Crohn's disease (also known as regional enteritis) is a chronic,
episodic, inflammatory condition of the gastrointestinal tract characterized by transmural inflammation (affecting the entire wall of the
involved bowel) and skip lesions (areas of inflammation with areas of normal lining between). Crohn's disease is a type of
inflammatory bowel disease (IBD) and can affect any part of the
gastrointestinal tract from mouth to anus; as a result, the symptoms
of Crohn's disease vary between affected individuals. The main gastrointestinal symptoms are abdominal pain, diarrhea (which may be bloody) or constipation, and weight loss. Crohn's disease can also cause
complications outside of the gastrointestinal tract such as skin rashes, arthritis, and
inflammation of the eye.[1]
The disease was independently described in 1904 by Polish surgeon Antoni Lesniowski and in
1932 by American gastroenterologist Burrill
Bernard Crohn, for whom the disease was eponymized. Crohn, along with two colleagues, described a series of patients with
inflammation of the terminal ileum, the area most commonly affected by the
illness.[2] Crohn's disease affects between
400,000 and 600,000 people in North America.[3]
Prevalence estimates for Northern Europe have ranged from 27–48 per 100,000.[4] Crohn's disease often develops in the teenage years, though individuals
in their earlier years are also at increased risk.[1][5] There is a
genetic component to susceptibility with highest relative risk in siblings, affecting males and
females equally.
Although the cause of Crohn's disease is not known, it is believed to be an autoimmune
disease that is genetically linked. The condition occurs when the immune system contributes to damage of the
gastrointestinal tract by causing inflammation.
Unlike the other major type of IBD, ulcerative colitis, there is no known medical
or surgical cure for Crohn's disease.[6] Instead, a number of medical treatments are utilized with the goal of putting and keeping the disease
in remission. These include aminosalicylic acid tablets (commonly marketed as
"Pentasa"), steroid medications, immunomodulators (such as azathioprine, 6-MP, and methotrexate), and newer biological medications, such as infliximab and Abbott Laboratories' Humira.[7]
Classification
Crohn's disease almost invariably affects the gastrointestinal tract. As a result, most gastroenterologists classify the
disease by the affected areas. Ileocolic Crohn's disease, which affects both the ileum (the last part of the small intestine that connects to the
large intestine) and the large intestine, accounts for fifty percent of cases.
Crohn's ileitis, affecting the ileum only, accounts for thirty percent of cases, and Crohn's colitis,
affecting the large intestine, accounts for the remaining twenty percent of cases, and may be particularly difficult to
distinguish from ulcerative colitis. The disease can attack any part of the digestive tract, from mouth to anus. However, individuals affected by the disease rarely fall outside
these three classifications, being affected in other parts of the gastrointestinal tract such as the stomach and esophagus.[1] Crohn's disease may also be classified by the behaviour of disease as it progresses. This was
formalized in the Vienna classification of Crohn's disease.[8] There are three categories of disease presentation in Crohn's disease: stricturing, penetrating,
and inflammatory. Stricturing disease causes narrowing of the bowel which may lead to bowel obstruction or changes in the caliber of the feces.
Penetrating disease creates abnormal passageways (fistulae) between the bowel and other
structures such as the skin. Inflammatory disease (or non-stricturing, non-penetrating disease) causes inflammation
without causing strictures or fistulae.[8][9]
Symptoms
Endoscopy image of
colon showing
serpiginous ulcer,
a classic finding in Crohn's disease
Many people with Crohn's disease have symptoms for years prior to the diagnosis.[10] The usual onset is between 15 and 30 years of age, with no difference
between men and women. Because of the patchy nature of the gastrointestinal disease and the depth of tissue involvement, initial
symptoms can be more vague than with ulcerative colitis. People with Crohn's disease will go through periods of flare-ups and
remission.
