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Inflammatory Bowel Disease

Anthony J. DiMarino, Jr., MD


Educational goals:
By the completion of this lecture you should be familiar with:
1. Differentiation of Crohn’s disease and ulcerative colitis from a clinical, radiologic and
pathologic prospective.
2. Extraintestinal manifestations of inflammatory bowel disease.
3. Approach to the pharmacologic, endoscopic and surgical therapy of inflammatory bowel
disease.

Introduction and Summary:


1. Crohn’s disease and ulcerative colitis are chronic inflammatory diseases of the
gastrointestinal tract. They are thought to result from inappropriate and ongoing activation of
the mucosal immune system driven by the presence of normal luminal flora. Ulcerative colitis
involves the rectum and colon while Crohn’s disease most commonly affects ileum and colon,
although any site in the gastrointestinal tract may be involved.
2. The differentiation in the inflammatory process of ulcerative colitis vs. Crohn’s is summarized.
Ulcerative colitis Crohn’s
GI Sites Colon All (ileo-colonic)
Rectum Involved 95% Involved or spared
Distribution Continuous Skip areas
Inflammation Mucosal Transmural
Granulomas Absent May be present
Crypt abscesses Usually present Usually absent
Postoperative recurrences No 60-70%
Appendectomy Protective Not protective
Monozygotic twins 5-15% concordance 50% concordance
Smoking May prevent disease May cause disease

3. The clinical presentation of inflammatory bowel disease most commonly includes diarrhea,
abdominal pain, and weight loss. Bloody diarrhea is characteristic of ulcerative colitis. These
symptoms are punctuated by spontaneous exacerbations and remissions.
4. The diagnosis of inflammatory bowel disease is generally made via colonoscopy with biopsy
if the colon is involved or gastrointestinal x-rays if the small intestine is involved.
5. The gastrointestinal complications of ulcerative colitis include hemorrhage, perforation, toxic
dilatation and colon cancer after 10 years of disease especially if pancolitis is present. The
bowel complications of Crohn’s disease include strictures, fistulas, intra-abdominal
abscesses and perianal disease. Cancer may occur in long-standing Crohn’s disease but is
less common than in ulcerative colitis.
6. Inflammatory bowel disease is associated with various extraintestinal manifestations
including peripheral and spinal arthritis, skin lesions including erythema nodosum and
pyoderma gangrenosum, inflammatory ophthalmic lesions and sclerosing cholangitis.
Because Crohn’s disease involves the small intestine, metabolic abnormalities may occur
including malabsorption, kidney stones and gallstones.
7. Medical therapy for inflammatory bowel disease includes anti-inflammatory agents such as 5-
aminosalicylates and corticosteroids as well as immunosuppressive medications such as 6-
mercaptopurine and cyclosporin. Cytokine inhibitors such as anti-TNF are new forms of
therapy. Surgical therapies are available and total colectomy is curative for ulcerative colitis.
Postoperative recurrence occurs in 60-70% of patients operated for Crohn’s disease.
8. Microscopic forms of colitis which may be related to ulcerative colitis or Crohn’s disease are
also recognized. They present with watery diarrhea, possible weight loss and a clinical
course characterized by spontaneous exacerbations and remissions. These conditions can
only be diagnosed by biopsy.
I. Types of IBD
A. Ulcerative colitis
B. Crohn’s disease
C. Microscopic colitis-mucosa appears grossly normal but microscopically inflamed
minor problem – (will not be discussed at this time)

II. IBD- Macroscopic


A. Ulcerative colitis- mucosal inflammation of the colon
B. Crohn’s disease- transmural inflammation anywhere in gastrointestinal tract from mouth
to anus, but primarily affecting the ileum, (33%) colon (20%) or both (45%)

III. Epidemiology of IBD


A. Equal frequency in males and females
B. Whites greater than blacks or Hispanics
C. Ashkenazi Jews greater than non-Jews
D. Incidence of UC fairly consistent; Crohn’s disease increasing

