MENU Etiology Pathogenesis Clinical Manifestation Treatment Nursing Care Case Study References

Inflammatory Bowel Disease 101 Inflammatory Bowel Disease Inflammatory bowel disease is a complex disorder character by the chronic inflammation of the digestive tract. There are two types of Inflammatory bowel disease; Ulcerative Colitis (UC)and Crohns Disease(CD). (Ferguson et al , 2007) Although Crohns Disease and Ulcerative Colitis are two forms of polygenic diseases that share similar manifestations, the two disease possess differentiating factors based primarily on their location and nature. Crohn's Disease Crohns Disease is a progressive that causes inflammation of the digestive tract. Crohn's disease can affect any part of the digestive tract, from the mouth to the anus, but normally affects the lower part of the small intestine, called the ileum. Affected organs usually experience swelling. Swelling extends deeps into the tissue lining of the infected organ. Swelling can cause pain and increase intestinal motility, resulting in diarrhea.(National Institution of Health, 2006 ) Ulcerative Colitis Ulcerative colitis is a disease that causes inflammation and sores, called ulcers, in the lining of the rectum and colon. Ulcers form where inflammation has killed the cells that usually line the colon, then bleed and produce pus. Inflammation in the colon also causes the colon to empty frequently, causing diarrhea. (National Institution of Health, 2006 )

                                                                                                                                                                  Next Section: Etiology

Etiology

Like most inflammatory and autoimmune disorders, CD and UC are caused by an interaction between genetic, immune and environmental factors.

Please one of the following:

Environmental Factors                                               Genetic Factors                                               Immununological Factors

Previous Section: IBD 101                                                                                                               Next Section: Pathogenesis

Etiology: Environment Factors

Environmental factors affecting the development of IBD

1. Smoking Cigarette smoking plays an integral role in the development of CD. Although cigerette smoking does play an important role in the development of UC, it is important to note that people who frequently develop UC are non smokers.Smoking affects both systemic and mucosal immunity, altering a wide range , altering a wide range of both innate and adaptive immune functions. Smoking Alters the ratio of T-helper to T-Suppressor cells, reduces T cell proliferation, modulates apoptosis and significantly decreases serum and mucosal immunoglobulin levels. Furthermore, smoking enhances small bowel permeability and colonic mucus production.
2. Diet
   Diet and food allergens have been linked to the etiology of both UC and CD. Foods and substances food to have the most profound effect on the development of IBD include: Alcohol, sugar and artificial sweeteners and foods containing high amounts of fatty acids.
3. Drugs
   Drugs such as oral contraceptives and NSAIDs have been hypothesized to correlates with the development of both UC and CD. Although proof that oral contraceptive, may cause IBD is ambiguous,studies have found that NSAIDs accelerate an in some cases worsen the colonic inflammation associated with blockade of protective prostaglandins and altered mucosal immune activity.
4. Geographical Location, Social Economic status, education and occupational status
   Traditionally, IDB has been intimately linked with Western and European societies. IDB more commonly affects white and blue collar workers. IDB is more common in indoor workers than it is in outdoor occupational workers. This can be attributed to the fact that individuals who work indoors tend to be more sedentary. This lack of activity in turn prolongs the time during which food antigens are in contact with the gut wall resulting in inappropriate stimulation and an inflammatory reaction.
5. Stress
   Although stress has not been identified as a primary cause of IDB in and of itself, it has been known to modulate the course of IDB. The exact mechanism underlying stress-induced exacerbation of IDB is unknown.
6. Microbial factors
   Several microoganisms such as; Listeria monocytogenes, Chlamydia tracomatis, Escherichia coli, Cytomegalovirus, Saccharomyces cerevisiae have been proposed to play an etiological role in the development of IDB. A viral etiology of IBD has also been identified within the recent years. Viral agents play a greater contribution in the development of Crohns Disease than Ulcerative Colitis. The finding of paramixovirus-like particles in Crohn's Disease endothelial granulomas suggests that Crohns Disease may be caused by the persistence of the Measles virus in the endothelial mucosa.
7. Intestinalpermeability
   Although not an environmental factor per se intestinal permeability has been postulated as an early predisposing factor to the pathogenesis of Crohn's Disease. Increased permeability as a result of increased entry of antigenic material has a known impact on the mucosal immune response to dietary and enteric bacterial antigens.