- Gastrointestinal symptoms
Abdominal pain may be the initial symptom of Crohn's disease. The pain is commonly
cramp-like and may be relieved by defecation. It is often
accompanied by diarrhea, which may or may not be bloody, though constipation is not uncommon
especially in those who have had surgery. The nature of the diarrhea in Crohn's disease depends on the part of the small
intestine or colon that is involved. Ileitis typically results in large-volume watery feces. Colitis may result in a smaller
volume of feces of higher frequency. Fecal consistency may range from solid to watery. In severe cases, an individual may have
more than 20 bowel movements per day and may need to awaken at night to defecate.[1][5][7][11] Visible bleeding in
the feces is less common in Crohn's disease than in ulcerative colitis, but may be seen in the setting of Crohn's
colitis.[1] Bloody bowel movements are
typically intermittent, and may be bright or dark red in colour. In the setting of severe Crohn's colitis, bleeding may be
copious.[5] Flatus and bloating may also add to the intestinal discomfort.[5]
Symptoms caused by intestinal stenosis are also common in Crohn's disease. Abdominal pain is
often most severe in areas of the bowel with stenoses. In the setting of severe stenosis, vomiting and nausea may indicate the beginnings of small bowel obstruction.[5]
Crohn's disease may also be associated with primary sclerosing
cholangitis, a type of inflammation of the bile ducts.
Perianal discomfort may also be prominent in Crohn's disease. Itchiness or pain around the anus
may be suggestive of inflammation, fistulization or abscess
around the anal area[1] or anal fissure. Perianal skin tags are also common in Crohn's
disease.[12] Fecal
incontinence may accompany peri-anal Crohn's disease. At the opposite end of the gastrointestinal tract, the mouth may be
affected by non-healing sores (aphthous ulcers). Rarely, the esophagus, and stomach may be involved in Crohn's disease. These can cause
symptoms including difficulty swallowing (odynophagia), upper abdominal pain, and
vomiting.[13]
- Systemic symptoms
Crohn's disease, like many other chronic, inflammatory diseases, can cause a variety of systemic
symptoms.[1] Among children,
growth failure is common. Many children are first diagnosed with Crohn's disease based on
inability to maintain growth.[14] As Crohn's disease may manifest at the time of the growth spurt in puberty, up to 30% of children with Crohn's disease may have retardation of growth.[15] Fever may also be present, though fevers greater than 38.5 ˚C (101.3 ˚F) are uncommon unless there is a complication
such as an abscess[1] Among older individuals, Crohn's disease may manifest as weight loss. This is usually related
to decreased food intake, since individuals with intestinal symptoms from Crohn's disease often feel better when they do not eat
and might lose their appetite.[14] People
with extensive small intestine disease may also have malabsorption of carbohydrates or lipids, which can further exacerbate weight loss.[16]
- Extraintestinal symptoms
In addition to systemic and gastrointestinal involvement, Crohn's disease can affect many other organ systems.[17] Inflammation of the interior portion of the eye,
known as uveitis, can cause eye pain, especially when exposed to light (photophobia). Inflammation may also involve the white part of the eye (sclera), a condition called episcleritis. Both episcleritis and uveitis can
lead to loss of vision if untreated.
Crohn's disease is associated with a type of rheumatologic disease known as
seronegative spondyloarthropathy. This group of diseases is characterized by
inflammation of one or more joints (arthritis) or muscle
insertions (enthesitis). The arthritis can affect larger joints such as the knee or shoulder
or may exclusively involve the small joints of the hand and feet. The arthritis may also involve the spine, leading to
ankylosing spondylitis if the entire spine is involved or simply sacroiliitis if only the lower spine is involved. The symptoms of arthritis include painful, warm, swollen,
stiff joints and loss of joint mobility or function.
