INTRODUCTION
A 22-year-old woman has had recurrent episodes of diarrhea, crampy abdominal pain, and slight fever over the last 2 years. At first the episodes, which usually last 1 or 2 weeks, were several months apart, but recently they have occurred more frequently. Other symptoms have included mild joint pain and sometimes red skin lesions. On at least one occasion, her stool has been guaiac-positive, indicating the presence of occult blood. Colonoscopy reveals several sharply delineated areas with thickening of the bowel wall and mucosal ulceration. Areas adjacent to these lesions appear normal. Biopsies of the affected areas show full-thickness inflammation of the bowel wall and several noncaseating granulomas.
· What is the most likely
diagnosis?
· What are the common
complications of this disease?
Summary: A 22-year-old woman has a 2-year history
of recurrent diarrhea, abdominal pain, slight fever, joint pain, and red skin
lesions. Colonoscopy reveals several sharply delineated areas with thickening of
the bowel wall and mucosal ulceration, which on biopsy show full-thickness
inflammation of the bowel wall and several noncaseating
granulomas.
· Most likely
diagnosis: Crohn disease.
· Common complications of
this disease: Malabsorption and malnutrition, fibrous strictures of the
intestine, and fistulae to other organs, such as from bowel to skin or bowel to
bladder.
CLINICAL
CORRELATION
Introduction
The patient's presentation is very characteristic for
inflammatory bowel disease, that is, a several-year history of diarrhea and
abdominal pain. Additionally, the colonoscopy revealing full-thickness
inflammation with noncaseating granulomas is consistent with Crohn disease.
Crohn disease is a chronic inflammatory condition that is ubiquitous in its
distribution in the gastrointestinal tract. It most commonly manifests in the
small intestine, in particular the terminal ileum. The disease exhibits
aggressive activity of the gastrointestinal immune system, but the exact cause
is unknown. Published studies in the United States report incidence rates that
vary between 1.2 and 8.8 per 100,000 population; the prevalence is 44 to 106 per
100,000. The condition is more common in the cold climates of the northeastern
United States than in the south. Those of Jewish ethnicity have a high
incidence. The disorder, which is slightly more common in females, has a bimodal
age distribution, peaking in the early twenties and again emerging in the
mid-sixties. Theories regarding pathogenesis have referred to genetics,
infection, autoimmune or allergic processes, thromboembolic disorders, and
dietary disorders.
Approach to
Inflammatory Bowel Disease
Discussion
The predominant symptoms of Crohn disease are
diarrhea, abdominal pain, and weight loss. These symptoms may be widely
variable, depending on the distribution of the inflammatory lesions in the
patient's intestines. The principal stimulus for diarrhea is the mucosal immune
response in association with cytokine release. If the colon is involved,
diarrhea may be more marked and tenesmus may occur. Abdominal pain
may be due to local inflammation or obstruction if it is experienced in the
central abdomen or right lower quadrant. Abscesses or fistulae also may
produce pain. Secondary causes of abdominal pain in relation to Crohn disease
are gallstones and renal colic. Malabsorption leading to weight
loss and failure to thrive may occur in children. Fat, protein, mineral, and
vitamin deficiencies may be associated with extensive or recurrent disease.
About one-third of patients develop perineal symptoms or signs such as anal
fistulae or fissures.
Nongastrointestinal symptoms of Crohn disease
involve the skin, joints, or eyes. Skin lesions include erythema
nodosum, pyoderma gangrenosa, aphthous stomatitis, and finger clubbing. The
rheumatologic manifestations often present as a large joint polyarthropathy
resembling ankylosing spondylitis or a small joint fleeting polyarthropathy that
is like rheumatoid arthritis. The human lymphocyte antigen B-27 (HLA-B27) may be
present. Inflammatory eye lesions are confined to the anterior chamber, such as
uveitis, iritis, episcleritis, and conjunctivitis. A chronic active
hepatitis may develop; more seriously, sclerosing cholangitis can
progress to cirrhosis. There is a predisposition to gallstones when
terminal ileal disease is present.
Physical
Examination
Physical examination may reveal a nutritional
deficiency. The extraintestinal manifestations may be apparent. Abdominal
examination may suggest partial bowel obstruction, an inflammatory mass,
focal areas of tenderness, or enterocutaneous fistulae. Perineal examination
may reveal fistulae or abscesses. Perianal skin tags with bluish
discoloration may be present. On rectal examination there may be a stricture, a
palpable ulcer, or perirectal abscesses. Bloody diarrhea may be detectable.
Clinical features compatible with anemia or hypoalbuminemia may be
present. Hypoalbuminemia may manifest with peripheral edema.
Approach to
Inflammatory Bowel Disease
Plain abdominal radiographs provide important
information in the acute presentation of symptoms, as they may demonstrate
intestinal obstruction or evidence of perforation. Biliary or renal calculi,
arthropathy, or osteoporosis also may be detected. Endoscopy of the lower and
upper gastrointestinal tract is used to identify disease and provide biopsy
evidence. Barium follow-through examination or small bowel enteroclysis may
demonstrate discrete lesions in the small intestine. Fistulograms are helpful to
surgeons by providing information about the site of the fistula and the presence
of obstruction or abscess cavity in association with it.