(Danese, Sans and Fiocchi, 2004)

Return back to Etiology                                                                                            Next Section:Genetic factors affecting IBD

Etiology: Genetic Factors

Genetic factors influencing affecting the development of IDB

Since the discovery of key areas of the IDB1 such as NOD2/ CARD15 , approximately nine distinct loci have been identified to play a role in the development of IDB. Genes associated with the development of IDB have been identified to affect bacterial recognition, immune response, mucosal transport or polarity. (Furguson et al 2007)

1. Genes affecting bacterial recognition
   
   • Autophagy-related 16 like 1 (ATG16l1)
     ATG16L1 has been identified as part of the autophagosome pathway playing an important role in the processing of bacteria.
   • Human beta defensin B2, B3, B3
     Studies have identified that patients with mutation in the CARD15 gene exhibit weaker expressions of the defensin gene.Of the most effected is the expression of human alpha defensin in the ileal Paneth cells. Individual with IDB also exhibit a reduction in the expression of Human Beta defensin within the colon, specifically the epithelial beta defensins HBD2, HBD3 and HBD4.
   • Caspase-activatin recruitment domain 15(CARD15)
     CARD15 has been strongly associated with the development of CD. The CARD15 encodes the Nucleotide-binding oligomerization domain-containing protein (NOD2) which has been thought to protect individuals against invasive bacteria, by eliminating intracellular pathogens in the epithelial cells at the gastrointestinal mucosa barrier. CARD15 functions as sensor for the presence of peptidoglycan located in the cell walls of bacteria. CARD15 is expressed by Macrophage cells and intestinal paneth cells and is involved in modulating the activity of the immune related transcription factor, NF Beta Kappa.
     
     CD has been linked to the pericentrometric region of chromosome 16. CARD15 acts as a susceptibility allele, with three polymorphisms R702W, G908R and 1007fs. Distinctive phenotypic associations with CD suggests that most CD patients with the CARD15 gene tend to be people of younger European descent with a family history of the disease as well as an obstructive or stenosing disease located in the ileum.
2. Genes affecting Immune response
   
   • Major Histocompatibility complex (MHC)
     Studies have shown that the IBD3 locus on chromosome 6p, containing the MHC region has been associated with development of UC.
   • Interleukin-23 receptor(IL23R)
     The IL23R gene located on chromosome region 1p31 is responsible for encoding a subunit of the receptor for IL23, a pro inflammatory cytokine.IL23 R has been associated with the development of CD
   • Toll-like receptor (TLRs)
     Toll receptors are pattern that induce innate immune responses in antigens-presenting cells, such as dendritic cells, which themselves are linked to adaptive immune response.TLR4 located in the gut lymphoid and epithelial cells act by sensing components of the colonic microbiota and inducing innate immune responses TLR4 are located on chromosomal region 9p. TLR4 plays a role in the development of both UC and CD.
3. Genes affecting mucosal transport
   
   • Sodium dependent organic cation transporters (SLC22A4 and SL22A5)
     SLC22A4 and SLC22A5 have been associated with the IBD5 locus responsible for the development of CD in adults. SLC22A4 and SLC22A5 genes function in the transport of 1-carnitine and elimination of cation drugs in the intestines
   • ATP-binding cassette subfamily B member 1 (ABCB1)
     The ABCB1 gene is located at the chromosomal region7q21.1. This gene encodes for adenosine triphosphate-dependent efflux transporter pump protein.ABCB1 is highly expressed in the epithelial surface of the intestines, where it plays a role in the protection of the epithelium against xenobiotics. ABCB1 has been suggest to be involved in the development of UC.
   • Drosophila discs large homologue 5(DLG5)
     The DLG5 gene is located on chromosome region 10q23. DLG5 is widely expressed in the small bowel, intestinal epithelial cells and colon. DLG5 has been associated with the development of Crohn's disease

(Furguson et al 2007)

Previous Section:Environmental factors affecting IDB           Back to Etiology                       Next Section: Immunological factor

Etiology: Immunological Factors.