Crohn's disease may also involve the skin, blood, and endocrine system. One type of
skin manifestation, erythema nodosum, presents as red nodules usually appearing on the
shins. Erythema nodosum is due to inflammation of the underlying subcutaneous tissue and is characterized by septal
panniculitis. Another skin lesion, pyoderma
gangrenosum, is typically a painful ulcerating nodule. Crohn's disease also increases the risk of blood clots; painful
swelling of the lower legs can be a sign of deep venous thrombosis, while
difficulty breathing may be a result of pulmonary embolism. Autoimmune hemolytic anemia, a condition in which the immune system attacks the
red blood cells, is also more common in Crohn's disease and may cause fatigue, pallor,
and other symptoms common in anemia. Clubbing, a deformity of
the ends of the fingers, may also be a result of Crohn's disease. Finally, Crohn's disease may cause osteoporosis, or thinning of the bones. Individuals with osteoporosis are at increased risk of
bone fractures.[4]
Crohn's disease can also cause neurological complications (reportedly in up to 15% of patients).[18] The most common of these are seizures, stroke, myopathy, peripheral
neuropathy, headache and depression.[18]
Crohn's patients often also have issues with Small bowel bacterial
overgrowth syndrome, which has similar symptoms.
- Complications
Crohn's disease can lead to several mechanical complications within the intestines, including obstruction, fistulae, and
abscesses. Obstruction typically occurs from strictures or adhesions which narrow the lumen, blocking the passage of the
intestinal contents. Fistulae can develop between two loops of bowel, between the bowel and bladder, between the bowel and
vagina, and between the bowel and skin. Abscesses are walled off collections of infection,
which can occur in the abdomen or in the perianal area in Crohn's disease sufferers.
Crohn's disease also increases the risk of cancer in the area of inflammation. For example, individuals with Crohn's disease
involving the small bowel are at higher risk for small intestinal cancer. Similarly, people with Crohn's colitis have a relative risk of 5.6 for developing colon cancer.[19] Screening for colon cancer with colonoscopy is recommended for anyone who has had Crohn's colitis for eight years, or more.[20]
Individuals with Crohn's disease are at risk of malnutrition for many reasons, including
decreased food intake and malabsorption. The risk increases following resection of the
small bowel. Such individuals may require oral supplements to increase their caloric
intake, or in severe cases, total parenteral nutrition (TPN). Most people
with moderate or severe Crohn's disease are referred to a dietitian for assistance in
nutrition.[21]
Cause
Schematic of NOD2 CARD15 gene, which is associated with certain disease patterns in Crohn's disease
The exact cause of Crohn's disease is unknown. However, genetic and environmental factors have been invoked in the
pathogenesis of the disease. Mutations in the
CARD15 gene (also known as the NOD2 gene) are associated with Crohn's
disease[22] and with susceptibility to certain phenotypes
of disease location and activity.[23]
Recently, research has indicated that Crohn's disease has a strong genetic link. [1] In earlier studies, only two genes
were linked to Crohn's, scientists now believe there are over eight genes that show genetics play a crucial role in the disease,
although environmental factors also are involved. For example, smoking raises one's risk.
Many environmental factors have also been hypothesized as causes or risk factors for Crohn's disease. Diets high in sweet,
fatty or refined foods may play a role. A retrospective
Japanese study found that those diagnosed with Crohn's disease had higher intakes of sugar, fat, fish and shellfish than controls
prior to diagnosis.[24] A similar study in Israel also
found higher intakes of fats (especially chemically modified fats) and sucrose, with lower
intakes of fructose and fruits, water, potassium,
magnesium and vitamin C in the diets of Crohn's disease sufferers before diagnosis,[25] and cites three large European studies in which sugar intake
was significantly increased in people with Crohn's disease compared with controls.
Smoking has been shown to increase the risk of the return of active disease, or
"flares".[26] Methods of hormonal contraception have also shown an association with the development of Crohn's
disease.[27]
Abnormalities in the immune system have often been invoked as being causes of Crohn's disease. It has been hypothesized that
Crohn's disease involves augmentation of the Th1 of cytokine response in inflammation.[28]
The most recent gene to be implicated in Crohn's disease is ATG16L1, which may reduce the effectiveness of autophagy, and hinder the body's ability to attack invasive bacteria.[29]
A variety of pathogenic bacteria were initially suspected of being causative agents of Crohn's disease. However, the current
consensus is that a variety of microorganisms are simply taking advantage of their host's weakened mucosal layer and inability to
clear bacteria from the intestinal walls, both symptoms of the disease. [30] Some studies have linked Mycobacterium avium subsp. paratuberculosis to Crohn's
disease, in part because it causes a very similar disease, Johne's disease, in cattle.
