What is known today about the etiology of IBD (environmental factors, diet, etc.)?
Ulcerative colitis (UC) and Crohn disease (CD) constitute the two major idiopathic inflammatory bowel diseases (IBDs). Clinicians now recognize that there is a spectrum of IBDs, encompassing various types and degrees of intestinal inflammation that must be distinguished from inflammation caused by infections, drugs, ischemia, and radiation. UC and CD are the most common and best understood of these idiopathic diseases; their etiologies, however, remain elusive.
Epidemiology: UC and CD share most epidemiologic characteristics. These diseases are relatively common in developed countries and infrequent in countries with poor sanitation. In North America and Europe, the incidence is approximately 100 per 100,000 population. The diseases can affect persons of any age, but they are most common in the second and third decades. Males and females are affected equally. No dietary factor has been identified as yet, although case-control studies suggest an association with the ingestion of large amounts of unrefined sugar and possibly with unsaturated fats (essentially, the Western diet).
Etiology: No single etiologic infectious agent has been associated with UC or CD. In recent years, a chronic measles-like viral infection, infection with Listeria monocytogenes, and infection with atypical mycobacteria have been hypothetically linked to CD without sufficient confirmation.
There are two major etiologic clues. The first is the primary familial association of IBD, which suggests a genetic predisposition. Once a proband has been identified, risk of disease occurring in a second family member is approximately 20% (40% if the proband is a child.
The second etiologic clue is the relation between cigarette smoking and UC and CD. Cigarette smoking is known to decrease the risk of UC; however, smoking is strongly associated with CD. Cigarette smoking also influences the course of IBD. Ex-smokers with UC are more likely to have refractory disease and to require surgery than are patients who smoke and those who have never smoked. Conversely, cigarette smokers with CD are more likely to have disease that is refractory to medical therapy. In cigarette smokers, CD often recurs more rapidly after surgical resection than in nonsmokers. It has not been established that nicotine is the primary factor in the opposite associations of cigarette smoking with UC and CD. Nicotine (as delivered by a patch) appears to have a modest ameliorative effect in UC, although not as potent an effect as that provided by cigarette smoking.
What are the basic factors that mediate immune response in IBD?
Immune response in IBD is not fully understood; there is humoral-, cell-mediated immunity, cytokine immunity—as well as environmental, genetic, microbial factors.
| Component | UC | CD |
|---|---|---|
| ANCA, antineutrophil cytoplasmic antibodies. | ||
| Environmental factors | Beneficial effect of smoking | Detrimental effect of smoking |
| No beneficial effect of diet | Symptoms improved by selected diets | |
| Normal intestinal permeability in healthy relatives | Increased intestinal permeability in healthy relatives | |
| Genetic associations | Largely different from CD | Largely different from UC |
| Microbial agents | Limited role of bacterial flora | Important role of bacterial flora |
| No association with M. paratuberculosis | Association with M. paratuberculosis | |
| No association with measles virus | Some association with measles virus | |
| Humoral immunity | Prominent antibody secretion | Moderate antibody secretion |
| Evidence for autoimmunity | Limited evidence for autoimmunity | |
| Strong association with ANCA | Weak association with ANCA | |
| Cell-mediated Immunity | Prominent neutrophil infiltration in the mucosa | Prominent T-cell infiltration in the mucosa |
| Normal/hyporeactive T cells | Hyperreactive T cells | |
| Normal T-cell apoptosis (?) | Resistance of T cells to apoptosis (?) | |
| Cytokines and mediators | Prominent production of eicosanoids | Moderate production of eicosanoids |
| Th2-like profile | Th1-like profile | |
| Increased cytokine production limited to involved mucosa | Increased cytokine production in involved and uninvolved mucosa | |
What are the similarities and differences in clinical symptoms and signs in Crohn disease vs ulcerative colitis? The inflammation is usually mucosal in ulcerative colitis but transmural in Crohn disease. How does this help to explain some of the clinical findings?
Since the inflammation in Crohn disease extends through the full thickness of the bowel wall to involve the serosa, deep fissure ulcers can develop. Further development of these ulcers can lead to adhesions and the formation of a fistula tract connecting with other structures such as an adjoining loop of intestine, bladder, vagina, or perianal skin. Abscess formation may also result. Less commonly there may be perforation. Also as a result of the transmural inflammation, fibrosis of the bowel wall occurs which can produce fibrosing strictures and possible obstruction of the small bowel.