Immunological factors affecting the development of IBD

Over the past decade science has been able to identify the role that both immune and nonimmune systems play in the mediation of IBD. In this section we highlight the role of humoral immunity, Cell mediated immunity, nonimmune cells, mediators of immune regulation and inflammation, mediators of healing and injury, and Mediators of cell contact play in the development of IBD. Although dysfunctions in the immune system are not primary causes of IDB they play an integral part in the pathogenesis of IBD

Humoral Immunity

• Mucosal B cells
  The development o f IDB results in the production of a humoral response, marked by striking increases in the production of immunoglobulin G(IgG). These surges in IgG production can be used to distinguish between the two forms of IBD. Different subclasses of IgG are expressed in each of the two forms of IBD. Individuals affected by UC experience an increase in IgG1. Conversely, those affected by CD experience an increase in IgG2.
• Autoantibodies and Autoantigens
  Individuals Patients with IBD display an array of circulating antibodies that seldom correlate with disease activity. Anticolon antibodies are not disease specific, nor are they tissue specific. Despite the lack of specificity in most cases it has been found that serum antibodies to Saccharomyces cerevisiae (Baker's yeast) increase in individuals with CD but not in individuals with UC.
• Antineutrophil cytoplasmic antibodies
  Studies have found a high prevalence of perinuclear antineutrophil cytoplasmic antibodies (pANCAs) in individuals with UC. These antibodies are found in a lesser degree in individuals with CD.
Cell-Mediated Immunity

• Systemic Immunity
  A study by Broberger and Perlmann indentified that immune cells (cytotoxic cells) implicated in the development of UC were capable of recognizing and destroying intestinal cells.
• Mucosal T cells
  CD can develop as a result of diffuse infiltration of the intestines by immune cells in the absence of obvious inflammation. CD68+ macrophages and lymphocyte cells can go by undetected in the "unaffected" mucosa of Individuals with CD and accumulate, resulting in tissue destruction and inflammation.
• Monocytes and Macrophages
  Macrophages have been found to be present in early IBD lesions, as illustrated by the presence of HLA- DR+ and ICAM-1+ cells in aphthous ulcers.
• PMNs, eosinophils Basophils and Mast Cells
  PMNs play a role in the amplification of inflammation in damaged tissues. Activation of mast cells leads to degranulation in IDB.
Nonimmune Cells
One of the most important developments in intestinal immunity is the realization that local immune cells are functionally integrated with nonimmune origin
• Epithelial cells
  Individuals with IBD often express abnormalities in epithelial cell phenotype and function. An abnormality in epithelial cells in the colon results in the defective capacity to induce suppressor T cells. Over time this abnormality may lead to the amplification of local immune reactivity and inflammation.
• Mesenchymal cells
  Mesenchymal cells function as structural cells, producing a variety of extracellular matrix proteins, needed in intestinal fibroblasts. Alterations in the production of Mesencheymal cells leads to an increase in the production of collagen type III, resulting in a thickening of the intestinal walls of individuals with CD.
• Nerve cells
  There enteric nervous system connects the neuroendocrine system to the immune system in the gut. Alterations in enteric neuromuscular function affect both motility and inflammation. An increase in stress, increases enteric neuromuscular activity resulting in inflammation of the intestines. Inflammation of the intestines leads to an expression of different concentrations and receptor density for substance P in CD. This expression differs from that expressed in the UC involved mucosa.
• Endothelial cells
  Microvascular endothelial cells function as the " gate keepers "of inflammation. Damage to these cells, as in the case of IBD, enhance intestinal mucosal endothelial cells' capacity to bind leukocytes, resulting in the persistence of the inflammatory response.
Mediators of Immunoregulation and Inflammation

