Crohn's disease

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Crohn's disease is a chronic inflammatory disease that can involve any part of the digestive tract, from the mouth to the anus. It typically affects the caecum and/or the terminal ileum as well as demarcated areas of large bowel, with other areas of the bowel being relatively unaffected. It is often associated with auto-immune disorders outside the bowel, such as aphthous stomatitis and rheumatoid arthritis.

Crohn's disease should not be confused with a non-progressive and non-degenerative digestive disorder called irritable bowel syndrome (IBS), which is not an autoimmune disease. Ulcerative colitis is a sibling autoimmune disease to Crohn's but only impacts the colon while Crohn's can impact any part of the digestive tract. Furthermore, Crohn's tends to affect multiple layers of the bowel lining, which can lead to many additional and hard-to-treat complications.

Contents

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Symptoms

Crohn's patients typically suffer from abdominal pain, chronic diarrhea and disrupted digestion, which may make it difficult for sufferers, particularly in the acute phase of the disease, to eat and/or digest food. The inflammation can be extremely painful and debilitating. Other common complications of Crohn's include fistulas of the colon, hemorrhoids, lipid absorption problems, and anemia. Bleeding is seen in 20% cases, against 98% cases in ulcerative colitis. Rectal bleeding may be serious and persistent, leading to anemia. Bruising of the shins, varying fever symptoms, varying levels of pain, and psychological damage is seen in many cases. Children with Crohn's disease may suffer delayed development and stunted growth.

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Epidemiology

The disease typically first appears in young adults in their late teens and twenties, although it is not unknown for symptoms to first appear quite late in life. Additionally, there has been an increase in cases occurring in young children. Recent studies suggest that up to 30% of all newly diagnosed cases are in children and teens under the age of 18. Estimates suggest that up to 60,000 people in the UK (about 1 in 1200) and 1,000,000 Americans have the disease (around 1 in 300). Some ethnic groups (such as Ashkenazi Jews) have a significantly higher rate of prevalence than others. Increased rates of disease have also been noted in some families, leading to speculation of a possible genetic link (see below). Epidemiological research indicates that Crohn's belongs to the group of diseases of affluence. In other words, the incidence of the disease is much higher in industrialized countries than elsewhere. However, this finding may be associated with the fact that Crohn's symptoms are typically diagnosed over a long period of time, in order to establish a pattern; in countries where medical help is less available, it may be difficult to arrive at a diagnosis.

Smoking increases the risk of Crohn's disease. Some women find that their disease is exacerbated by taking oral contraceptives, while others find it can help keep their flare ups at bay.

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Causes

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Barrier problem and autoimmunity to the luminal flora

The efficacy of immunosuppression, as well as scanty reports of complete disease resolution after bone marrow transplant, is highly suggestive of an autoimmune pathogenesis. A definite epitope to which the autoimmunity is directed is unknown, which also hampers the search for a virus or other pathogen that could induce molecular mimicry.

Present evidence suggests that there is not a single causative antigen but that the response of the mucosal immune system is polyclonal. It is mostly directed against a multitude of bacterial, not dietary, antigens. This overreaction to the normal bacteria of the intestinal flora may be due (1) to a barrier problem of the epithelial lining of the gut or (2) to a disturbed regulation of the mucosal immune system. Multiple lines of recent evidence suggest that the deficient epithelial barrier may be due to relative lack of defensins, i.e. endogenous peptide antibiotics secreted by the small and large intestinal epithelium. This lack would then allow a slow bacterial invasion with the consequence of a secondary immune response. This hypothesis also allows us to explain the frequent finding of M. paratuberculosis in the Crohn´s mucosa discussed below. A molecular mechanism for a potential dysregulation has not yet been identified.

Since Crohn's disease is often found in families, it is likely that it has a genetic component. Studies have identified a gene named CARD15 (or NOD2) which is suspected to participate in the inflammatory process at the heart of Crohn's disease. While mutations or polymorphisms (common variations) in this gene do not directly cause the disease, they may help determine who is affected or how serious one's symptoms are. One study reported that 50% of patients with Crohn's disease carried one or more mutations in CARD15. Some mutations were associated with more severe cases or earlier age of onset. While a number of independent studies have reported the association of CARD15 with Crohn's disease, some populations like the Japanese do not have these mutations. Mutations in NOD2 have been linked to low levels of alpha defensins in Paneth cells of the small intestine. Further studies are in progress to delineate the contribution of this gene.