In ulcerative colitis, the inflammation is typically confined to the mucosa and the serosa is usually unaffected. Thus one does not usually see fissure ulcers, fistulas, adhesions, perianal or other abscesses, mural thickening, strictures, or obstruction in ulcerative colitis or the clinical complications resulting from them.
| Feature | Ulcerative Colitis | Crohn Disease | |
|---|---|---|---|
| Hanauer, S.B., Scientific American Medicine, "Inflammatory Bowel Diseases", June 2001. | |||
| History | Smoking status | Nonsmoker or ex-smoker | Smoker |
| Physical examination | Symptoms | Rectal bleeding, cramps | Diarrhea, abdominal pain, weight loss, nausea, vomiting |
| Signs | Normal perianal findings, no abdominal mass | Perianal skin tags, fistulas, abscesses; abdominal mass; clubbing of digits | |
| Laboratory tests | Endoscopy | Rectal involvement; continuous superficial inflammation; terminal ileum usually normal | Rectal sparing; local ulceration with normal intervening mucosa (skip lesions); terminal ileum inflammation |
| Radiology | Lead-pipe (ahaustral) colon | Focal, asymmetrical, transmural ulceration; strictures, inflammatory masses, and fistulas | |
| Histology | Diffuse, continuous, superficial inflammation; crypt architecture | Focal inflammation, aphthous ulcers, lymphoid aggregates, transmural inflammation, granulomas (15-30%) | |
| Serology | Elevated p-ANCA (60-80% of patients) | poor association with p-ANCA | |
What is the prognosis and the basic treatment options for patients with IBD?
The treatment of UC and CD is based on the location, extent, and severity of disease as well as on the prior response to therapy. Factors contributing to exacerbations of activity or refractoriness to therapy should be sought. These factors include concomitant medications (e.g., NSAIDs, antibiotics), intercurrent infections (e.g., C. difficile), changes in menstruation, and changes in diet or lifestyle (including changes in smoking habits). There are more similarities than differences in the treatment of UC and CD; however, those differences are vital.
Irritable bowel syndrome is common in the general population and is equally prevalent in patients with IBD. A dietary history is important in identifying aggravating foods contributing to digestive symptoms. Approximately one half of patients with IBD receive complementary therapies. (A careful review of the patient's use of vitamins, health foods, fiber, homeopathic agents, and herbs may help identify factors contributing to changes in bowel habits. Many patients with IBD suffer from concurrent irritable bowel syndrome. Although the usual stress of daily living does not affect the inflammatory activity of IBD, many patients report that stress precedes a worsening of symptoms. Antispasmodics, primarily anticholinergic agents (e.g., dicyclomine, clidinium bromide, hyoscyamine, propantheline, and belladonna alkaloids), treat cramping abdominal discomfort or symptoms of irritable bowel syndrome accompanying UC and CD. Similarly, antidiarrheal preparations (e.g., diphenoxylate, loperamide, and codeine) can be used to reduce the frequency of bowel movements and rectal urgency in patients with mild to moderate UC and CD. Antimotility agents should be avoided in severe or fulminant disease because of the risk of inducing toxic megacolon (Hanauer).
The general measures to control the symptoms of both diseases include correction of fluid--electrolyte imbalances, iron, folate, or vitamin B 12 supplementation as needed for the treatment of anemia; and dietary adjustments aimed at maintaining adequate nutrition. Total parenteral nutrition may be required for the short-term treatment of severe acute disease, but "bowel rest" and hyperalimentation are of dubious value in the long term.
In Ulcerative Colitis, corticosteroids are useful for inducing remissions or improvement in an acute attack, and they may be required for long-term management. However, the possible benefits of corticosteroids in the long term are offset by their many adverse side effects. Sulfasalazine is metabolized by colonic bacteria, releasing sulfapyridine and 5-aminosalicylate (5-ASA); the latter is believed to be the active compound. Sulfapyridine is absorbed systemically, which accounts for the side effects of sulfasalazine (e.g., headache, occasional megaloblastic anemia, skin rash)…. Because the relative risk for development of ulcerative colitis is greater in nonsmokers than in smokers (the opposite is true in Crohn disease), nicotine is being tried in the treatment of ulcerative colitis; some benefit has been reported, but additional research is needed.
There is no uniformly effective treatment available for Crohn disease. However, corticosteroids have documented efficacy in diminishing the activity of the disease process. Sulfasalazine has some effectiveness, especially in colonic Crohn disease, but is less effective than corticosteroids. Metronidazole may be at least as effective as sulfasalazine. When Crohn disease cannot be controlled by these medications, the immunosuppressive agent azathioprine and its metabolite 6-mercaptopurine are sometimes tried; their use can result in a reduction in the corticosteroid dose needed, but this advantage may be offset by their toxic effects (Schrier).
Patients with ulcerative colitis or Crohn disease have recurrent relapses and remissions throughout their lives. Patients with ulcerative proctitis have symptoms that are a nuisance but are easily managed. With proctitis alone, there is no risk of life-threatening complications or future development of malignancy. Patients with diffuse colitis have a more debilitating illness, but modern therapy is successful and there is no excess mortality over that of the general population. A total proctocolectomy cures ulcerative colitis. This operative procedure is generally recommended only (1) for patients with disease unresponsive to medical therapy and (2) in long-standing disease to prevent the development of malignancy. Patients with Crohn disease have a higher mortality rate than that of either the general population or patients with ulcerative colitis. (Rubin)