Important Note

Tufts ended funding for its Open Courseware initiative in 2014. We are now planning to retire this site on June 30, 2018. Content will be available for Tufts contributors after that date. If you have any questions about this please write to

Tufts OpenCourseware
Author: Laurence Scott Bailen, M.D.
Color Key
Important key words or phrases.
Important concepts or main ideas.

1. Objectives: Inflammatory Bowel Disease

  1. Understand the idiopathic Inflammatory Bowel Diseases comprise two primary disorders: Ulcerative colitis and Crohn's disease

  2. Understand the currently accepted hypothesis for the pathophysiology of Crohn’s disease and Ulcerative Colitis

  3. Be able to describe the different symptoms, radiologic findings, endoscopic findings, and pathologic findings in patients with Ulcerative colitis and Crohn’s disease

  4. Understand the complications and extra-intestinal manifestations of ulcerative colitis and Crohn’s disease

  5. Understand what medications are used to treat inflammatory bowel disease

2. Definition

Inflammatory bowel disease (IBD) is comprised of two major disorders – ulcerative colitis (UC) and Crohn’s disease (CD – also referred to in the past as regional enteritis, Crohn’s ileitis, and granulomatous colitis). Each has distinct clinical, endoscopic, pathologic, and radiologic appearances but the etiology and pathogenesis remains poorly understood. There are many disorders that can cause inflammation in the intestinal tract such as infectious colitis, radiation colitis, or vascular insufficiency (ischemic colitis). The major difference is that the etiology of these inflammatory conditions is well defined. Because of the lack of identifiable causes UC and CD are defined by typical clinical, pathologic, radiologic, endoscopic, and laboratory features.

Ulcerative colitis is characterized by recurring episodes of inflammation limited to the mucosal layer of the colon. It typically involves the rectum and extends in a continuous, non-interrupted fashion to involve more proximal (i.e., to the right colon) portions of the colon. Ulcerative proctitis refers to disease limited to the rectum. Distal colitis or proctosigmoiditis refers to disease that extends to the mid-sigmoid colon. Left sided ulcerative colitis refers to disease that extends to the splenic flexure. Pancolitis refers to disease extending proximal to the splenic flexure; patients with pancolitis may not always have disease that extends to the cecum.

Crohn’s disease is characterized by transmural inflammation, as opposed to inflammation limited to the mucosa as in ulcerative colitis that can have “skip” lesions rather than extend in a continuous fashion. The transmural inflammation can lead to fibrosis in the intestinal wall which may cause intestinal strictures leading to intestinal obstruction. The transmural inflammation may also cause sinus tracts to develop which can penetrate the bowel serosa leading to microperforations causing abscesses or fistulous connections. Fistulae may develop between two loops of bowel (entero-entero), between small intestine and colon (entero-colonic), between intestine and skin (entero-cutaneous), between intestine and bladder (entero-vesical), or between intestine and vagina (entero-vaginal).

CD may involve the entire gastrointestinal tract from mouth to anus. Most patients (~80%) have small bowel involvement, with approximately 30% having disease exclusively in the terminal ileum (ileitis). (Figure 1) About 50% have disease limited to the ileum and right colon (ileo-colitis). About 20% have disease limited to the colon which typical “spares” the rectum. A very small group of patients have predominant involvement in the mouth and gastroduodenal area and even fewer patients have disease in the esophagus and proximal small intestine. Approximately one-third of patients have perianal disease (anal fissures, fistulae, or perianal abscesses).

Figure 1: Distribution of Crohn's Disease

Distribution of Crohn's Disease
Distribution of Crohn's Disease

3. Epidemiology and Risk Factors for IBD

3.1. Epidemiology

The incidence of UC has remained constant over the past several decades (~ 3 to 15:100,000). In contrast, the incidence of Crohn’s disease has steadily risen since its description in the early part of the 20th century. The incidence of UC and CD are now approximately equivalent. UC and CD are more common in northern climates and well developed areas of the world such as North America, United Kingdom, and Scandinavia. The incidence is lowest in underdeveloped countries and southern climates. It is estimated that approximately 500,000 people in the United States have IBD.

3.2. Risk Factors

  1. Age and Gender : Most cases of UC and CD present between age 15 to 40. There is a bimodal age distribution for both disorders recognizing a second peak between age 50-80. The cause of this second peak is not clearly understood. Men and women are at similar risk of developing IBD. However, women may be more susceptible to CD and men to UC although this is certainly not absolute.

  2. Ethnic and racial predisposition : UC and CD and more common in Jews than non-Jews. In Israel, the rates of IBD are higher in European and American born Jews than in Jews from Asia or Africa. UC and CD are uncommon in non-whites in underdeveloped areas.

