28 Inflammatory Bowel Disease (Including Pharmacology) (1) Flashcards Preview

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1

Crohn's Disease and Ulcerative Colitis

  • 2 major forms of/
  • characterized as/
  • etiology
  • Despite effective medications, a large percentage of people with IBD require/

  • 2 major forms of inflammatory bowel disease (IBD).
  • characterized as chronic inflammatory diseases with spontaneously relapsing and remitting courses.
  • etiology
    • a genetically susceptible host mounts an inappropriate immune response to an otherwise innocuous environmental or infectious agent that results in chronic systemic inflammation particularly affecting the gastrointestinal tract.
    • The inappropriate host immune response to intestinal bacteria and antigens (self) and a defect in the intestinal epithelial layer, i.e. “leaky” or permeable, appear to be important factors in the immune mediated process.
  • Despite effective medications, a large percentage of people with IBD require surgery at some point during their life.

2

Epidemiology

  • The highest reported incidence of IBD is in/
  • frequency
  • The most common age of onset of IBD
  • gender
  • geography
  • Historically, IBD was thought to occur primarily in/

  • The highest reported incidence of IBD is in North America and Europe and it is increasing.
  • Crohn’s disease and ulcerative colitis occur with the same frequency in the population (50:50 split),
    • UC was more common in past years
    • Crohn’s has become a more common diagnosis at the present time.
  • The most common age of onset of IBD is between 10 and 40 years with a small percentage presenting late in life or before the age of 10. 
  • slight female predominance
    • in children, there is a male predominance of Crohn’s disease prior to puberty.
  • There is a “north-south gradient” 
    • highest prevalence rates in northern latitudes
    • high rates in Florida and Arizona go against the north-south gradient, but might be explained by migration from northern states.
  • Historically, IBD was thought to occur primarily in Caucasians, especially in persons of Ashkenazi Jewish ancestry,
    • distribution among ethnic and racial groups may be changing.

3

Ulcerative Colitis:
Definition (p.9+29-30)

  • The inflammation/ulceration in ulcerative colitis
  • the description of disease is based on the extent of colon inflamed, 

  • The inflammation/ulceration in ulcerative colitis
    • confined to the mucosa,
    • always involves the rectum,
    • extends proximally in the colon in a contiguous fashion.
    • limited to the colon only
  • the description of disease is based on the extent of colon inflamed,
    • ulcerative proctitis in ~25% of cases (rectum only inflamed),
    • left-sided ulcerative colitis in ~50% of cases (inflammation involves the colon distal to the splenic flexure),
    • pan-ulcerative colitis in ~25% (inflammation extending beyond the splenic flexure).

4

Ulcerative Colitis:
Symptoms and Signs (p.11)

  • The two most typical symptoms of ulcerative colitis
  • Other common symptoms
  • uncommon unless a complication presents
  • Physical exam findings 
    • ?
    • may include/

  • The two most typical symptoms of ulcerative colitis
    • painless diarrhea
    • bleeding (usually fresh appearing blood=hematochezia).
  • Other common symptoms include rectal urgency, tenesmus, abdominal cramps and nocturnal bowel movements.
  • Unless a complication presents, e.g. toxic megacolon or cancer, severe abdominal pain, fever, and weight loss are uncommon.
  • Physical exam findings 
    • There are few physical signs of ulcerative colitis, and unless severe most people with ulcerative colitis appear well
    • may include:
      • mucosal membranes that are pale if anemia is present,
      • orthostatic hypotension if dehydration develops,
      • the abdomen is usually benign,
      • on rectal exam there is either fresh red blood or hemoccult-positive stool.