Both Crohn's disease and ulcerative colitis are chronic, they affect men and women approximately equally, and they are most common in northern Europe and North America. Approximately 20 percent of individuals with Crohn's disease have a blood relative with some form of IBD. The onset of Crohn disease is usually between the ages of 15 and 30 with a second smaller peak of incidence between the ages of 50 and 70. Over the past decade, several reports have noted an increase in the prevalence of Crohn disease in various geographic regions. Although there are many theories concerning the cause of Crohn's disease and ulcerative colitis, none have been proven. Since many of the symptoms of Crohn's disease and ulcerative colitis are similar, diagnosis is often difficult, time consuming, and invasive. Approximately 10-12 percent of cases are not initially classifiable and are referred to as "indeterminate colitis." Over time, about half of these patients are eventually diagnosed with CD or UC.

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Decreased immunity

Recent evidence suggests that the autoimmune hypothesis behind Crohn's disease may be incorrect. A new study (Feb 2006) by scientists at University College in London found that people with Crohn's disease encounter a lowered immune system response under several circumstances [1]. These circumstances included trauma to the rectum (via biopsy), trauma to the skin (via abrading the skin), and when killed bacteria are injected into the forearm.

When the bacteria were injected into the forearm, the Crohn's patients had less blood flow to the injection site than non-Crohn's patients. The authors theorize that correcting this decreased blood flow may improve the immune response to injury. Sildenafil (Viagra) is a medication which opens up blood vessels (also known as a vasodilator). When this drug was given to Crohn's patients, blood flow improved to the injection site. However, using sildenafil on a long-term basis may be detrimental due to its serious side effects, which may include strokes, vision loss, and life-threatening hypotension. (However, the more serious side effects occur primarily in patients with pre-existing cardiac conditions.) Moreover, it is still unknown whether Crohn's disease is actually alleviated by this treatment.

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Anti-Saccharomyces cerevisiae Antibodies (ASCA) IgG and IgA

Anti-Saccharomyces cerevisiae antibodies (ASCA) have been found to be significantly more prevalent in patients with Crohn disease compared to patients with ulcerative colitis or healthy controls. These antibodies, which can include antibodies in both the IgG and IgA classes, appear to be directed against mannose sequences in the cell wall mannan of Saccharomyces cerevisiae. The presence of IgG or IgA ASCA has been shown to have a high specificity for Crohn disease. However, the majority of Crohn´s patients do not exhibit this antibody, although when positive it may be helpful in differentiating Crohn disease from ulcerative colitis in some patients. A pathogenetic role of these anitbodies is unproven.

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Anti-Neutrophil Cytoplasmic Antibodies (ANCA) IgG

Anti-neutrophil cytoplasmic antibodies (ANCA) that demonstrate atypical perinuclear staining (atypical pANCA; classic perinuclear pattern on ethanol-fixed human neutrophils, but absent on formalin-fixed neutrophils) are found in 70 percent of patients with UC, but only 20 percent of patients with CD.

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OmpC IgA

The OmpC IgA assay is promoted by one laboratory as a way to detect patients with Crohn disease who are ASCA negative but none of these serum assays is part of the routine diagnostic workup in these patients.

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Mycobacterial infection

The disease has long been suspected of being due to a Mycobacterium because of the similarity of many features to human tuberculosis and veterinary Johne's Disease. Mycobacterium avium subspecies paratuberculosis (MAP), which causes Johne's disease in cattle, is a primary area of research for many scientists and doctors involved in Crohn's disease. MAP has been proven to affect both cattle and human hosts and is passed on through the mammary glands. Current pasteurization methods have proved ineffective in ridding dairy products of Mycobacterium Paratuberculosis. This remains a controversial area of research, although recent studies have lent more credence to the theory, and government agencies in some countries have begun investigations into the possibility.

Nearly all practicing physicians and many researchers are unwilling to accept that MAP is a primary cause of Crohn's. Dozens of studies have been done in which evidence of MAP infection could not be found in tissue and blood samples of Crohn's patients. However, other studies ([2]) have been performed which (with more stringent methodology) show that MAP was found in up to 90% of the Crohn's patients in the study. Mycobacteria are known to be fastidious, which means they are extremely difficult to grow in culture. Therefore, unless very stringent precautions are taken, cultures for mycobacteria can underestimate the presence of the bacterium.