  3. Genetic Factors : Several observations support a role for genetic factors in the etiology of IBD.

    1. IBD tends to run in families: 10-25% of patients have a first degree relative with either CD or UC. There seems to be concordance for the same disease category among families. There also may be concordance for disease location and type among families. However, the majority of patients (~80%) have no family history of IBD.

    2. Twin studies show a higher concordance for IBD in monozygotic twins than dyzogtic. In addition, there is a higher rate of concordance for CD than UC.

    3. Specific genes responsible for IBD are becoming better understood. Several genetic alterations probably contribute to the complex pathophysiology of IBD. Several linkage studies have been done and one genetic mutation conferring susceptibility to CD is located on chromosome 16, the CARD 15 gene (capsase recruitment domain family member 15 – formerly known as NOD2). The identification of this mutation was recently (2001) reported. The wild-type CARD 15 protein activates nuclear factor kappa B (NFκB) in macrophages making it responsive to bacterial lipopolysaccharides. This process was deficient in subjects with a CARD 15 mutation. NF-KB is a nuclear transcription factor responsible for the activation of various inflammatory mediators. The CARD 15 gene is found in 25-35% of CD patients and is associated with disease in the distal ileum. It also may be associated with fibrostenosing disease.

    4. Several studies have documented associations of IBD with major histocompatibility complex (MHC) loci.

      1. There is an association with HLA (Human Leukocyte Antigen)-DR2 and UC.

      2. Extra-intestinal complications are more commonly observed in CD patients with HLA-A2, HLA-DR1, and HLA-DQw5.

    5. Other candidate genes include those for tumor necrosis factor alpha (TNF-α), interleukin 1 receptor antagonist (IL-1 RA), organic cation/carnitine transporters (chromosome 5), epithelial scaffolding protein (chromosome 10), PPARγ (a nuclear receptor that inhibits NFκB activity. On chromosome 3).

  4. Environmental Factors

    1. Smoking: Smoking has different effects on UC and CD. Cigarette smoking has been shown to reduce the risk of developing UC. Current smokers have a 40% lower risk of developing UC than non-smokers. In contrast, smoking may increase the risk of developing CD. Smokers are more than twice as likely to develop CD than non-smokers. In addition, cigarette smoking may exacerbate CD. The basis for the differential effects of smoking on UC and CD is not completely understood. However, nicotine may have affects on the mucosal immune system as trials with transdermal nicotine have shown some benefit in patients with mild-moderate UC.

    2. Diet: There is no specific diet that has been linked as a risk factor for the development of IBD. Some studies have suggested an association of a diet high in refined sugar and CD, but this is certainly not conclusive.

    3. Oral contraceptives: There are conflicting data on the relationship of oral contraceptives and IBD. Some studies suggest a higher likelihood of developing CD or UC if a woman takes oral contraceptives. However, other case control studies show no association. The use of oral contraceptives does not seem to affect the course of IBD.

    4. Nursing and other perinatal events: In one study, children who were not breast fed were more likely to have CD. However, other studies have not confirmed the association with breast feeding and IBD. In addition, children with CD were more likely to have had a diarrheal illness during childhood.

    5. Nonsteroidal antiinflammatory drugs (NSAIDs): NSAIDs, such as aspirin or ibuprofen, may increase the risk for the development of IBD and may exacerbate underlying IBD. NSAIDs inhibit the cycloxygenase (COX) -1 and 2 enzymes involved in arachidonic acid metabolism. Aspirin, ibuprofen, most other NSAIDs inhibit both COX-1 and COX-2. Newer medications, celecoxib and rofecoxib, specifically inhibit COX-2. The effect of these newer medications on the development or course of IBD is not known. Independent of IBD, NSAIDs may rarely cause intestinal strictures and small bowel inflammation.

    6. Appendectomy: Several studies suggest that a previous appendectomy may protect against the development of UC. However, no protective effect has been noted for the development of CD.

    7. Psychosocial: There is no consistent type of psychopathology in patients with IBD as had been suggested in older literature. Stress, although not causal, may play a role in exacerbating symptoms in patients with UC and CD.

    8. Infectious agents: A variety of infectious organisms have been implicated in the pathogenesis of IBD. Organisms such as measles virus (paramyxovirus), mycobacterium paratuberculosis, and Listeria moncytogenes have all been looked at as possible etiologic agents in CD. This data is not conclusive. In UC, some studies suggest a possible role for Escherichia coli, although this data is also not conclusive. Normal intestinal microflora may contribute to the development of IBD in susceptible hosts as animals genetically altered to be susceptible to colitis do not develop IBD when raised in germ free environments.