5

Ulcerative Colitis:
Diagnosis

  • The diagnosis of ulcerative colitis 
    • made by/
    • confirmed by/
  • most common symptom of ulcerative colitis
  • Someone presenting with a new onset of this symptom should always undergo/

  • The diagnosis of ulcerative colitis
    • made by careful history and physical examination
    • confirmed by endoscopic, radiologic, and pathologic testing.
  • Bloody diarrhea is the most common symptom of ulcerative colitis, but many other colitides will present with this symptom,
    • e.g. infectious colitis, medication induced colitis (such as NSAIDs), ischemic colitis, radiation colitis, and Crohn’s disease that is confined to the colon and is termed Crohn’s colitis (approximately 20% of people with Crohn’s disease have only the colon inflamed).
  • Someone presenting with new onset bloody diarrhea should always undergo stool testing for infection: bacterial culture (Salmonella, Shigella, Campylobacter, E Coli O157:H7), analysis for ova and parasites, and Clostridium difficile.

6

Ulcerative Colitis:
Diagnosis (p.37)

  • Colonoscopy
    • usefulness
    • allows/
    • Endoscopic features associated with ulcerative colitis
    • The endoscopic appearance is likened to/
  • Endoscopy
    • allows for/
    • Histological features of ulcerative colitis
    • The hallmark histologic features that differentiate ulcerative colitis from an acute infection
  • radiologic testing
    • done more for/
    • The typical feature on a plain abdominal radiograph
    • Barium enema reveals/

  • Colonoscopy
    • the most useful test to visualize the colon and make the diagnosis of ulcerative colitis.
    • allows visualization of the entire colon and terminal ileum.
    • Endoscopic features associated with ulcerative colitis include diffuse granularity of the mucosa (due to micro-ulceration), erythema, friability (bleeding upon touching the mucosa with the scope), mucopurulent exudates, and spontaneous bleeding.
    • The endoscopic appearance is likened to “wet sandpaper.”
      • Deep, large ulcers (macro-ulceration) of the mucosa may be present, but in the majority of people with ulcerative colitis, endoscopically apparent ulcers are usually not seen (in contrast to Crohn’s disease).
  • Endoscopy
    • allows for tissue biopsies and histopathologic analysis.
    • Histological features of ulcerative colitis include an inflammatory infiltrate within the mucosa, cryptitis, crypt abscesses, and a decrease in the number of goblet cells.
    • The hallmark histologic features that differentiate ulcerative colitis from an acute infection is crypt architectural distortion, with branching and shortening of crypts due to chronic injury.
  • radiologic testing
    • done more for exclusion of a complication, e.g. toxic megacolon
    • The typical feature on a plain abdominal radiograph is that of a “lead pipe” colon with loss of normal haustra, usually pronounced in the left colon.
    • Barium enema reveals shallow ulcerations, shortening of the colon, disappearance of haustra, and a rigid, nondistensible colon.

7

Ulcerative Colitis:
Complications

  • The most common complications associated with ulcerative colitis:
  • Toxic megacolon
    • frequency and severity
    • occurs in the setting of/
    • present with/
    • what may develop which requires emergency surgery.

  • The most common complications associated with ulcerative colitis:
    • significant bleeding associated with anemia
    • toxic megacolon and perforation
    • growth delay in children
    • cancer (which may present as a stricture)
      • UC patients with a colon stricture should be evaluated for cancer,
      • stricture formation in Crohn’s disease is common and usually benign
  • Toxic megacolon
    • rare but potentially life-threatening
    • occurs in the setting of severe inflammation of the colon (usually pancolonic) that results in impaired motility and dilation of the colon.
    • present with severe abdominal pain, fever, distention of the abdomen, and they appear toxic.
    • Perforation of the colon may develop which requires emergency surgery.

8

Ulcerative Colitis:
Complications

  • Patients with ulcerative colitis are at increased risk of developing/
  • Colon cancer in ulcerative colitis tends to/
    • These features are in contrast to “garden variety” colon cancer, which usually /
  • Increased risk factors associated with colon cancer in ulcerative colitis
  • Surveillance colonoscopy for dysplasia/cancer/
  • indication for a total proctocolectomy
  • Patients with PSC and ulcerative colitis require/