[31] The mannose bearing
antigens, mannins, from yeast may also elicit pathogenic anti
saccharomyces cerevisiae antibodies.[32] Newer studies have linked specific strains of enteroadherent E. coli to the disease but failed to find evidence of contributions by other species. [33]
Pathophysiology
H and E section of
colectomy showing transmural inflammation.
At the time of colonoscopy, biopsies of the colon are
often taken in order to confirm the diagnosis. There are certain characteristic features of the pathology seen that point toward Crohn's disease. Crohn's disease shows a transmural pattern of
inflammation, meaning that the inflammation may span the entire depth of the intestinal
wall.[1] Grossly, ulceration is an outcome seen in highly active disease. There is usually an abrupt transition between unaffected
tissue and the ulcer. Under a microscope, biopsies of the affected colon may show mucosal inflammation. Transmural inflammation results in formation of lymphoid
aggregates throughout the wall of the colon. This inflammation is characterized by focal infiltration of neutrophils, a type of inflammatory cell, into the epithelium. This typically occurs in the area overlying lymphoid
aggregates. These neutrophils, along with mononuclear cells, may infiltrate into the
crypts leading to inflammation (crypititis) or abscess (crypt abscess).
Granulomas, aggregates of macrophage derivatives known as
giant cells, are found in 50% of cases and are most specific for Crohn's disease. The granulomas of Crohn's disease do not show
"caseation", a cheese-like appearance on microscopic examination that is characteristic of granulomas associated with infections
such as tuberculosis. Biopsies may also show chronic mucosal damage as evidenced by
blunting of the intestinal villi, atypical branching of the crypts, and change in the tissue type
(metaplasia). One example of such metaplasia, Paneth cell metaplasia, involves
development of Paneth cells (typically found in the small intestine) in other parts of the gastrointestinal system.[34]
Diagnosis
Endoscopic image of Crohn's colitis showing deep ulceration.
Crohn's disease can mimic
ulcerative colitis on endoscopy. This
endoscopic image is of Crohn's colitis showing diffuse loss of
mucosal architecture,
friability of mucosa in sigmoid colon and
exudate on wall, all of which can be found with ulcerative colitis.
The diagnosis of Crohn's disease can sometimes be challenging,[10] and a number of tests are often required to assist the physician in making the
diagnosis.[5] Sometimes even with all the tests the
Crohn's does not show itself. A colonoscopy has about a 70% chance of showing the disease and the rest of the tests go down in
percentage. Disease in the small bowel can not be seen through some of the regular tests; for example, a colonoscopy can't get
there.
- Endoscopy
A colonoscopy is the best test for making the diagnosis of Crohn's disease as it allows
direct visualization of the colon and the terminal ileum, identifying the pattern of
disease involvement. Occasionally, the colonoscope can travel past the terminal ileum but it varies from patient to patient.
During the procedure, the gastroenterologist can also perform a biopsy, taking small samples of tissue for laboratory analysis which may help confirm a diagnosis. As 30% of
Crohn's disease involves only the ileum,[1]
cannulation of the terminal ileum is required in making the diagnosis. Finding a patchy
distribution of disease, with involvement of the colon or ileum but not the rectum, is suggestive
of Crohn's disease, as are other endoscopic stigmata.[35]
Wireless capsule endoscopy is a technique where a small capsule with a built-in
camera is swallowed, the camera takes serial pictures of the entire gastrointestinal tract and is passed in the patient's faeces.