4. Pathogenesis of IBD

The development of UC and CD involves the interaction of three major elements:

Figure 2. 3 Major Elements in the Development of UC and CD

3 major elements in the development of UC and CD
3 major elements in the development of UC and CD

Before discussing the interaction of these elements, a review of the intestinal mucuosal immune system follows.

4.1. Brief Review of Normal Intestinal Mucosal Immune System

In the process of digestion and absorption the intestine must discriminate harmless food antigens from infectious or toxic agents. To protect the intestine from infectious or toxic agents the intestine relies on a mucosal barrier and a natural and acquired immune system:

  1. Mucosal barrier : Made up of intact intestinal epithelium, surface mucus overlying the epithelium, normal peristalsis, and protective secretory products (gastric acid, bile acids).

  2. Natural (innate) immune response is comprised of neutrophils, macrophages, and natural killer cells that make up the initial response to foreign antigen exposure.

  3. Acquired immune system , comprised of B and T lymphocytes, confers specific immunity to foreign antigen. The acquired immune system responds to foreign antigens as they are presented by “professional” antigen presenting cells (e.g., macrophages) in association with molecules of the major histocompatibility complex (MHC).

The acquired immune system is made up of both humoral and cell mediated immunity. The humoral response consists of antibody secreting B-cells in the gut. This is largely IgA antibody. Secretory IgA antibodies are transporting across the intestinal epithelium into the lumen where they interact with foreign antigen. Cellular immunity, mediated by T-lymphocytes, is divided into CD4+ helper cells and CD8+ cytotoxic or suppressor T cells. CD4+ cells respond to processed antigen on professional antigen presenting cells (APCs) in association with MHC Class II molecules. CD8+ cells respond to processed antigen on all cell types in association with MHC Class I molecules.

CD4+ helper T-cells are also subdivided into Th1 cells and Th2 cells:

  1. Th1 cells: secrete interferon (IFN)γ, tumor necrosis factor (TNF)α, interleukin (IL) – 2, and IL-12. These cytokines help induce cell mediated immunity.

  2. Th2 cells: secrete IL-1ra (IL-1 receptor antagonist), TGF-β (transforming growth factor beta) and IL-4, IL-5, IL-6, and IL-10 that help regulate B-cell differentiation and subsequent immunoglobulin synthesis,

All of the cells previously described make up the gut associated lymphoid tissue (GALT). These cells are distributed in the lamina propria, between epithelial cells, and in lymphoid follicles all in the intestinal wall. The epithelial cells, APCs, lymphocytes, and other leukocytes secrete cytokines (soluble protein mediators) which regulate responses to foreign antigens. The intestinal microcirculation and afferent neuronal elements may also affect immune function.

4.2. Pathogenesis of IBD: Working Hypothesis

The current working hypothesis for the pathogenesis of IBD involves several steps in the development of an inflammatory response:

Initiating events →

Perpetuating events →

Immunoregulatory abnormalities →

Tissue damage →

Clinical symptoms




Luminal bacteria

Bacterial products

Dietary antigens

Genetic susceptibility

T lymphocytes


TH1 vs. TH2


Anitgen presentation




O2, NO








Initiating Events

Initiating events include previously discussed environmental factors such as infectious agents, toxins, smoking, or NSAIDs. These events may disrupt the intestinal mucosal lining which is the first barrier antigens encounter in the intestine. Enhanced mucosal permeability may be a primary defect in patients with CD. That is, CD patients may have baseline alterations in the intestinal mucosal barrier that make them susceptible to initiation of an inflammatory response. This hypothesis has been tested in mucosal permeability studies. In addition, patients with UC may have reduction in the amount or alteration in the composition of mucin which is part of the mucosal barrier.

Perpetuating Events

Once the inflammatory process begins luminal bacteria, bacterial products, or dietary antigens gain access to the intestinal mucosa and to the sytemic circulation through breaks in the intestinal mucosal barrier and intestinal epithelium. These antigens are then processed and presented on antigen presenting cells (e.g. macrophages in the lamina propria) to T lymphocytes. When T-cells are activated they stimulate other intestinal inflammatory cells (including other T cells) to secrete inflammatory cytokines, arachidonic acid metabolites, proteases, nitric oxide, and toxic oxygen radicals which perpetuate and amplify the inflammatory response resulting in tissue damage to the intestine. The inflammatory cytokines also upregulate adhesion molecules and chemokines (cytokines which aid in chemotaxis) which leads to the recruitment of granulocytes (neutrophils, eosinophils, and monocytes). These effector cells exit the local microvasculature, transit through the mucosa, cross the basement membrane, and form crypt abscesses with disruption of epithelial barrier function.