Computerized tomography is the mainstay in terms
of providing information about thickened loops of bowel, abscesses, and
fistulous tracts. Magnetic resonance imaging, including cholangiography, may be
helpful. Ultrasound may reveal thickened terminal ileum, abscesses, and evidence
of bilary tract disease. Ultrasound examination of the renal tract may reveal
obstruction or stone formation. Endoscopic ultrasound may be useful in assessing
bowel wall involvement and the extent of the disease process. Studies of bone
density may be required.
Endoscopy allows detailed examination of the
mucosa of the upper and lower intestines, with the added advantage of allowing
biopsies of abnormal areas to be taken. Capsule endoscopy is an innovation that
permits detailed photography of the small intestinal lumen. There may be
eletrolyte abnormalities in Crohn disease. The erythrocyte sedimentation rate
(ESR) frequently is elevated above 30 mm/h, and the serum vitamin B12
level may be reduced.
Crohn Disease
Versus Ulcerative Colitis
These inflammatory bowel diseases share certain
features, but there are fundamental and often distinguishing features. On
occasion it may be very difficult to determine whether a patient has Crohn
disease or ulcerative colitis, and in these circumstances the condition often is
designated indeterminate colitis. The fundamental differences between Crohn
disease and ulcerative colitis are that Crohn disease begins in the
submucosa and ulcerative colitis begins in the mucosa of the gut.
Ulcerative colitis, as its name suggests, is a disease confined to the colon and
rectum, whereas, as was stated above, Crohn disease is ubiquitous
throughout the bowel. Full-thickness involvement of the bowel, although more
common in Crohn disease, may occur in both disorders. Fibrosis cicatrization
and fistula formation are confined almost exclusively to patients with
Crohn disease. The histopathologic feature that differentiates the two
conditions is the presence of granulomas in Crohn disease. Aphthoid
ulcers are more likely to occur in patients with Crohn disease. Both
conditions are associated with an increased incidence of colon cancer,
which, however, is more likely to develop in long-standing ulcerative
colitis than in Crohn disease. The incidence of malignant change in the
colon or rectum of ulcerative colitis is about 20 percent after 25 years of
disease activity. Many patients develop ulcerative colitis at a young age
and therefore may develop cancerous changes in the colon in their forties or
fifties. A further important consideration is that patients with inflammatory
bowel disease live with episodes of diarrhea and occasional rectal bleeding so
that the heralding features of malignancy may be observed by referring to the
underlying inflammatory disease.
Treatment
Pain Control and Anti-Inflammatory
Agents
The treatment of Crohn disease can be divided
into four areas of management: dealing with symptoms, treating mucosal
inflammation, nutritional management, and surgery. Abdominal pain and
diarrhea are dealt with mostly by addressing intestinal inflammation. Pain may
be due to the stretching of nerve endings as a result of distention from
obstruction or inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs)
should be avoided, and narcotics lead to addiction in this chronic condition.
Acetominophen, Tramadol and Darvocet are used most frequently for pain control.
5-Aminosalicylic acid derivatives such as Azulfidine, Asacol, Pentasa, and
Rowasa are used widely and have some effect. They are more effective in
ulcerative colitis than in Crohn disease.
Steroids
Corticosteroids have been the mainstay in the acute
treatment of Crohn disease for many years. Steroids should be used only when
more conservative measures fail. The strategy employed is to induce remission by
using high doses (prednisolone 60 mg per day) in the short term, followed by a
temporary regime as soon as remission is induced. Maintenance therapy should
employ the lowest dose possible. About 20 percent of patients require long-term
steroids.
Second-Line Agents
Steroid sparing in long-term management can be
achieved with 6-mercaptopurine. This drug is slow to act and unpredictable in
terms of achieving a therapeutic response. In doses of 50 to 125 mg daily, bone
marrow suppression and other side effects are rare. The antibiotic metronidazole
is also used as second-line therapy with a degree of success, particularly in
treating fistulae. In addition to its properties as an antibiotic, the drug has
an effect on the immune system. Other antibiotics that have been used to some
effect are ciprofloxacin and clarithromycin.
Immune Suppressants
The immune suppressants methorexate and cyclosporine
have been shown to confer some benefit in the short term. The latest, still
experimental, strategy in the treatment of Crohn disease involves the role of
cytokines. Anti-tumor necrosis factor has been shown to be effective. Other
cytokine therapies, such as the use of interleukin-11 (IL-11) and IL-10, have
been reported to be efficacious in about 30 percent of cases.
Surgery
The cumulative risk of undergoing surgery
sometime in their lives for patients with Crohn disease is nearly 90
percent, and the cumulative risk of recurrent disease at 20 years is 70
percent. Many recurrences may be asymptomatic, however. The major indication for
surgery is failed medical therapy, usually in the presence of obstruction,
fistula formation, and electrolyte or nutritional problems.