IV. Etiology
A. Inflammatory bowel disease is thought to result from inappropriate and ongoing activation
of the mucosal immune system driven by the presence of normal luminal flora. This
aberrant response is most likely facilitated by defects in both the barrier function of the
intestinal epithelium and the mucosal immune system.
B. Familial occurrence in 10-25% of first degree relatives
C. Food antigens and bacterial products initiate a cascade reaction after they enter the gut
epithelium. Antigen presenting cells (dendritic cells) promotes differentiation of type 1
helper T cells (Th1) in Crohn’s and type 2 helper cells (Th2) in ulcerative colitis. Th1
secretes interferon-γ, which in turn activates macrophages. In addition to producing the
key cytokines that stimulate Th1 (interleukin-12, interleukin-18, and macrophage
migration inhibitor factor), macrophages produce a mix of inflammatory cytokines,
including interleukin-1, interleukin-6, and most notably tumor necrosis factor (TNF), which
target a broad variety of other types of cells. The latter include endothelial cells, which
then facilitate the recruitment of leukocytes to the mucosa from the vascular space, as
well as fibroblasts and epithelium, modulating their functional properties. These events
subsequently lead to the release of leukotrienes, proteases and free radicals, which are
toxic to gut epithelial cells. Significantly higher levels of TNF-α have been found in the
intestinal mucosa of patients with Crohn’s disease compared to controls. The
development of anti-TNF-α antibody, anti-interleukin-12, anti-interferon-γ, which inhibit
the bioavailability of the different cytokines, is an exciting new strategy in the treatment of
Crohn’s disease.
V. Differentiation of UC and Crohn’s
Ulcerative colitis Crohn’s
GI Sites Colon All (ileo-colonic)
Rectum Involved 95% Involved or spared
Distribution Continuous Skip areas
Inflammation Mucosal Transmural
Granulomas Absent May be present
Crypt abscesses Usually present Usually absent
Postoperative recurrences No 60-70%
Appendectomy Protective Not protective
Monozygotic twins 5 -15% concordance 50% concordance
Smoking May prevent disease May cause disease

VI. Ulcerative Colitis


A. Distribution
1. Proctitis
a) Limited to rectum – 45%
b) Rectal bleeding, often with constipation
c) Responds to topical (intrarectal) therapy
2. Proctocolitis-rectum and left colon – 20%
3. Panproctocolitis-entire colon and rectum – 35%
B. Clinical Symptoms
1. Diarrhea with blood and mucus
2. Tenesmus
3. Crampy abdominal pain
4. Constitutional symptoms: fever, weight loss, nausea
5. Signs and symptoms of anemia
6. Extraintestinal manifestations (see below)

C. Ulcerative Colitis Clinical assessment of disease activity

Variable Mild disease Severe disease Fulminant Disease


Stools (no/day) <4 >6 >10
Blood in stool Intermittent Frequent Continuous
Temperature (°C) Normal >37.5 >37.5
Pulse (beats/min) Normal >90 >90
Hemoglobin Normal <75% of normal value Transfusion required
ESR (mm/hr) ≤30 >3 >30
Colonic features on -------- Air, edematous wall, Dilatation
radiography thumb printing
Clinical signs -------- Abdominal Abdominal distention and
tenderness tenderness
D. Diagnosis, ulcerative colitis
1. Lab studies
a) Anemia, leukocytosis with shift to left, thrombocytosis
b) Hypoalbuminemia
c) Elevated erythrocyte sedimentation rate, C reactive protein, orosomucoid
d) Elevated gamma globulin
e) Stool cultures negative for pathogens
2. Barium enema
a. Acute: ulceration
b. Chronic: ahaustral foreshortened colon
3. Sigmoidoscopy or colonoscopy with biopsy
a. Diffusely abnormal mucosa, beginning in the rectum and extending proximally for
variable distance with friability, ulceration, mucopurulent exudates, pseudopolyps
b. On biopsy—acute and chronic mucosal inflammation with polymorphonuclear
leukocytes, crypt abscesses

E. Complications of ulcerative colitis


1. Colonic complications of severe disease
a) Hemorrhage
b) Perforation
c) Toxic dilatation (“megacolon”)—sudden acute, dilatation of transverse colon:
Patient becomes acutely ill with high fever, tachycardia, 50% require emergent
colectomy
d) Colon cancer—correlates with extent of colonic involvement and duration of
disease > 10 years
2. Extracolonic complications
a) Arthritis
1. peripheral-, mono- or pauciarticular, involves medium-sized joints, looks like
rheumatoid disease but negative rheumatoid factor, parallels disease activity,
non-symmetrical
2. Axial-ankylosing spondylitis, sacroilitis; independent of disease activity;
associated with HLA-B27
b) Skin lesions: erythema nodosum, pyoderma gangrenosum
c) Eye lesions: episcleritis, uveitis
d) Hepatobiliary disease: sclerosing cholangitis, intrahepatic “pericholangitis,”
cholangiocarcinoma