The distal ileum and colon contain high concentrations of bacteria (more than 1012 organisms/gram). These bacteria include organisms which could be directly responsible for IBD or pathogens that promote IBD in the context of an underlying genetic mucosal or immune defect. No single infectious agent has been shown to have a consistent pathogenetic role in IBD. The importance of microbial agents in the pathogenesis of IBD is highlighted by animal studies in which mice, genetically engineered to lack certain anti-inflammatory (e.g. IL-10) cytokines, who develop IBD in the presence of normal microflora do not develop IBD in germ free environments.

Immune Dysregulation

Many studies suggest that the inflammatory response seen in IBD is partly due to an abnormal systemic immune system and/or specific defects in cellular or humoral immunity. Several examples illustrate this issue:

There are increased numbers of circulating B cells and autoantibodies in patients with IBD suggesting abnormal B cell regulation. Perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) have been found to be elevated in UC. Anti-Saccharomyces cerevisiae antibodies (ASCA) are more likely to be elevated in CD. These findings are not absolute and there are no studies showing that this antibody production is directly involved in the pathogenesis of IBD.

Lymphoid cells isolated from lesions of patients with IBD display numerous activation markers. T-cells isolated from IBD mucosa show increased proliferation to antigens in vitro suggesting that they may respond abnormally to resident antigens.

There is also evidence of dysregulation in the balance of pro- and anti-inflammatory regulatory cytokines. It is likely that mucosal cytokine responses are under genetic influence. In non-inflamed mucosa the predominant cytokines present are of the Th2 variety (IL-4, IL-10, IL-1ra, TGF-β). In CD the tendency is to generate a Th1, or inflammatory, cytokine profile (IL-1, IL-2, TNF-α, IFN-γ). The situation in UC is less clear – it may be a modification of a Th2 cytokine response.

Tissue Damage

The activation of macrophages and T-cells, the generation of the Th1 or Th2 response leads to the production of proinflammatory cytokines which aid in the recruitment of more inflammatory cells and subsequently lead to tissue damage and amplification of the inflammatory response.

Figure 4: Pathogenesis of IBD – Image not available due to copyright restrictions.

5. Clinical Symptoms and Diagnosis of Ulcerative Colitis

Patients with UC may present in a variable manner with mild, moderate, or severe disease. The extent of symptoms often correlates with the anatomic extent of the disease and is helpful in tailoring therapy.

Patients with mild disease may present insidiously with intermittent rectal bleeding often associated with the passage of mucus. Mild diarrhea may also be present, usually less than four stools per day. Patients may also have mild crampy abdominal pain, urgency to move the bowels, and tenesmus (painful straining on passage of stool). Anatomically, patients with mild disease usually have disease limited to the rectum (proctitis) or recto-sigmoid (proctosigmoiditis).

Patients with moderate disease usually have frequent (up to 10 times per day) loose, bloody stool, crampy abdominal pain, and may have a low grade fever. They may have a mild anemia. Their nutritional status is preserved. Anatomically the disease usually involves most of the left colon.

Patients with severe disease have extensive colonic involvement associated with frequent (more than 10) loose bloody stools daily, severe abdominal cramps, high fever, and anemia often needing blood transfusion. These patients may have weight loss which may lead to malnutrition.

The natural history of UC is variable. The majority of patients have a course marked by periods of exacerbation of symptoms followed by often long periods of remission. A smaller number of patients have continued symptoms and are unable to achieve remission – most of these patients have moderate or severe disease. About 15% of patients will develop fulminant severe colitis and require urgent colectomy on initial presentation.

Physical examination is often normal but in more severe disease one may observe pallor, weight loss, abdominal tenderness, and red blood on digital rectal examination.

5.1. Diagnosis of Ulcerative Colitis

Diagnosis is made by obtaining a typical history, performing a flexible sigmoidoscopy with biopsies, occasionally obtaining a barium enema (BE), ruling out other possible causes of the symptoms, and more recently, obtaining antibody blood tests. Flexible sigmoidoscopy helps in establishing the diagnosis and determining the extent of the disease. In UC, normal colonic mucosa vascular markings are blurred giving an erythematous appearance. There may be petechiae, tiny granular ulcers, exudates, friability to touch, and hemorrhage. It is important to remember that colonic involvement in UC is continuous beginning in the rectum. In CD the disease is more patchy (there are “skip” areas: i.e., areas of intestine which are normal). Colonic biopsy specimens typically show acute changes such as cryptitis and crypt abscesses and chronic changes such as branching of crypts, atrophy of glands, and loss of mucin in goblet cells. Barium enema (BE) is now rarely used in the diagnosis of UC. Findings on BE may include a reticulated pattern with punctate collections of barium in microulcerations. In more severe disease other findings include deeper ulcerations, loss of haustrae, and shortening of the colon.

