Inflammatory bowel disease is characterized by repetitive episodes of inflammation of the gastrointestinal tract caused by an abnormal immune response to gut microflora. Inflammatory bowel disease (IBD) encompasses two types of idiopathic intestinal disease that are differentiated by their location and depth of involvement in the bowel wall. Ulcerative colitis (UC) involves diffuse inflammation of the colonic mucosa. Most often UC affects the rectum (proctitis), but it may extend into the sigmoid (proctosigmoiditis), beyond the sigmoid (distal ulcerative colitis), or include the entire colon into the cecum (pancolitis). Crohn disease (CD) results in transmural ulceration of any portion of the gastrointestinal tract (GI) most often affecting the terminal ileum and colon. Both diseases are classified by extent (mild, moderate, or severe) and location. CD also is classified by phenotype- inflammatory, structuring, or penetrating.
Besides the GI tract, both Crohn disease and ulcerative colitis have many extraintestinal manifestations. While in most patients, the disorders can be distinguished, in at least 10% of patients, the features are so similar that it is not possible to initially differentiate between the two disorders.
Both disorders have a genetic predisposition; neither is curable and they both carry enormous morbidity. Finally, both increase the risk of colorectal cancer.
IBD occurs in genetically susceptible individuals after an inappropriate immune response to the intestinal flora.
To date, the cause of IBD remains a mystery. Many causes have been implicated but none is universally present in all patients. The one consistent feature of Crohn disease is that it has a strong link with tobacco. On the other hand, it appears that smoking protects against ulcerative colitis. The role of diet remains debatable.
The CARD15 gene has been associated with IBD but because of its polymorphic features, it is not possible to determine which part of the GI tract will be affected. The role of genes in ulcerative colitis is not as strong as in Crohn disease.
The North American incidence of IBD ranges from 2.2 to 19.2 cases per 100,000 person-years for ulcerative colitis and 3.1 to 20.2 cases per 200,000 person-years for CD. Prevalence in the United States of adult ulcerative colitis was 238 per 100,000 population and 201 per 100,000 population from data in a large study based on insurance claims. IBD is much more prevalent in North America and Europe than in Asia or Africa. Although most IBD occurs in people age 15 to 30 years, up to 25% of patients will develop IBD by adolescence. There appears to be a bimodal distribution with a second peak of 10% to 15% developing IBD after age 60.
Crohn disease is slightly more common in females compared to males, but ulcerative colitis appears to be equally present in both genders. IBD is generally a disorder of developed countries and colder climates.
The intestinal immune system is key to the pathogenesis of IBD. The intestinal epithelium prevents bacteria or antigen entry into the circulation by sealed intercellular junctions. In IBD, these junctions are defective from either a primary barrier function failure or as a result of severe inflammation. Additional protective mechanisms include mucus production by goblet cells and Paneth cells secretion of a-defensins with intrinsic antimicrobial activity. Excessive inflammatory reactions lead to continued deterioration of the epithelium and further exposure to intestinal microbes thereby furthering worsening the inflammation.
In ulcerative colitis, there is always mucosal inflammation that leads to edema, ulcers, bleeding and electrolyte losses. The inflammation in ulcerative colitis usually starts in the rectum and progresses in an uninterrupted fashion to the proximal colon. In Crohn disease, there are skip lesions. In close to 20% of patients with UC, the disease remains confined to the rectum. Pancolitis is seen in about 15% of patients. As the disorder becomes chronic, the colon becomes more rigid and short with a loss of the haustral markings leading to a 'lead-pipe' appearance on a barium enema.
Crohn disease can affect any segment of the GI tract; the disease may induce strictures, inflammation or lead to the development of fistulas. The key feature of Crohn disease is that it involves all layers of the bowel (transmural). During the later phase of the disease, the mucosa will reveal a cobblestone appearance due to the linear ulcers between the normal mucosa. Crohn disease most affects the colon and ileum and only 5% of cases affect the gastroduodenal segments. Sparing of the rectum is typical of Crohn disease but anorectal complications like fistulas and abscesses are very common.
UC predisposes patients to the extraintestinal involvement of the skin, eyes, and bones. Most commonly these involved inflammatory arthropathies and primary sclerosing cholangitis. CD preferentially attacks the ileum and colon but can involve the esophagus, duodenum or stomach. Pediatric-onset cases have greater upper GI tract involvement. As in the case of UC, CD predisposes patients to extraintestinal manifestations including arthritis, aphthous stomatitis uveitis, erythema nodosum, and ankylosing spondyloarthropathy.
In Crohn disease, the incidence of kidney disease and gallstones is high because of malabsorption of bile salts and fatty acids. Patients with Crohn disease who undergo resection of the ileum but intact colon are also more likely to develop calcium oxalate renal stones.
Microscopic evaluation in active IBD patients reveals pronounced infiltration of the lamina propria with a mix of neutrophils, macrophages, dendritic cells, and natural killer T cells. Increased numbers and activation of these cells, increases the level of tumor necrosis factor-a (TNF-a), interleukin-1b, interferon-g, and cytokines of the interleukins-23-TH17 pathway.