F. Therapy
1. Medical: 5-aminosalicylates, corticosteroids, nicotine patch if ex-smoker,
immunosuppressives (azathioprine, 6-mercaptopurine), cyclosporine, antibiotics,
nutritional support. Investigational agents like (probiotics, rosiglitazone, heparin,
keratinocyte growth factor, anti-α4β7 integrin)

2. Surgical: colectomy for medically uncontrolled disease, hemorrhage, perforation,


toxic dilatation, risk of cancer
• Indications for surgery in ulcerative colitis include:
1. Exsanguinating hemorrhage or persistent transfusion requirement
2. Toxic megacolon and/or suspected perforation
3. Suspected cancer
4. Significant dysplasia
5. Growth retardation unresponsive to nutritional supportive therapy
6. Systemic complications, especially pyoderma gangrenosum and intractability

VII. Crohn’s Disease


A. Distribution
1. Ileocolitis 45%-terminal ileum involved in 90%
2. Small bowel disease alone 33%-terminal ileum involved in 90%
3. Colonic disease alone 20%
4. Other sites:
a) perianal 3-36%
b) oral 6-9%
c) esophagus <1%
d) stomach/duodenum 0.5-5%
5. Total small bowel-jejunioileitis <5%

B. Clinical Presentation
1. Acute-right lower quadrant pain, mimicking appendicitis
2. Chronic
a) Pain, usually crampy, worsening, 1-2 hours after meals
b) Watery diarrhea
c) Fever
d) Weight loss
e) Perianal disease
f) Anemia or chronic disease, vitamin deficiency, or occult blood loss
g) Constitutional symptoms: fatigue, malaise, growth retardation in children

Table: Crohn’s Disease Activity Index (CDAI)


B
Variable Multiplication factor
Number of liquid or soft stools (each day for 7 day) 2
Abdominal pain (0, none; 1 or 2 intermediate; 3 severe) 5
General well-being (0, good; 1, 2, or 3, intermediate; 4, poor) 7
Number of complications 20 each
• Arthralgia or arthritis
• Iritis or uveitis
• Erythema nodosum, pyoderma gangrenosum, or
aphthous stomatitis
• Anal fissure, fistula or abscess
• Other fistula
• Fever (>37.80C) during previous week
Use of opiates for diarrhea (0, no; 1, yes) 30
Abdominal mass (0, none; 2, questionable; 5, definite) 10
< 47 hematocrit (men);< 42 hematocrit (women) 6
Percentage deviation above or below standard weight 1

If Total:
<150 inactive or remission
>450 critically ill

C. Diagnosis
1. Laboratory studies similar to ulcerative colitis
2. Barium x-rays
a) small bowel x-rays-enteric involvement
1) Narrowing of bowel, especially terminal ileum (“string sign”), “skip” areas with
normal bowel interposed between diseased segments
2) Manifestations of transmural inflammation
b) Fistulas and sinus tracts
c) Inflammation and deep ulceration
d) Inflammatory masses-mesenteric thickening or abscesses with adherent bowel
loops
e) Barium enema-colonic involvement
1) Deep ulcerations
2) Strictures
3) Fistulas
4) “Skip” areas; rectal sparing
3. Colonoscopy, biopsy-colonic or terminal ileal involvement
a) Perianal disease, perineal ulceration
b) Apthoid lesions
c) Stellate ulcers, discreet ulcers, longitudinal ulcers, confluent ulcers
d) “Skip” areas or rectal sparing
e) Psuedopolyps
f) Transmural inflammation or granulomas on biopsy