Several recent studies have described the presence of various autoantibodies in the serum of patients with IBD. Some of these autoantibodies may be useful in establishing the diagnosis of IBD and differentiating UC from CD. Peri-nuclear antineutrophil cytoplasmic antibodies (P-ANCA) are more often elevated in patients with UC and anti-Saccharomyces cerevisiae antibodies (ASCA) are more often elevated in patients with CD. The combination of an absent P-ANCA and positive ASCA has a positive predictive value for the diagnosis of CD of around 85%. The combination of a positive P-ANCA and a negative ASCA has a positive predictive value of approximately 75% for the diagnosis of UC. At this stage autoantibody testing is used as an adjunct to conventional testing and clinical diagnosis.

Differential Diagnosis : One needs to rule out other diseases that may “mimic” UC. Other entities such as radiation colitis, ischemic colitis, and a variety of infectious colitides (Salmonella, Shigella, Campylobacter, Clostridium difficile, and Escherichia coli 0157:H7) should be excluded based on history and stool cultures. In immunocomprised patients, cytolomegalovirus colitis and Kaposi’s sarcoma involving the colon may mimic UC. Non-steroidal anti-inflammatory drugs (NSAIDs) may not only cause gastric ulcers but they also may exacerbate underlying colitis or cause similar symptoms to UC.

5.2. Complications of Ulcerative Colitis

Local Complications:

  1. Massive hemorrhage: occurs in up to 3% of patients with UC. May require urgent colectomy.

  2. Fulminant colitis: occurs in about 15% of patients. About 20% of these patients will develop toxic megacolon. Toxic megacolon is a rare but potentially lethal complication of UC. Diagnosis is based on clinical history, physical exam (toxic appearance, fever, tachycardia, abdominal distension, absent bowel sounds, abdominal tenderness), and x-rays (plain abdominal films show colonic dilation). Toxic megacolon requires emergent colectomy.

  3. Colonic stricture: very rare in UC.

  4. Colon cancer: very important concern in the management of patients with UC. Risk of developing colon cancer in UC is related to the duration of the disease (risk rises relative to the general population after 7-8 years of having the disease) and the extent of disease (risk greater in patients with pan-colitis as opposed to left sided or proctosigmoiditis). Patients usually have a colonoscopy every 1-2 years (after having the disease for 8-10 years) to screen for colon cancer or pathologic signs of dysplasia.

Extra-intestinal Complications:

  1. Eyes: Uveitis and episcleritis

  2. Skin: Erythema nodosum and pyoderma gangrenosum

  3. Joints: Peripheral arthritis, ankylosing spondylitis, sacroiliitis

  4. Liver: Primary sclerosing cholangitis

  5. Venous and arterial thromboembolism

  6. Autoimmune hemolytic anemia

Table 1. Relation of Extraintestinal Manifestations of Colitis to Activity of Colitis

Related to Activity of Colitis

Usually Related to Activity of Colitis

Unrelated to Activity of Colitis

Peripheral arthritis

Erythema nodosum


Apthous ulceration of mouth

Pyoderma gangrenosum



Ankylosing spondylitis

Primary sclerosing cholangitis

Table 2. Complications of IBD




Toxic megacolon

Severe hemorrhage






Erythema nodosum

Pyoderma gandrenosum

Iritis, uveitis, episcleritis


Primary sclerosing cholangitis







1% or less

6. Clinical Symptoms and Diagnosis of Crohn's Disease

The clinical manifestations of CD are much more varied than UC given the transmural involvement of the inflammatory process and the variability and extent of the disease. Patients with ileitis and colitis experience diarrhea, abdominal pain, weight loss, and fever. Diarrhea, however, may have multiple causes in patients with CD: inflamed bowel may cause excessive fluid secretion and impaired fluid absorption, malabsorption of bile salts due to resected or inflamed terminal ileum may lead to stimulation of colonic secretion due to excess bile salts reaching the colon, and bile salt malabsorption may also lead to steatorrhea (fat malabsorption). Bacterial overgrowth syndrome (see syllabus section on “Pathophysiology of Diarrhea”) may develop and cause diarrhea in patients with CD who have small bowel strictures, entero-colonic fistulae, or in patients with prior surgical resections.

Systemic symptoms, particularly weight loss and nutritional deficiencies, are often the major symptoms in patients with CD. In children with CD these issues are of particular importance as growth failure is often a major problem.

Patients with CD most commonly have disease localized to the ileum and colon, ileum alone, or colon alone. The pattern of disease in patients with CD may be divided into three broad categories:

  1. Inflammatory disease manifested by diarrhea and abdominal pain

  2. Fibro-stenotic disease manifested by small intestinal or colonic strictures which may lead to bowel obstruction causing symptoms of abdominal pain, nausea, vomiting, fever. This often requires surgical resection of the strictured segment of bowel. Recently (2002) several studies have confirmed that mutations in the NOD2/CARD 15 gene confer susceptibility to ileal and fibrostenosing manifestations of Crohn’s disease.