• Immunoregulator cytokines
  Individuals affected by UC exhibit decreased Interleukin - 2 bioactivity in the intestinal mononuclear cells. This is not the case concerning individuals affected by Crohn's disease. Individuals with active CD exhibit an increase in IL-2 mRNA. The production of interferon gamma by the intestinal mucosal mononuclear cells has been thought to suppressed in both forms of IBD. However, spontaneous release of interferon gamma intestinal mucosal mononuclear cells increases interferon gamma mRNA expression by lamina propria mononuclear cells and the presence of interferon gamma secreting cells in actively inflamed mucosa. Research has found decreases in interleukin-4 in both individuals with UC and CD. Studies have found increases in interleukin 5 production in individuals with UC. A decrease in the production of interleukin 5 was found in individuals with CD.
• Proinflammatory cytokines
  Proinflammatory cytokines have been found in high concentrations in both Ulcerative Colitis and CD. Although not specific to IBD, high concentrations of IL-1 have been found in the gut. Elevated levels of Tumor necrosis factor - alpha have be associated with the development of UC and CD in children. IL-6 Levels have been found to be high in individuals with CD but not those with UC.

Previous Section:Genetic factors affecting IBD          Return to Etiology                               Next Section: Pathogenesis

Pathogenesis

Pathophysiology

Ulcerative Colitis

• It begins in the rectum (proctitis) and spreads proximally along the entire colon (pancolitis) in a continuous fashion.
• The mucosa of the rectum and the colon is hyperemic and edematous in the affected area.
• Multiple abscesses develop in the crypts of Lieberkuhn (intestinal glands).
• As the disease advances, the abscesses break through the crypts into the submucosa, leaving ulcerations.
• These ulcerations destroy the mucosal epithelium, causing bleeding and diarrhea – the loss of fluid and electrolytes caused by the decreased mucosal surface are for absorption.
• Protein loss through the stool is also evidenced due to breakdown of cells.
• Areas of inflamed mucosa can form pseudopolyps, tonguelike projections into the bowel lumen.
• Granulation tissue develops, and the mucosa musculature becomes thickened, shortening the colon.

Crohn’s Disease

• It is characterized by inflammation of segments of the GI tract.
• It can affect any part of the GI tract
  • Most often seen in the terminal ileum and the colon.
  • Involvement of the esophagus, the stomach, or the duodenum is uncommon.
• T-helper cell cytokines such as interleukin-12 and tumor necrosis factor (TNF) stimulate the inflammatory response, which begins in the intestinal submucosa and extends to all the layers of the bowel wall.
• Activated neutrophils and macrophages promote inflammation and cause tissue injury.
• The inflammation can affect some segments of the intestine but not others resulting in discontinuous skip lesions.
• Ulcerations are deep and longitudinal and penetrate between islands of inflamed edematous mucosa, causing the classic cobblestone appearance.
• Thickening of the bowel wall occurs, as well as narrowing of the lumen with stricture development – promotes obstruction.
• Abscesses or fistula tracts that communicate with other loops of bowel, the skin, the bladder, the rectum or the vagina may develop.
• Histologically, granulomas are present in 50% of clients and may be located in any layer of the bowel wall – giving the affected area a cobblestone appearance.

Previous Section: Pathogenesis                                      Home                                            Next Section:Clinical Manifestations

Clinical Manifestation

Clinical Manifestations

As IBD is a chronic intermittent disease, symptoms can range from mild to severe during relapses and may decrease or even disappear during remissions. Symptoms generally depend on the section of the bowel involved.