  • Patients with ulcerative colitis are at increased risk of developing colon cancer,
  • Colon cancer in ulcerative colitis tends to be multiple, arise from flat mucosa, infiltrate broadly, have a uniform distribution throughout colon, more extensive infiltration, more anaplastic, and occur at a younger age.
    • These features are in contrast to “garden variety” colon cancer, which usually occurs later in life, arise from adenomatous polyps, and tend to most commonly involve the left colon.
  • Increased risk factors associated with colon cancer in ulcerative colitis include the duration of disease, extent and severity of disease in the colon, concomitant primary sclerosing cholangitis (PSC).
    • After 10 years of disease, patients with pan-colitis have an increased risk of colon cancer.
    • The incidence of cancer developing in the decade between 10 and 20 years is 2-5% with an additional 1-5% developing each decade thereafter.
  • Surveillance colonoscopy for dysplasia/cancer begins after a patient has had ulcerative colitis for greater than 8 years: every 1-3 years thereafter.
  • Evidence of high-grade dysplasia or cancer on surveillance colonoscopy is an indication for a total proctocolectomy.
  • Patients with PSC and ulcerative colitis require surveillance colonoscopies annually from the year of diagnosis.

9

Crohn's Disease:
Definition (p.15+28+32)

  • ?
  • common complications

  • Inflammation of Crohn’s disease is transmural and can occur in a patchy distribution (“skip lesions”) anywhere from the mouth to the anus in the gastrointestinal tract:
    • 35% of patients with Crohn’s disease have only small bowel disease,
    • 45% have ileocolonic disease,
    • 20% have disease limited to colon (termed Crohn’s colitis).
  • Due to the transmural nature of Crohn’s disease, strictures and fistulas are common complications.

10

Crohn's Disease:
Symptoms and Signs (p.16)

  • The most common symptoms
  • Since Crohn’s disease commonly involves the ileum and right colon, some patients present with/
  • The 20% of patients presenting with Crohn’s colitis may have symptoms of/
  • Fibrostenotic strictures of the small intestine 
  • Internal and external fistulas
  • About one-third of Crohn’s patients/
  • The physical signs

  • The most common symptoms are fatigue, abdominal pain, weight loss, fever, nausea, vomiting, and diarrhea.
  • Since Crohn’s disease commonly involves the ileum and right colon, some patients present with appendicitis-like symptoms (right lower quadrant abdominal pain and fever).
  • The 20% of patients presenting with Crohn’s colitis may have symptoms of bloody diarrhea (and mimic ulcerative colitis).
  • Fibrostenotic strictures of the small intestine
    • a common complication
    • cause obstructive symptoms: nausea/vomiting, abdominal distention, bloating, and early satiety.
  • Internal and external fistulas
    • develop in 30%-40% of patients with Crohn’s disease
    • may be complicated by intra-abdominal and peri-anal abscesses, respectively.
  • About one-third of Crohn’s patients have no symptoms despite active inflammation with ulceration.
    • They only develop symptoms after a complication such as obstruction, abscess, or fistulization.
  • The physical signs
    • malnutrition and dehydration (orthostatic hypotension), fever, oral ulcerations, abdominal tenderness or palpation of an abdominal mass (phlegmon), hyperactive or high pitched bowel sounds (obstruction), guarding or rebound tenderness (abscess or perforation), perianal skin tags (representing anal Crohn’s disease), and perianal fistula or abscess.

11

Crohn's Disease:
Diagnosis

  • A careful history and physical
  • Unlike ulcerative colitis, patients with Crohn’s disease may/
  • endoscopy and pathology
  • radiographic studies
  • In pediatric patients
  • A colonoscopy
  • Upper endoscopy
  • An enteroscopy
  • External exam of anus at time of colonoscopy may reveal/
  • Exam of the mouth at the time of upper endoscopy may reveal/
  • Endoscopic features of Crohn’s disease