  3. Fistulizing disease : Transmural inflammation may lead to sinus tracts, serosal penetration, and bowel wall perforation. This complication may present acutely with localized peritonitis, fever, abdominal pain often resulting in an abscess. Typically, the abscess is located in the right lower quadrant of the abdomen corresponding to the site of bowel most often involved in CD. Management includes antibiotics and often percutaneous drainage of the fluid collection by computed tomography (CT) scan guidance.
    Fistulae may present insidiously. They may occur from one loop of bowel to another (enteroenteric fistula), from bowel to bladder (enterovesical fistula – symptoms include dysuria, pneumaturia, and fecaluria), from bowel to skin (enterocutaneous), from bowel to vagina (enterovaginal – symptoms include passage of stool and gas through the vagina), from bowel to retroperitoneum (leading to a psoas muscle abscess or to ureteral obstruction and hydronephrosis).

Perianal disease : approximately 30% of patients with CD may have perianal disease and these symptoms may dominate the clinical picture. Patients may have perianal fistulae, perianal/perirectal abscesses, or anal fissures.

6.1. Diagnosis of Crohn's Disease

The diagnosis of CD is based on a typical clinical history and physical exam findings. Diagnostic testing includes endoscopic and radiologic tests which help establish the diagnosis. Antibody testing (as mentioned above) is also being evaluated as a diagnostic tool. Colonoscopy is used to help diagnosis CD, flexible sigmoidoscopy is not sufficient given the patchy nature of the disease and the typical absence of involvement or “sparing” of the rectum. Endoscopic findings in CD include focal ulcerations (often deep) called apthous ulcers which are adjacent to normal appearing mucosa which give a “cobblestone” appearance to the mucosa. “Skip areas” of involvement are typical with areas of normal appearing bowel interrupted by large areas of obvious disease. This is clearly different from the continuous involvement in UC.

Barium studies are more helpful in the diagnosis of CD than UC. Small bowel barium studies (performed by having the patient swallow barium and following its course through the small intestine) are often useful in diagnosing ileal CD. Barium findings include: a) “string sign” where only a narrow column of barium passes through an area of stricturing, b) nodularity and ulceration c) fistula tracts d) separation of bowel loops due to bowel wall thickening from transmural inflammation. Abdominal and pelvic CT scanning can help determine if an abscess is present.

Intestinal biopsy in CD is often confirmatory rather than diagnostic. Similar to UC, acute and chronic inflammation is seen. However, in CD the lesions are more focal. Granulomas are noted in about 30% of intestinal biopsies from CD patients and are usually diagnostic.

Differential diagnosis: Infections need to be excluded. If the colon is the primary site of involvement in CD one also needs to differentiate CD from UC as treatment is often quite different. Findings suggestive of CD include: involvement of the small bowel, sparing of the rectum, absence of gross bleeding in the stool, perianal disease, focality of lesions, granulomas on biopsy. See Table 3 for a comparison of UC and CD.

6.2. Complications of CD

  1. Extra-intestinal complications: similar to UC

  2. Complications related to malabsorption due to small bowel disease:
    Bile acids are absorbed in the terminal ileum to complete the entero-hepatic circulation. Bile acids may be malabsorbed by a diseased terminal ileum or not absorbed completely if the ileum is partially resected. Bile salt malabsorption may lead to several problems:

  • Watery diarrhea due to stimulatory effects on colonic water and electrolyte absorption

  • Reduced concentration of bile acids limits what is necessary for micelle formation for fat absorption leading to steatorrhea.

  • May lead to gallstone formation due to reduction in the bile acid to cholesterol ratio making bile more lithogenic.
    Steatorrhea may lead to malnutrition, clotting abnormalities (due to malabsorption of Vitamin K – a fat-soluble vitamin), and osteoporosis due to poor calcium and Vitamin D absorption. CD patients may also develop nephrolithiasis (kidney stones). Steatorrhea leads to increased oxalate absorption and hyperoxaluria predisposing to calcium oxalate stone development (not uric acid stones). Excess fat in the intestinal lumen leads to binding of free calcium to fatty acids leaving more oxalate free and absorbable.
    Patients with CD are also at risk for Vitamin B12 malabsorption and should receive monthly B12 injections.

    Patients with primarily Crohn's Colitis are also at increased risk of colon cancer. However, screening regimens are not as clearly defined as they are for UC. Patients with CD are also at increased risk for small bowel tumors (rare), lymphoma, and squamous cell carcinoma of the anus.

  • Malignancy
    Patients with primarily Crohn's Colitis are also at increased risk of colon cancer. However, screening regimens are not as clearly defined as they are for UC. Patients with CD are also at increased risk for small bowel tumors (rare), lymphoma, and squamous cell carcinoma of the anus.

