrent disease is usually seen on the ileal side of the anastomosis.
Upper gastrointestinal symptoms may have to be investigated by way of upper gastrointestinal endoscopy, which may reveal deep longitudinal ulcers and cobblestone mucosa. Capsule endoscopy may also have a useful role in those with chronic gastrointestinal bleeding.
Imaging
Barium enema will show similar features to those of colonoscopy in the colon. The best investigation of the small intestine is small bowel enema (Fig. 65.28). This will show up areas of delay and dilatation. The involved areas tend to be narrowed, irregular and, sometimes, when a length of terminal ileum is involved, there may be the string sign of Kantor. Sinograms are useful in patients with enterocutaneous fistulae. CT scans are used in patients with fistulae and those with intra-abdominal abscesses and complex involvement (Fig. 65.29).Magnetic resonance imaging (MRI) has been shown to be useful in assessing perianal disease.
Phenotyping
The Vienna classification was introduced by the World Congress of Gastroenterology in 1998. This was born out of the observation that, following presentation, the location and behaviour of the CD varied. This has relevance in studies carrying out genetic analysis of CD as there are different sub-categories with varied disease progression. Points that are recorded at presentation include age of onset, disease site in the gut, behaviour and data such as sex, ethnic origin, family history of inflammatory bowel disease and extraintestinal manifestations.Figure 65.27 Colonic Crohns disease. Note the normal mucosa on either side of the inflammatory stricture (courtesy of Dr B. Warren, John Radcliffe Hospital, Oxford, UK).
Figure 65.28 Small bowel enema examination showing a narrowed terminal ileum involved with Crohns disease the string sign of Kantor.
Figure 65.29 Computerised tomography enteroclysis showing small bowel dilatation secondary to strictured terminal ileum involved with Crohns disease (courtesy of Dr H. Bungay, John Radcliffe Hospital,Oxford, UK).
Treatment
Medical therapy
Steroids
Steroids are the mainstay of treatment. These are effective in inducing remission in moderate to severe disease in 7080% of cases. Steroids can also be used as topical agents in the rectum with reduced systemic bioavailability, but long-term use causes adrenal suppression. They are better at inducing remission than mesalamine but has no role in maintenance. Patients suffering a relapse are treated with up to 40 mg of prednisolone orally daily, supplemented by 5-ASA compounds in those patients with colonic involvement, although there is some evidence that this may help small bowel disease as well. Meta-analysis has shown that aminosalicylates can be used after remission to reduce the absolute risk of recurrence.
Antibiotics
Those who have symptoms and signs of a mass or an abscess are also treated with antibiotics. Metronidazole is used, especially in perianal disease. Its mechanism is unknown and is thought to play a role in suppressing cell-mediated immunity. In a randomised controlled trial, it reduced disease activity in ileocolonic and colonic disease, but not small bowel disease.Immunomodulatory agents
Azathioprine is used for its additive and steroid-sparing effect and is now standard maintenance therapy. It is a purine analogue, which is metabolised to 6-mercaptopurine and works by inhibiting cell-mediated events. It may take up to 12 weeks to have an effect. Ciclosporin acts by inhibiting cell-mediated immunity. Short-course intravenous treatment is associated with 80% remission; however, there is relapse after completion of treatment.Monoclonal antibody
Infliximab, the murine chimeric monoclonal antibody directed towards tumour necrosis factor alpha, targets patients with severe, active disease who are refractory to conventional treatments and who are at high risk of surgical interventions. A placebo- controlled trial reported the effects of single-dose infliximab on induction of remission in CD. Response after 1 month was 65% in the CD group. This compared with 17% in the placebo group. After 3 months the effects were 41% and 12% respectively. With maintenance regimes, this benefit was still apparent after a year. Infliximab is also effective in the treatment of fistulae (treatment group had a 60% reduction in fistulae compared with 26% in the placebo group). This benefit is reduced after a year. Long-term safety issues have yet to be resolved. There is a potential risk of malignancy.Nutritional support
Nutritional support is essential. Severely malnourished people may require intravenous feeding or nasoenteric feeding regimens. Anaemia, hypoproteinaemia and electrolyte, vitamin and metabolic bone problems must all be addressed. It has been shown that parenteral nutrition can induce remission in up to 80% of patients, which is comparable to steroids, but there is no synergism or additive effect. However, relapse is high after a short duration (Summary box 65.6).