Controversy still exists over how radical the surgeon
should be in treating Crohn disease. Some studies show that the more
disease-free the margins are after the resection, the less likely there is to be
recurrent disease. Conversely, there is a danger that overly radical resections
will leave the patient with the short bowel syndrome and its nutritional
consequences. Conservative surgery in the form of stricturoplasty for short
stenotic lesions that are producing obstructions can be helpful without the loss
of any bowel. For longer diseased segments, resection is preferred to bypass.
For colonic Crohn disease with severe rectal and anal involvement, a
proctocolectomy with ileostomy may be required. Meticulous care is required in
performing anastomoses in patients with Crohn disease, as healing is often
impaired and the risk of anastomotic leakage therefore is
increased.
COMPREHENSION
QUESTIONS
[6.1] A 44-year-old man presents with multiple
episodes of bloody diarrhea accompanied by cramping abdominal pain. A
colonoscopy reveals the rectum and distal colon to be unremarkable, but x-ray
studies find areas of focal thickening of the wall of the proximal colon,
producing a characteristic "string sign." Biopsies from the abnormal portions of
the colon revealed histologic features that were diagnostic of Crohn disease.
Which of the following histologic features is most characteristic of Crohn
disease?
A. Dilated submucosal blood vessels with focal
thrombosis
B. Increased thickness of the subepithelial
collagen layer
C. Noncaseating granulomas with scattered giant
cells
D. Numerous eosinophils within the lamina
propria
E. Small curved bacteria identified with
special silver stains
[6.2] Which one of the therapies listed below is used
most often to treat an individual with a history of Crohn disease who acutely
develops abdominal pain and bloody diarrhea but has no clinical evidence of
obstruction or fistula formation?
A. Aspirin
B. Interleukin-10
C. Metronidazole
D. Prednisolone
E. Surgery
[6.3] What is the fundamental distinguishing feature
between Crohn disease and ulcerative colitis?
A. Crohn disease begins in the rectum;
ulcerative colitis may have "skip lesions."
B. Crohn disease begins in the submucosa;
ulcerative colitis begins in the mucosa.
C. Crohn disease has an increased risk of
malignancy; ulcerative colitis has a very low association with
malignancy.
D. Crohn disease is associated with crypt
abscesses; ulcerative colitis, with pericolonic abscesses.
E. Crohn disease is associated with the
formation of inflammatory polyps; ulcerative colitis, with hamartomatous
polyps.
ANSWERS
[6.1] C. Microscopic examination of the
abnormal bowel from an individual with Crohn disease will reveal transmural
inflammation with fibrosis, but the histologic feature that is most diagnostic
of Crohn disease is the presence of noncaseating granulomas. This characteristic
histologic feature, however, may be present in only about 50 percent of
patients; however, the diagnosis of Crohn disease can still be made without
finding granulomas by the characteristic clinical presentation, which includes
the production of fissures, fistulae, and bowel obstruction by the transmural
inflammation.
[6.2] D. In the absence of bowel obstruction or
fistula formation, several types of medical therapies have been used to treat
the acute inflammation associated with Crohn disease. Corticosteroids, such as
high-dose prednisolone, have been used commonly to treat the acute symptoms and
induce remissions. In contrast, the antibiotic metronidazole may be used to
treat patients with fistula formation, whereas the use of cytokines such as
interleukin-10 is experimental. Surgical resection of bowel usually is done to
treat problems such as obstruction.
[6.3] B. Crohn disease and ulcerative colitis
are both inflammatory bowel diseases characterized by marked acute inflammation,
but the fundamental difference is that with Crohn disease the inflammation
begins in the submucosa and may involve the entire bowel wall, whereas
ulcerative colitis begins in the mucosa and the inflammatory response remains
superficial in location. Another important difference is that the inflammation
in ulcerative colitis begins in the rectum and distal portions of the colon and
precedes proximally without "skip lesions," whereas the inflammation in Crohn
disease can be found throughout the gastrointestinal tract.
PATHOLOGY
PEARLS
· Crohn disease is transmural
(full thickness) and can occur anywhere along the gastrointestinal
tract.
· Intestinal strictures and
fistulae are complications of Crohn disease.
· Individuals with Crohn
disease have an increased risk of colon cancer, but the risk is lower than that
with ulcerative colitis.
· Nongastrointestinal
symptoms of Crohn disease involve the skin, joints, and eyes. Skin
lesions include erythema nodosum, pyoderma gangrenosa, aphthous stomatitis,
and finger clubbing.
REFERENCES
Friedman S, Blumberg RS. Inflammatory bowel disease.
In: Kasper DL, Fauci AS, Longo DL, et al. Harrison's principles of internal
medicine, 16th ed. New York: McGraw-Hill, 2004:1776-1788.
Liu C, Crawford JM. The gastrointestinal tract. In:
Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of
disease, 7th ed. Philadelphia: Elsevier Saunders,
2004:846-849.
Copyright © 2006 by the
McGraw-Hill Companies, Inc. All rights reserved.