The histopathology in ulcerative colitis will show the involvement of only the mucosa and submucosa with the formation of cryptic abscesses and mucosal ulcers. Biopsy specimens show neutrophilic infiltrate along with crypt distortion and crypt abscesses. Granulomas are not seen in ulcerative colitis. The disease is contiguous and usually involves the rectum. Another feature of ulcerative colitis is the presence of pseudopolyps. In Crohn disease, the entire intestinal wall is involved and granulomas may be seen. Inflammation in Crohn disease is transmural characterized by lymphocytic infiltrate.
UC most commonly presents as bloody diarrhea with or without mucus. Patients commonly describe tenesmus, a sensation of incomplete evacuation, and abdominal pain. The physical exam may reveal predominantly left lower or left upper quadrant abdominal pain. Signs of an acute abdomen including guarding, rebound tenderness or percussion tenderness warrant investigation for toxic megacolon.
Presentations of Crohn’s disease vary considerably depending on the region of gastrointestinal involvement. Manifestations vary based on the underlying etiology of inflammation, fistula formation, or stricture formation. The symptom complex of right lower quadrant pain, weight loss, and non-bloody diarrhea are suggestive of Crohn disease flare-up. Fistula formation may result in fecaluria, pneumaturia, and rectovaginal fistulas. Masses in the right lower quadrant suggest an abscess.
Affected children may present with growth retardation and/or delay in sexual maturation.
The World Gastroenterology Organization based symptoms for IBD:
Diagnosing IBD requires a combination of clinical findings, inflammatory laboratory markers, imaging findings, and endoscopic biopsies. Hematologic findings include microcytic anemia, leukocytosis, and thrombocytosis, Inflammatory markers such as the erythrocyte sedimentation rate (ESR) and high-sensitivity C-reactive protein (hsCRP) are commonly elevated.
In some patients, the diagnosis may require ruling out parasitic disease like giardia, amebiasis, tuberculosis, and Strongyloides.
Complete blood count will identify anemia, leukocytosis and albumin levels.
Fecal calprotectin levels can be used as a marker for intestinal inflammation. Levels of perinuclear antineutrophilic cytoplasmic and anti-saccharomyces cerevisiae antibodies may be elevated in Crohn disease. Finally, stool studies must be done to rule out ova and parasitic organisms.
The abdominal x-ray can assess for the presence of free air, bowel obstruction or toxic megacolon.
Barium studies are done to characterize the bowel disease; a lead pipe appearance indicates ulcerative colitis; sparing of the rectum is indicative of Crohn disease and thumb printing is indicative of mucosal inflammation. Further, the barium studies may reveal skip lesions and stricture formation in the ileum, which are indicative of Crohn disease.
Ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI) have all been used in the diagnosis of IBD or to assess for complications. US usage in trained individuals can evaluate the right lower quadrant for ileal disease. MRI can evaluate for rectal fistulas. Most commonly, CT is employed to evaluate for perforation or bowel obstruction. CT enterography can be helpful in assessing for strictures or in operative planning.
Endoscopy evaluation with either esophagogastroduodenoscopy, colonoscopy, or both is essential to obtaining biopsies to confirm a diagnosis of IBD.
The goal of treatment is to induce remission for either UC or CD. Treatment of IBD is divided into the management of the mild, moderate, and severe disease. Agents formerly reserved for the more severe disease are now employed sooner. UC treatment depends greatly on the extent of disease and presence of extraintestinal manifestations. For those with mild to moderate disease limited to the rectum, aminosalicylate agents like mesalamine are mainstays. Mesalamine is administered rectally but may be combined with oral therapy to induce or maintain remission. For those patients with the moderate disease who are refractory to mescaline, oral glucocorticoids or immunomodulators such as TNF-a monoclonal antibodies (infliximab) may be an option. Up to 25% of all UC patients will require total colectomy for the uncontrolled disease. Proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the procedure of choice for elective cases.
Flareups are usually managed with corticosteroid therapy. For those who have more than 1-2 flareups a year, the use of anti-TNF agents or other immunosuppressive is recommended.
CD treatment depends on the portion of the GI tract involved, the degree of fistulizing or structuring, and any extraintestinal complications. Treatment of mild ileocecal disease is usually begun with mesalamine, which can be further augmented with the use of oral budesonide, a steroid with significant first-pass metabolization to limit systemic side effects. For more extensive disease, systemic steroid therapy with prednisone is necessary. The goal is to wean these steroids within six weeks. In those patients who cannot wean, an immunomodulating agent is added. 6-mercaptopurine (Purinethol), azathioprine (Imuran), or low-dose methotrexate. In those patients with moderate to severe disease, anti-tumor necrosis factor (anti-TNF) should be initiated. Before initiating biologic therapy, patients must complete purified protein derivative (PPD) to assess for latent tuberculosis. Surgical treatment may be necessary for those with severe fistulizing disease including diverting ostomy.