It has been used in the search for Crohn's disease in the small bowel, which cannot be reached with colonoscopy or
gastroscopy.[36]The utility of capsule
endoscopy for this, however, is still uncertain.[37]
- Radiologic tests
A small bowel follow-through may suggest the diagnosis of Crohn's disease and
is useful when the disease involves only the small intestine. Because colonoscopy and gastroscopy allow direct visualization of only the terminal ileum and beginning of the
duodenum, they cannot be used to evaluate the remainder of the small intestine. As a result, a
barium follow-through x-ray, wherein barium
sulfate suspension is ingested and fluoroscopic images of the bowel are taken over
time, is useful for looking for inflammation and narrowing of the small bowel.[36][38] Barium enemas, in which barium is inserted into the rectum and fluoroscopy used to image the bowel,
are rarely used in the work-up of Crohn's disease due to the advent of colonoscopy. They remain useful for identifying anatomical
abnormalities when strictures of the colon are too small for a colonoscope to pass through, or in the detection of colonic
fistulae.[39]
CT and MRI scans are useful
for evaluating the small bowel with enteroclysis protocols.[40]They are additionally useful for looking for intra-abdominal complications of
Crohn's disease such as abscesses, small bowel obstruction, or fistulae.[41] Magnetic resonance
imaging (MRI) are another option for imaging the small bowel as well as looking
for complications, though it is more expensive and less readily available[42]
- Blood tests
A complete blood count may reveal anemia, which
may be caused either by blood loss or vitamin B12 deficiency.
The latter may be seen with ileitis because vitamin B12 is absorbed in the ileum.[43] Erythrocyte sedimentation rate, or ESR, and C-reactive protein measurements can also be useful to gauge the degree of inflammation.[44] It is also true in patient with ilectomy done in response to
the complication. Another cause of anaemia is anaemia of chronic disease, characterized by its microcytic and hypochromic
anaemia. There are reasons in anaemia, including medication in treatment of inflammatory bowel disease like azathioprine can lead
to cytopenia and sulfasalazine can also result in folate malabsorption, etc. Testing for anti-Saccharomyces cerevisiae antibodies (ASCA) and anti-neutrophil cytoplasmic antibodies (ANCA) has been evaluated to identify
inflammatory diseases of the intestine[45] and to
differentiate Crohn's disease from ulcerative colitis.[46]
Comparison with ulcerative colitis
The most common disease that mimics the symptoms of Crohn's disease is ulcerative
colitis, as both are inflammatory bowel diseases that can affect the colon with
similar symptoms. It is important to differentiate these diseases, since the course of the diseases and treatments may be
different. In some cases, however, it may not be possible to tell the difference, in which case the disease is classified as
indeterminate colitis.[7][1][5]
Comparisons of various factors in Crohn's disease and ulcerative colitis
|
Crohn's disease |
Ulcerative colitis |
| Terminal ileum involvement |
Commonly |
Seldom |
| Colon involvement |
Usually |
Always |
| Rectum involvement |
Seldom |
Usually[47] |
| Involvement around the anus |
Common[48] |
Seldom |
| Bile duct involvement |
No increase in rate of primary sclerosing cholangitis |
Higher rate[49] |
| Distribution of Disease |
Patchy areas of inflammation |
Continuous area of inflammation[47] |
| Endoscopy |
Deep geographic and serpiginous (snake-like) ulcers |
Continuous ulcer |
| Depth of inflammation |
May be transmural, deep into tissues[48][1] |
Shallow, mucosal |
| Fistulae |
Common[48] |
Seldom |
| Stenosis |
Common |
Seldom |
| Autoimmune disease |
Widely regarded as an autoimmune disease |
No consensus |
| Cytokine response |
Associated with Th1 |
Vaguely associated with Th2 |
| Granulomas on biopsy |
Can have granulomas[48] |
Granulomas uncommon[47] |
| Surgical cure |
Often returns following removal of affected part |
Usually cured by removal of colon |
| Smoking |
Higher risk for smokers |
Lower risk for smokers[47] |
Treatment
-
Treatment is only needed for people exhibiting symptoms. The therapeutic approach to Crohn's disease is sequential: to treat
acute disease and then to maintain remission. Treatment initially involves the use of medications to treat any infection and
to reduce inflammation. This usually involves the use of aminosalicylate anti-inflammatory drugs and corticosteroids, and may
include antibiotics.