Table 3. Comparison of Ulcerative Colitis and Crohn's Disease




Rectal bleeding

Very common



Frequent small stools

Present but less bothersome

Predefecatory urgency



Abdominal Pain

Usually left lower quadrant, mild

Usually right lower quadrant and more bothersome

Endoscopic findings

Diffuse, continuous erythema pinpoint ulcerations, friability

Rectal involvement: almost always

Larger ulcers, skip areas,

cobblestone appearance

Rectum usually spared

Biopsy findings

Cryptitis and crypt abscesses

Branching of crypts, atrophy of glands

No granulomas

More chronic inflammatory,

mononuclear cell infiltrate

Granulomas in 30%

Barium x-ray findings

Loss of haustra, foreshortening of colon,

pinpoint ulcers, no fistulae

Rare loss of haustra or foreshortening of colon;

deep ulcerations, nodular or stenotic terminal ileum, skip areas, istulas may be visible

Recurrence after resection


Very frequent (>50%)

7. Treatment of Inflammatory Bowel Disease

Treatment of UC and CD involves medical and in some cases surgical therapy. The first phase of treatment is to induce a remission and the second phase is to maintain the remission. However, as previously mentioned UC and CD are chronic diseases marked by episodes of recurrent symptoms making complete remission or cure very difficult to maintain in the majority of patients. Most patients will require some form of long term therapy. Treatment is tailored to the extent and location of the disease and to the disease severity.

7.1. Commonly Used Medications in the Medical Management of IBD

  1. 5-Aminosalicylates (5-ASA)
    These medications may be roughly divided into sulfa-free compounds (mesalamine, olsalazine, and balsalizide) and their parent compound sulfasalazine. Sulfasalazine was developed in the 1930’s when an antibiotic sulfapyridine and an anti-inflammatory agent (5-ASA) were combined into one medication to treat rheumatoid arthritis. It was later found to be beneficial in patients with colitis. Sulfasalazine has been used for many years in the management of colitis. Sulfasalazine is formed by connecting the sulfapyridine moiety to 5-ASA by a diazo bond. This diazo bond is split by bacteria in the colon. Sulfapyridine is absorbed and metabolized in the liver and excreted in the kidney. The 5-ASA remains in the colon where it has its primary effect. Studies have shown that the 5-ASA component is the active ingredient responsible for the therapeutic efficacy of the drug and the sulfapyridine moiety is a carrier molecule preventing absorption of the 5-ASA in the proximal intestine.
    Studies have shown sulfasalazine to be effective in inducing and maintaining remission of mild-moderate ulcerative colitis in a dose-dependent fashion. However, sulfasalazine is not without side effects and is often tolerated poorly by patients. The majority of side effects are related to the sulfapyridine moiety. Side effects include nausea, malaise, and headaches. There also is a high incidence of allergic reactions to sulfa. Sulfasalazine may cause gastric upset although this side effect is reduced when using enteric coated formulations. Hematologic side effects include hemolysis, macrocytic anemia, and neutropenia. In men, sulfasalazine may cause abnormal sperm morphology or motility which is reversible when the medication is stopped.
    Other 5-ASA drugs eliminate the sulfa component. Several pharmaceutical companies have sought ways to deliver 5-ASA to the colon. Pentasa (mesalamine) incorporates the 5-ASA into ethylcellullose microgranules which provide gradual sustained release of 5-ASA in a time and pH dependent manner. Once the medication passes the pylorus it begins to slowly release 5-ASA. Approximately 50% of the 5-ASA is released in the small intestine and 50% in the colon therefore this drug may be beneficial in patients with gastroduodenal and small bowel CD. Another preparation is a delayed release mesalamine preparation with a pH-dependent acrylic resin (eudragit) coating. The coat dissolves at a pH of 7 which usually occurs in the distal ileum and proximal colon. Olsalazine conjugates two 5-ASA molecules and connects them with a diazo bond which is cleaved in the colon by colonic bacteria. Olsalazine is not used frequently as it has a bothersome common side effect: diarrhea. Balsalazide is another 5-ASA product which was recently approved by the FDA. It is a prodrug in which the 5-ASA is linked via a diazo bond to an inert carrier molecule. The 5-ASA is released in the colon by action of colonic bacteria.
    5-ASA is also incorporated into topical agents such as suppositories and enemas. These are used to treat left sided colitis, proctosigmoiditis, or proctitis.
    5-ASA agents work by inhibiting cyclooxygenase and 5-lipoxygenase pathways of arachidonic acid metabolism providing an anti-inflammatory effect. 5-ASA agents also alter the immune system by diminishing antibody secretion and lymphocyte function. These drugs may also act as scavengers of reactive oxygen metabolites and may reduce neutrophil and macrophage chemotaxis.