D. Complications
1. Intestinal complications
a) Obstruction
b) Fistulas
1. Enteroenteric or enterocolic
2. Entero- (or colo-) vesical: entero- (or colo-) vaginal
3. Enterocutaneous
4. Retroperitoneal
c) Inflammatory masses or abscesses
d) Retroperitoneal complications
1. Hydonephrosis, hydroureter, especially on right
2. Psoas abscess
e) Cancer- in long-standing disease, less common than with ulcerative colitis
2. Systemic complications
a) Arthritis: peripheral or axial
b) Aphthous stomatitis
c) Episcleritis, uveitis
d) Skin lesions: erythema nodosum, pyoderma gangrenosum
e) Hepatobiliary: gallstones, sclerosing cholangitis (with colonic disease)
f) Kidney stones
g) Amyloidosis
h) Malabsorption: fistulas, bacterial overgrowth, short bowel syndrome, ileal disease
with bile acid loss

E. Therapy
1. Medical
a) 5-aminosalicylates-for distal small bowel or colonic disease
b) Corticosteroids
c) Immunosuppressive (azathioprine, 6-mercaptopurine)-for maintenance: steroid
sparing, fistulas
d) Antibiotics and metronidazole-for colonic or perianal disease
e) Newer agents includes immunosuppressive drugs (tacrolimus, mycophenolate
mofetil, thalidomide), anti-inflammatory cytokines (IL-10, IL-11, anti-interleukin-
12, interferon-γ), anti-α4β7 integrin, anti-α4 integrin, CDP571, a humanized
monoclonal antibody, fish oil, etc.
f) anti-TNF-α monoclonal antibody
1. Binds specifically to TNF-αand neutralizes its bioavailability in a dose-
dependent manner
2. Remission has been reported in up to 81% of steroid-resistant cases and
68% of cases with fistula
3. Indications
• Medically resistant disease
• Fistulizing disease
• Intolerance to corticosteroids or immunosuppressive therapy
• High surgical risk
• Maintenance of remission in anti TNF-α responders
• Retreatment of active disease in anti TNF-α responders
4. Potential complication
• Infection, hypersensitivity, infusion reaction, possible antibody
development, tuberculosis.
2. Surgery
Indications for surgery in Crohn’s disease include:
1. Fistulae unresponsive to medical therapy
2. Drainage of abscesses
3. Intestinal obstruction
4. Perforation
5. Uncontrollable symptoms
6. Toxic megacolon
Post-op recurrence is 50 - 70% in 10 years

VIII. Differential Diagnosis: Ulcerative Colitis and Crohn’s


A. Proctitis: Radiation proctitis (prostate or cervix radiation), infections (including gonococcal
proctitis)
B. Proctocolitis: Radiation colitis, ischemic, colitis, antibiotic-related pseudomembranous
colitis, infectious colitis (salmonella, shigella, campylobacter, amoebae, CMV, etc.)
C. Small bowel disease
1. Acute: Appendicitis, cecal diverticulitis, Meckel’s diverticulitis, pelvic disease (pelvic
inflammatory disease, ruptured ectopic pregnancy, endometriosis, ovarian cyst),
infection (Yersinia)
2. Chronic: Radiation enteritis with stricture, ischemic stricture, infections (Yersinia,
tuberculosis, amoebae), tumors of the ileum, lymphosarcoma, carcinoid, carcinoma
3. Diffuse small bowel disease: Non-granulomatous jejunoileitis, lymphoma,
eosinophilic enteritis, amyloidosis

References

1. Brignola C, Cottone M, Pera A. Mesalamine in the prevention of endoscopic recurrence


after intestinal resection for Crohn’s Disease. Gastro 1995:108:345-9.
2. Ehrenpreis ED, Kane SV, Cohen LB, Cohen RD, Hanauer SB. Thalidomide therapy for
patients with refractory Crohn's disease: an open-label trial. Gastroenterology
1999;117:1271-1277.
3. Hanauer SB, Sandborn W. Management of Crohn’s disease in adults. Am J
Gastroenterol 2001:96:635-641.
4. Podolsky DK. Inflammatory bowel disease. N Engl J Med 2002; 347:417-429
5. Present D. Anti-TNF-alpha chimeric antibody is effective in the treatment of the fistulae
of Crohn’s disease: a multicenter, randomized, double-blind, placebo-controlled study.
Am J Gastroenterol 1997;112:A468
6. Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered human antibody to TNF
(CDP571) for active Crohn's disease: a randomized double-blind placebo-controlled trial.
Gastroenterology 2001;120:1330-1338.

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