Summary box 65.6Principles of management of CD
Close liaison between physician and surgeon is crucialMedical therapy should always be considered as an alternative to surgery, although surgery should not be delayed when a clear indication for surgery exists
Patients must be optimised as far as possible prior to surgery, and this may require preoperative total parenteral nutrition
CD is a chronic relapsing disease with a high likelihood of reoperation; the surgeon must take every reasonable effort to preserve bowel length and sphincter function
Indications for surgery
Surgical resection will not cure CD. Surgery is therefore focused on the complications of the disease. As many of these indications for surgery may be relative, joint management by an aggressive physician and a conservative surgeon is thought to be ideal.
These complications include:
recurrent intestinal obstruction;
bleeding;
perforation;
failure of medical therapy;
intestinal fistula;
fulminant colitis;
malignant change;
perianal disease.
Surgery
In patients with active CD, prompt surgery is important when medical treatment fails. The main surgical principle is to preserve functional gut length and maintain gut function. Resection is kept to a minimum so as to deal with the local problem. The whole of the gastrointestinal tract has to be examined carefully at the time of laparotomy. If, on occasion, CD is diagnosed during the course of an operation for suspected appendicitis, the appendix should be removed. If the ileum is thick, rigid and pipe-like, senior help should be sought so that an ileocaecal resection can be carried out.
The course of the disease after surgery is unpredictable, but recurrence is common. It does not seem to be related to the presence of disease at the resection line. Recurrence rates vary from site to site, but the cumulative probability of recurrence requiring surgery for ileal disease is of the order of 20%, 40%, 60% and 80% at 5, 10, 15 and 20 years, respectively, after previous resection. Restorative operations have a higher incidence of recurrence than, for example, proctocolectomy and ileostomy. Preoperative factors that are imperative include adequate bowel preparation, deep venous thrombosis prophylaxis, steroid cover, nutritional support and consideration of stoma in those who are malnourished.
Ileocaecal resection is the usual procedure for ileocaecal disease with a primary anastomosis between the ileum and the ascending or transverse colon depending on the extent of the disease.
Segmental resection. Short segments of small or large bowel involvement can be treated by segmental resection. The usual indication is stricture.
Colectomy and ileorectal anastomosis. In patients with widespread colonic disease with rectal sparing and a normal anus. this can be a useful option.
Emergency colectomy. This accounts for 8% of operations for acute colonic disease. The indications are similar to those for UC. If medical treatment induces remission, then delayed surgery is sensible because of the high risk of recurrent active disease.
Laparoscopic surgery. Resections and diversion are safe in uncomplicated CD. This is coupled with extracorporeal anastomosis and results in small peri-umbilical incisions. The advantages include better cosmesis and early discharge.
Temporary loop ileostomy. This can be used either in patients with acute distal CD, allowing remission and later restoration of continuity, or in patients with severe perianal or rectal disease.
Proctocolectomy. Patients with colonic and anal disease failing to respond to medical treatment or defunction will eventually require a permanent ileostomy.
Strictureplasty. Multiple strictured areas of CD (Fig. 65.30) can be treated by a local widening procedure, strictureplasty, to avoid excessive small bowel resection (Fig. 65.31) (Lee).
Anal disease is usually treated conservatively by simple drainage of abscesses, placing setons around any fistulae and, occasionally in patients with inactive disease, primary repair of a rectovaginal or high fistula-in-ano could be attempted.
The differences between UC and CD are given in Summary box 65.7.
Summary box 65.7Differences between UC and CDUC affects the colon; CD can affect any part of the gastrointestinal tract, but particularly the small and large bowel
UC is a mucosal disease whereas CD affects the full thickness of the bowel wall
UC produces confluent disease in the colon and rectum whereas CD is characterised by skip lesions
CD more commonly causes stricturing and fistulation
Granulomas may be found on histology in CD but not in UC
CD is often associated with perianal disease whereas this is unusual in UC
CD affecting the terminal ileum may produce symptoms mimicking appendicitis, but this does not occur in UC
Resection of the colon and rectum cures the patient with UC, whereas recurrence is common after resection in CD
THE END
Printed By:
Haider Hashim
7th of December 2011