It is vital to assess the bone density in patients who are administered steroids; osteoporosis has significant morbidity in these patients. If steroid use for more than 3 months is expected, then calcium supplements and bisphosphonates should be introduced.
A stepwise approach that is used for IBD management is outlined below.
The first step in pharmacologic therapy for IBD is aminosalicylates. If the patient does not respond to an appropriate dose of aminosalicylates, the second step is the addition of corticosteroids, which tend to result in a significant decrease in inflammation. Once the response is seen, the dose can be tapered.
The immune-modifying agents (e.g Anti-TNF agents) are the step III drugs. These are used when the patient does not respond to corticosteroids, steroids are required for prolonged periods, or the steroids cannot be tapered down without recurrence of symptoms.
Lately, a step-down approach is being favored more for patients with high-risk or severe disease. This includes the early introduction of higher step medications such as anti-TNF agents with rapid de-escalation when the response is seen. Step down approach improves patient outcomes and prevents complications in patients with high-risk or severe disease.Step IV includes clinical trial agents that tend to be disease-specific i.e some work only for ulcerative colitis and other for Crohn disease. Examples of these experimental agents include thalidomide and interleukin (IL)-11 for Crohn disease, butyrate enema, nicotine patch, and heparin for ulcerative colitis. Multiple contraindications and serious side effects are associated with these experimental agents.
In patients presenting with new diarrhea, infectious etiologies of diarrhea including parasites Escherichia coli 0157:H7 and Clostridium difficile must be ruled out first. Other colitis etiologies should be considered including, but not limited to, microscopic, lymphocytic, and collagenous. Those presenting with abdominal pain must have other causes considered as well including, but not limited to, appendicitis, irritable bowel disease, celiac disease and functional abdominal pain.
The objective measure that is most commonly used for Crohn disease is Crohn Disease Activity Index (CDAI). This index, which includes patients' demographic characteristics, subjective complaints and symptoms, laboratory values, and extraintestinal findings, classify the disease activity. Different online tools are available to calculate this score and help predict the disease stage. Another tool for Crohn disease is Harvey-Bradshaw Index (HBI). Similarly, such tools are also available for ulcerative colitis and include Simple clinical colitis activity index (SCCAI), Mayo Score / Disease Activity Index (DAI), and Seo index for disease quantification.
The prognosis for both UC and CD depends on the extent of disease and treatment response. The stool markers lactoferrin and calprotectin are useful in determining postoperative recurrence of CD. Some evidence exists that these can also be used to predict future flares. However, patients with IBD tend to have much higher mortality compared to the general population. Causes of death include primary disease, infections, and respiratory illness. Heart disease is not a risk factor for death in IBD. Finally, psychological morbidity is very high in IBD patients and the quality of life is poor.
Continued surveillance for dysplasia is critical for long-standing UC patients. Cumulative risk of colorectal cancer is estimated to be as high as 30% for those with the disease of 30 years or more. The extraintestinal manifestation of primary sclerosing cholangitis leads to liver failure.
Patients with IBD need life long follow up for their disease. There is no particular diet or supplement that has been shown to delay or prevent the symptoms of the disease.
There are several gaps in our knowledge regarding the care of patients with IBD. Even though many advances have been made in treatment, a number of patients continue to miss out on these treatments. The best care for patients with IBD is from an interprofessional team that is dedicated to this pathology and is fully aware of the latest guidelines. Patients with IBD lead an unpredictable life with constant flare-ups and hence the interprofessional team should establish dedicated phone and support lines staffed by nurses and pharmacists. A network of healthcare providers should be easily accessible to deal with emergencies. Physician and allied healthcare collaboration are vital if one is to avoid delay in treatment. The goal is to halt the disease before widespread bowel damage and disability occurs. Furthermore, patient and healthcare communication should be improved and the patients should be supported during times of crises. Finally, evidence suggests that there is a great need to establish centers of excellence so that patients receive a consistent level of quality care across different healthcare settings. (Level V)
The mortality of patients with IBD is about 1.5 -5 times higher compared to the general population. Patients with Crohn disease suffer the highest morbidity and mortality. The major cause of death include infections, the progression of disease, surgical complications, and multiorgan involvement. More important, patients with IBD also have a high rate of colorectal cancer. Patients who develop pancolitis have the highest risk of colon cancer within two decades. Hence screening colonoscopy is recommended at 1-2 year intervals.
In addition to the disease, these patients are also managed with potent medications like steroids and biological agents, which have a host of adverse effects. Thus, the importance of the pharmacist who should be alert for any adverse reaction. Patients with IBD are also at risk for asthma or COPD.
Finally, IBD has enormous mental morbidity. Many patients develop depression, suicidal tendencies, and anxiety. thus, at every visit, the nurse should monitor the patient's mental status and make appropriate referrals.
The quality of life for most patients is poor to okay.
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