  2. Corticosteroids
    Corticosteroids have long been used in the management of IBD. At pharmacological doses the biologic effects of steroids have beneficial and significant deleterious effects. Steroids are useful in active disease but, because of long term side effects (osteoporosis, diabetes, hypertension, glaucoma, cataracts, poor wound healing), they are not useful as maintenance therapy. Steroids reduce pro-inflammatory cytokine production, inhibit a variety of leukocyte functions, and interfere with arachidonic acid metabolism. Steroid drugs may be administered orally, intravenously, or topically in enema formulations.
    Corticosteroids have consistently been shown to be highly effective in moderate to severe UC and CD. However, no benefit has been shown for maintenance of remission. There are some patients who are unable to wean off of steroids and are therefore termed “steroid dependent”. Newer corticosteroids have been developed which have high potency but low bioavailability which minimize the side effects. Budesonide is such a drug which is available in an enema formulation and a delayed release capsule.

  3. Antibiotics
    Antibiotics (classically metronidazole, ciprofloxacin, or clarithromycin) have been used to treat primarily ileal CD, fistulas, and abscesses. Clinical trials have clearly shown a benefit in the use of metronidazole for perianal CD but otherwise clinical trial data is less clear on the benefit of antibiotics. Antibiotics are not usually used in UC but one recent trial showed some benefit in patients with UC who took ciprofloxacin.

  4. Immune Modulators
    The thioguanine agents 6-mercaptopurine (6-MP) and azathioprine (AZA) are used in CD and UC primarily for patients who are steroid dependent. AZA is a prodrug which is rapidly converted to 6-MP. The final active metabolite, 6-thioguanine (6-TG), is incorporated into ribonucleotides exerting an antiproliferative effect on mitotically active lymphocytes. 6-MP and AZA also possess direct anti-inflammatory properties and inhibit cytotoxic T-cell and natural killer cell function. Metanalysis have shown 6-MP and AZA to be beneficial in maintaining remission in CD and UC with a steroid-sparing effect. These drugs are also beneficial in patients with fistulizing CD. Side effects include bone marrow suppression (neutropenia, anemia), pancreatitis (5% incidence), elevated liver enzymes (rare), and possibly increasing the risk for non-hodgkins lymphoma (although this remains a hotly debated issue).
    Other immune modulators include methotrexate and cyclosporine which are used less frequently.

  5. Biological Response Modifiers
    Infliximab is a chimeric monoclonal IgG1 antibody directed against TNFα. The antibody neutralizes TNF and effectively clears it. Infliximab is given by a single intravenous infusion. Infliximab is approved for use in moderate to severe CD and fistulizing CD (approved by the FDA in 10/1998). Clinical responses to infliximab have been remarkable – 65% of patients responded after 4 weeks compared to 17% in the placebo group. Improvement or closure of fistulae has also been impressive. The long-term use of infliximab is not yet known but one year treatment studies have been reported confirming prolonged responses in patients who received repeated doses at 8 week intervals.
    Other biological agents include other anti-TNF antibodies as well as IL-10, IL-11, and anti-integrin antibodies (alpha-4 integrins) which are in clinical trials in patients with CD and UC.iuiiu.

  6. Other Agents

    Probiotics : Nonpathogenic bacteria (yogurt organisms like lactobacillus) which repopulate the intestinal flora with “good” bacteria. Studies are very preliminary with the use of these agents in UC and CD.
    Thalidomide : banned by the FDA except in clinical trials due to the teratogenic effects but it is effective as an anti-TNF( agent. Early clinical trials in CD have been encouraging.
    Nicotine : Transdermal nicotine has been used to treat mild to moderate UC given the observation that patients who smoke have lower risk of developing UC. Randomized controlled trials have shown modest benefit with few side effects.

7.2. Surgical Therapy

Medical therapy is central to the management of IBD. However, approximately 50% of patients with IBD will require at least one surgical procedure. It is very important to distinguish between CD and UC before considering surgical therapy as CD will recur in most patients and UC is usually cured after total colectomy. Indications for surgery include catastrophic complications of IBD such as massive hemorrhage, perforation, fulminant colitis, toxic megacolon, and acute bowel obstruction. Other indications include colonic dysplasia or cancer. More nebulous indications for surgery include intractable disease that fails to respond to medical therapy.

In UC, a total colectomy with ileal pouch-anal anastomosis can be performed which prevents the need for a colostomy (see Figure 5). In CD the surgical procedure performed is dictated by the location and extent of disease.

Figure 5. Ileal Pouch-anal Anastomosis Anatomy. Image not available due to copyright restrictions.