For this reason, PCR is a more promising technique than culture. Researchers have identified an insertion sequence called IS900 that is unique to the MAP organism, and many studies have been performed using PCR to test for the presence of MAP. However, the problem with PCR is that it will detect dead or near-dead ("non viable") MAP organisms, so often times a combination of PCR and careful culture is needed to prove that MAP is present.

Researchers using PCR and careful culture have found that live MAP bacteria are present in significant numbers of Crohn's patients, and other studies using PCR and culture have shown that live MAP bacteria are present in significant percentages of pasteurized milk in the United States, the United Kingdom, and the Czech Republic.

Many experts in the field now suggest, however, that there is no single microbial species that causes Crohn's disease. More likely, Crohn's represents the loss of immunological tolerance to one's own gut bacteria or commensal microflora. For this reason, Crohn's is often considered a defect in the barrier function of the intestinal epithelium, combined with immune dysfunction arising in genetically susceptible individuals.

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Complications

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Short-term

The bowel shows segmental "hose pipe" thickening and shows full thickness chronic inflammation, giant cell granulomas, and fissures with acute inflammation. Fistula formation is quite common in Crohn's. Bowel obstruction is a known complication which may require surgical resection. Approximately 50% of surgical cases require additional surgery within five years because the disease tends to reappear at the site where the bowel was rejoined, and some patients eventually develop short bowel syndrome which makes it extremely difficult to digest food. For this reason, surgery is considered by many doctors only as a last resort in the treatment of Crohn's.

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Long-term risks

Some patients can be treated with the existing drugs quite effectively and can go into long-term remission, sufficient to allow the patient to lead a normal life. Patients are at somewhat larger risk of small bowel and colon cancers. The relative risk of small bowel cancer is high, but due to the very low prevalence of these cancers in the general population, overall risk remains very low. The risk is higher in the colon, and patients with long-standing colonic disease should have regular colonoscopies both to check for precancerous growths and to monitor the success of treatment. Overall, Crohn's disease does not seem to have as great a risk of malignancy compared to ulcerative colitis.

Crohn's disease has also been shown to carry a higher burden of osteoporosis, independent of steroid medications, with men having a higher risk than women [3].

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Treatment

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Medication

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Acute treatment (Steroids)

Steroids are often necessary in initial stages and during flare-ups, although long-term steroid therapy is discouraged because of its well-known side effects. Traditionally, Corticosteroids such as prednisone are used because they have the longest medical history of anti-inflammatory use. However, their side-effects are also the most severe, causing insulin resistance and frank diabetes, hypertension (high blood pressure), glaucoma, osteoporosis, severe psychological issues, and many other problems after long-term use.

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Chronic treatment (Steroid-sparing)

A well-established group of drugs, especially useful in mild-to-moderate disease, are salicylates - 5-ASA derivates - 5-aminosalicylic acid compounds such as sulfasalazine (Azulfidine ®, Salazopyrin ®), mesalamine (Pentasa®, Asacol®), olsalazine, and balsalazide. Immunomodulating drugs such as azathioprine, 6-mercaptopurine and methotrexate are given mainly in moderate-to-severe cases. Research trials are being conducted on treatment with drugs in the same family as thalidomide. Infliximab (brand name Remicade®) is given in patients with therapy-resistant or fistulating Crohn's. Adalimumab (brand name Humira®) has been used in patients who show allergic reaction or diminished response to infliximab.

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Surgery

Surgery (resection of parts of the bowel) is avoided, as this does not cure the disease - it can recur at any site in the digestive tract. 50% of all Crohn's patients eventually undergo one or more resections to control highly active disease. Most often, this is of the terminal ileum. In some cases of wide-spread intractable Crohn's colitis, removal of the colon and rectum (protocolectomy) is required. In these cases, the patient is left with an ileostomy.

According to the Crohn's and Colitis Foundation of America, patients who have had a resection have a 20% chance of recurrence of Crohn's after two years, increasing to approximately 50% after five years. Patients who have had a proctocolectomy with ileostomy have a recurrence rate of less than 20%. Crohn's most commonly recurs at the site of the anastomosis or ileostomy.