Ulcerative Colitis

UC consists of chronic intermittent periods of exacerbation and remission that occur unpredictably, but it can also appear as an acute crisis. The major symptoms are bloody diarrhea and abdominal cramping pain. In mild UC, less mucosa is involved so the frequency of bleeding, bowel movements and pain, is minimal. In moderate UC, there is an increase in stool output (4-5 per day), increased amount of bleeding, and increased systemic symptoms such as fever, malaise, and anorexia. Severe forms of UC can involve the entire colon and are characterized by frequent bloody stools containing mucus (10-20 stools per day), urgency, tachycardia, and continuous and cramping pain. In addition, weight loss of more than 10% of total body weight, dehydration, fever, and anemia are present, resulting from fluid loss, bleeding, and inflammation.
Complications can include hemorrhoids, anal fissures, and perirectal abscess. Hemorrhage can result from inflamed, ulcerated mucosa, but severe hemorrhage is rare. The most common complications are fulminant colitis, bleeding, and toxic megacolon, which is extensive dilation and paralysis of the colon. Edema, fibrosis, and strictures can obstruct the colon. Perforation is possible although it is unusual, mostly occurring in the left side of the colon. Having UC for more than 10 years puts an individual at a greater risk of developing colorectal cancer. Extraintestinal manifestations include alterations in coagulation, hepatobiliary disease, and polyarthritis. The most common extraintestinal complications are skin lesions such as erythema nodosum and pyoderma gangrenosum.

Crohns Disease

Clinical manifestations of CD vary according to the anatomic site involved, the extent of the disease process, and the presence of complications. Onset of symptoms is usually insidious with nonspecific complaints. The major symptoms are diarrhea and abdominal pain, and occasionally, rectal bleeding if the colon is involved. The diarrhea is usually non-bloody and results from inflammation or malabsorption. The pain can be severe and intermittent, or constant. Weight loss, fatigue, and fever can accompany CD. Other manifestations include abdominal cramping, tenderness, and distension. Malabsorption of vitamin B12 (leading to anemia) and vitamin D can occur. Folic acid can be deficient and proteins may be lost (leading to hypoalbuminemia). Extraintestinal manifestations can include arthritis and finger clubbing. As the disease progresses, malnutrition, weight loss, electrolyte imbalances, dehydration, anemia, increased peristalsis, right lower quadrant and umbilical pain, and perianal disease can occur.
Complications include strictures and obstruction, fistulas between segments of the bowel, cutaneous fistulas, and urinary tract infections from fistulas that communicate with the urinary tract. Perforations, peritonitis, and formation of intra-abdominal abscesses can occur as a result of the inflammation of the bowels that may involve all layers. Damage to the intestinal mucosa causes the impaired absorption that leads to nutritional abnormalities. Extraintestinal complications are similar to those of UC and include renal disorders such as nephrolithiasis, ankylosing spondylitis, pyoderma gangrenosum and erythema nodosum, uveitis, liver disease cholelithiasis, and arthritis.
Clinical manifestations and complications of IBD are summarized in the following chart:
,

	Ulceraterive Colitis	Crohn's Disease
Clinical Manifestations
Diarrhea	Common; 4 times/ day	Common(May or may not be present)
Blood stools	Common	Less common
Abdominal pain	Mild to severe	Moderate to severe
Cramping	Possible	Common
Rectal Bleeding	Common	Fairly common
Abdominal mass	Rare	Common
Weight loss	Common	Common/Severe
Fever(intermittent)	During acute episodes	Common
Tenesmus	Severe	Rare
Malabsorption and Nutritional deficiences	None/Minimal incidence	Common
Co-Morbities	Extraintestinal manifestations	Extraintestinal manifestations
Clinical Course	Exacerbations and remissions	Exacerbations and remissions
Complications
Fistula	Rare	Common
Anal abcesses	Rare	Common
Strictures	Rare	Common
Perforation	Common	Common
Toxic megacolon	Common	Rare
Carcinoma	Increased incidence after 10 years	Slightly greater than the general population
Recurrence after surgery	Cure with Colectomy	40 - 60% or more recurrence after segmental resection of the small or large bowel

Previous Section: Pathogenesis                                                  Home                                                  Next Section:Treatment