Once remission is induced, the goal of treatment becomes maintaining remission and avoiding flares. Because of side-effects,
the prolonged use of corticosteroids must be avoided. Although some people are able to maintain remission with aminosalicylates
alone, many require immunosuppressive drugs.[48]
Surgery may be required for complications such as obstructions, fistulas and/or abscesses, or
if the disease does not respond to drugs within a reasonable time. For patients with an obstruction due to a stricture, two
options for treatment are strictureplasty and resection of that portion of bowel. According to a retrospective review at the
Cleveland Clinic, there is no statistical significance between strictureplasty
alone versus strictureplasty and resection specifically in cases of duodenal involvement. In these cases, re-operation rates were
31% and 27%, respectively, indicating that strictureplasty is a safe and effective treatment for selected patients with duodenal
involvement.[50]
Prognosis
Crohn's disease is a chronic condition for which there is currently no cure. It is
characterized by periods of improvement followed by episodes when symptoms flare up. With treatment, most people achieve a
healthy height and weight, and the mortality rate for the disease is low. Crohn's disease is associated with an increased risk of
small bowel and colorectal carcinoma.[51]
Crohn's cannot be cured by surgery, though surgery does happen with blockages, whether partial or a full blockage occurs.
After the first surgery, the Crohn's usually shows up at the site of the resection though it can appear in other locations. After
a resection, scar tissue builds up which causes strictures. A stricture is when the intestines becomes too small to allow
excrement to pass through easily which can lead to a blockage. After the first resection, another resection may be necessary
within five years of the first surgery.
Due to one of the symptoms of the disease; that is, skip lesions (shown on imaging scan) that can appear anywhere from the
mouth to the anus, dietician follow up may be essential in patients receiving multiple surgical operations.[citation needed]
Many patients will have temporary stoma formations together with possible associated complications.[attribution needed]
Epidemiology
The incidence of Crohn's disease has been ascertained from population studies in Norway and
the United States and is similar at 6 to 7.1:100,000.[52][53]
Crohn's disease is more common in northern countries, and shows a higher preponderance in northern areas of the same
country.[54] The incidence of Crohn's disease in
North America is 6:100,000, and is thought to be similar in Europe, but lower in Asia and Africa.[52] It also has a higher incidence in Ashkenazi Jews.[7]
Crohn's disease has a bimodal distribution in incidence as a function of age: the disease tends to strike people in their teens and twenties,
and people in their fifties through seventies.[1][5] It is rare in
early childhood. There is no association with gender, social class or occupation.[citation needed] Parents, siblings or children of people with Crohn's disease are 3 to 20
times more likely to develop the disease.[55] Twin
studies show a concordance of greater than 55% for Crohn's disease.[56]
History
Inflammatory bowel diseases were described by Giovanni Battista Morgagni
(1682-1771), by Polish surgeon Antoni Leśniowski in 1904 (leading to the use of the eponym "Leśniowski-Crohn disease" in
Poland) and by Scottish physician T. Kennedy Dalziel in
1913.[57]
Burrill Bernard Crohn, an American gastroenterologist at New York City's Mount Sinai Hospital, described
fourteen cases in 1932, and submitted them to the American Medical
Association under the rubric of "Terminal ileitis: A new clinical entity". Later that year, he, along with colleagues Leon
Ginzburg and Gordon Oppenheimer published the case series as "Regional ileitis: a pathologic and clinical entity".[2]
See also
References
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- ^ a b Crohn BB, Ginzburg L, Oppenheimer GD. "Regional ileitis: a pathologic and
clinical entity." Mt Sinai J Med 2000 May;67(3):263-8. PMID 10828911
- ^ Loftus, E. V.; P. Schoenfeld,
W. J. Sandborn (January 2002). "The epidemiology and natural history of Crohn's disease in population-based patient cohorts from
North America: a systematic review". Alimen