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Dietary

Paying close attention to diet can help reduce the number and severity of flare-ups for many sufferers. Patients are encouraged to follow a nutritious diet and limit any foods that seem to worsen symptoms. Individual reactions vary. Some foods commonly avoided by Crohn's patients are:

  • Dairy foods. Some people are lactose intolerant (unable to digest the sugar lactose, found in milk products). Taking lactase tablets or specially prepared dairy products may help. Note: Many lactose-intolerant patients are still able to eat yogurt with active cultures, which may even be helpful
  • Foods high in fiber, but because a high-fiber diet has other benefits, these foods might be avoided only during flare-ups.
  • Foods associated with inflammation (alcohol, hot spices, and caffeine).
  • Saturated fats, found in meat and dairy products. However some fats such as in fish oil may actually be helpful.
  • Products containing corn or gluten (those made from wheat, oats, barley, or triticale).
  • Common allergenic foods, such as soy, eggs, peanuts, tomatoes.
  • Gas-producing foods such as cabbage family vegetables (broccoli, cabbage, cauliflower and brussels sprouts), dried peas and lentils, onions and chives, peppers and carbonated drinks
  • Simple sugars,
  • Dried fruits or high-sugar fruits, such as grapes, watermelon, or pineapple.
  • Sorbitol (an artificial sweetener)

And some foods may also be beneficial:

  • Fluids to keep the body hydrated and prevent constipation
  • Fruits may be protective
  • A high protein diet with lean meats

Other advice:

  • Trying small frequent meals may also help.
  • There have also been some suggestions that prebiotics such as psyllium may help in the healing process. Furthermore, probiotics (live culture) may also be helpful in aiding recovery of the intestines.
  • Tamarind which is used extensively in India in many dishes may aggravate diarrhoea in Crohn's patients and especially post resection patients.
  • Those who are lactose intolerant may not want to increase their calcuim intake to reverse some 75% of the effects of Crohns. Consult your doctor for another lactose free solution.
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Helminthic therapy (Current research)

Helminthic therapy is a promising new treatment for Crohn's disease and Ulcerative Colitis which has shown great results in clinical trials. It argues that the absence of intestinal worms (due primarily to higher hygiene standards) from the human intestinal tract may cause the immune system, which is not evolutionary adapted to this condition, to over-react causing inflammation and other negative effects, and that reintroducing helminths through ingesting eggs of a certain species (which is not dangerous to humans) can help downregulate and normalize immune responses.

It is interesting to note that both the helminthic therapy and the fecal bacteriotherapy induce a characteristic TH2 white cell response in the diseased areas which seems to be the key in achieving and maintaining remission, and may prove to be of key significance in further research. If the theories behind these new treatments prove correct, they could also very elegantly explain the similarities, differences and reasons behind Crohn's disease and ulcerative colitis (one being induced by lack of certain helminth parasites in the bowel, the other by lack of certain bacteria).

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Stem cell therapy

Another promising therapy is Stem cell treatment. There have been reports of major improvements in some cases [4], and at least one clinical trial is currently recruiting patients [5].

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Differential diagnosis

Crohn's disease and ulcerative colitis are quite distinct diseases but in practice there are sometimes difficulties distinguishing between them, especially in mild cases - these are usually simply classified as "chronic inflammatory bowel disease" or "indeterminate colitis".

Crohn's disease is often initially misdiagnosed as food poisoning, gastroenteritis, appendicitis (due to the common locus of pain in the lower right-hand quadrant of the abdomen), and irritable bowel syndrome.

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History and name

Crohn's disease was first described by Giovanni Battista Morgagni (1682-1771), and subsequent cases were described by John Berg in 1898, and by Polish surgeon Antoni Leśniowski in 1904 (hence the use of the eponym "Leśniowski-Crohn disease" in Poland). Scottish physician T. Kennedy Dalziel described nine cases in 1913. Burrill Bernard Crohn, an American gastroenterologist, described fourteen cases in 1932, characterizing the disease as "Terminal ileitis: A new clinical entity"; the description was changed to "Regional ileitis" on publication. It is by virtue of alphabetization rather than contribution that Crohn's name appeared as first author: because this was the first time the condition was reported in a widely-read journal, and the disease has come to be known as Crohn's disease for reasons of publicity rather than precedence.

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Literature

  • Korzenik J. R., Dieckgraefe B. K. (2000). "Is Crohn's disease an immunodeficiency? A hypothesis suggesting possible early events in the pathogenesis of Crohn's disease." Dig Dis Sci 45(6), 1121-9.
  • Baumgart DC, Wiedenmann B, Dignass A: Biologische Therapie chronisch-entzündlicher Darmerkrankungen. Z Gastroenterol 2003; 41: 1017–1032.
  • Burgdorf W: Cutaneous manifestations of Crohn´s disease. Journal Am Acad Dermatol 1981; 5: 689.
    • Hautmanifestationen des Morbus Crohn
  • Cheifetz A, Smedley M, Martin S, Reiter M, Leone G, Mayer L, Plevy S: The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003; 98: 1315–1324.
  • D'Haens G, Van Deventer S, Van Hogezand R, Chalmers D, Kothe C, Baert F, Braakman T, Schaible T, Geboes K, Rutgeerts P: Endoscopic and histological healing with Infliximab antibodies in Crohn´s disease: a European multicenter trial. Gastroenterology 1999; 116: 1029–1034.
  • Ghosh S, Goldin E, Gordon FH et al.: Natalizumab for active Crohn´s disease. New Engl J Med 2003; 348: 24–32.
  • Grange F, Djialali-Bouzina F, Weiss AM, Polette A, Guillaume JC: Corticosteroid-resistant pyoderma gangraenosum associated with Crohn`s disease: rapid cure with infliximab. Dermatology 2002; 205: 278–280.
  • Herfarth H., Obermeier F., Andus T., Rogler G., Nikolaus S., Kuehbacher T., Schreiber S.: Improvement of arthritis and arthralgia after treatment with infliximab (Remicade) in a German prospective, open-label, multicenter trial in refractory Crohn´s disease. Am Journal of Gastroenterol 2002; 97: 2688–2690.
  • Petrelli, E. A., McKInley M., Troncale F. J.: Ocular manifestations of inflammatory bowel disease. Ann Ophthalmol 1982; 14: 356.
  • Podolsky D. K. : "Inflammatory Bowel Disease". New Engl J Med 2002; 347: 417–429.
  • Present D. H., Rutgeerts P, Targan S, Hanauer SB, Mayer L, van Hogezand RA, Podolsky DK, Sands BE, Braakman T., DeWoody K. L., Schaible TF, van Deventer SJ: Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340: 1398–1405.
  • Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, Kamm MA, Korzenik JR, Lashner B. A., Onken J. E., Rachmilewitz D., Rutgeerts P., Wild G., Wolf D. C., Marsters P. A., Travers S. B., Blank M. A., van Deventer S. J.: Infliximab maintenance therapy for fistulizing Crohn's disease. New England Journal Med 2004; 350: 876–885.
  • Targan SR, Hanauer S. B., van Deventer SJ, Mayer L., Present DH, Braakman T., DeWoody KL, Schaible TF, Rutgeerts PJ: A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn´s disease. Crohn´s Disease cA2 Study Group. New Engl J Med 1997; 337: 1029–1035.
  • Wehkamp,J., J.Harder et al.,..., Schroeder, J., Stange, E.F. 2004. NOD2 (CARD15) mutations in Crohn´s disease are associated with diminished mucosal a-defensin expression. Gut 53: 1658-1664.
  • Wehkamp, J., N.H. Salzman et al., ..., Stange, E.F., Bevins, C. L. 2005. "Reduced Paneth cell {alpha}-defensins in ileal Crohn's disease". PNAS 102: 18129-18134.
  • Weiner S. R., Clarke J., Taggart N., Utsinger P.D. : Rheumatic manifestations of inflammatory bowel disease. Semin Arthritis Rheum 1991; 20: 353.
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External links

  • Communities
    • CrohnsForum.com (An online community for those who suffer from Crohn's Disease)
Health science - Medicine - Gastroenterology - edit
Diseases of the esophagus - stomach
Halitosis | Nausea | Vomiting | GERD | Achalasia | Esophageal cancer | Esophageal varices | Peptic ulcer | Abdominal pain | Stomach cancer | Functional dyspepsia
Diseases of the liver - pancreas - gallbladder - biliary tree
Hepatitis | Cirrhosis | NASH | PBC | PSC | Budd-Chiari syndrome | Hepatocellular carcinoma | Acute pancreatitis | Chronic pancreatitis | Pancreatic cancer | Gallstones | Cholecystitis
Diseases of the small intestine
Peptic ulcer | Intussusception | Malabsorption (e.g. celiac disease, lactose intolerance, fructose malabsorption, Whipple's disease) | Lymphoma
Diseases of the colon
Diarrhea | Appendicitis | Diverticulitis | Diverticulosis | IBD (Crohn's disease, Ulcerative colitis) | Irritable bowel syndrome | Constipation | Colorectal cancer | Hirschsprung's disease | Pseudomembranous colitis
de:Morbus Crohn

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