  • A careful history and physical is imperative
  • Unlike ulcerative colitis, patients with Crohn’s disease may go undiagnosed for years due to symptoms that are attributed to other gastrointestinal disorders, e.g. irritable bowel syndrome, gall bladder disease, peptic ulcer.
  • endoscopy and pathology are useful in confirming the diagnosis of Crohn’s disease,
  • radiographic studies are often necessary to evaluate the small intestine.
  • In pediatric patients, falling off of the growth curve is often seen in the 6-12 months preceding the diagnosis of Crohn’s disease suggesting a pre-symptomatic phase of illness.
  • A colonoscopy is useful for visualizing the colon and terminal ileum.
    • Inspection of terminal ileum is especially important since the majority of patients with Crohn’s disease have inflammation in this region.
  • Upper endoscopy, which visualizes the esophagus, stomach, and proximal duodenum, is useful in diagnosing Crohn’s disease limited to the esophagus or gastroduodenal area
  • An enteroscopy, which is a longer upper scope into the jejunum, not only visualizes the esophagus, stomach, and proximal duodenum (similar to upper endoscopy), but also inspects of the distal duodenum and jejunum.
  • External exam of anus at time of colonoscopy may reveal an anal fissure, fistula/abscess, anal skin tags, or anal stricture.
  • Exam of the mouth at the time of upper endoscopy may reveal aphthous ulcers.
  • Endoscopic features of Crohn’s disease include: aphthous ulcers, irregular punched-out or longitudinal “serpiginous” ulcers, pseudopolyps, inflammatory polyps, “cobblestone” appearance of the mucosa, strictures, and fistula.

12

Crohn's Disease:
Histopathologic Features (p.36)

  • many of the same findings as/
  • inflammation
  • goblet cells and mucin
  • granulomas

  • many of the same findings as with ulcerative colitis,
  • the inflammation is transmural,
  • goblet cells and mucin are usually preserved,
  • granulomas
    • may be present.
    • pathognomonic for Crohn’s disease,
    • only present in 50% of cases
    • its absence does not exclude the diagnosis of Crohn’s disease.
    • Only 20% of Crohn’s patients will demonstrate granulomas with endoscopic pinch biopsies.

13

Crohn's Disease:
Radiographic Testing (p.33-34)

  • includes/
  • Small bowel follow-through (SBFT)
  • Typical features of Crohn’s disease on barium studies
  • CT scans
  • Newer CT enterography (CTE) and MR enterography (MRE)

  • includes barium studies (barium enema, upper gastrointestinal and small bowel follow-through series), computed tomographic (CT) scans, and Magnetic Resonance Imaging (MRI).
  • Small bowel follow-through (SBFT) is particularly useful as the majority of small intestine is not accessible to the standard endoscopes and often harbors Crohn’s disease.
  • Typical features of Crohn’s disease on barium studies include mucosal nodularity, ulceration, and narrowing, separation of bowel loops (due to inflammation), a “string sign” due to barium passing through a tight stricture, “string of sausage” sign due to barium passing through multiple strictures with associated dilation of proximal loops of intestine (secondary to obstruction from stricture), and fistula and sinus tracts.
  • CT scans are particularly useful at assessing for an abscess, retroperitoneal disease, and may identify transmural bowel inflammation, which is termed as “creeping fat.”
  • Newer CT enterography (CTE) and MR enterography (MRE), may provide the luminal definition of a SBFT with extraluminal detail of a traditional CT or MRI.
    • have largely replaced the SBFT with MRE growing in acceptance due to limited radiation exposure compared with CT scans.

14

Crohn's Disease:
Complications (p.18-121)

  • surgery
  • Common complications
  • Cancer
  • for patients with extensive Crohn’s colitis the strategy of colorectal cancer surveillance/

  • Although surgery is not a cure for Crohn’s disease, 50%-80% of patients with Crohn’s disease will require surgical management of a complication.
  • Common complications
    • fibrostenotic stricture with associated obstructive symptoms (usually small bowel obstruction with vomiting and abdominal bloating/distention), abscesses either intra-abdominal due to sinus/fistula tracts or perianal due to fistula.
  • Cancer
    • rare
    • increased incidence of gastrointestinal cancer in Crohn’s disease with 2/3 occurring in diseased segments of bowel (e.g. lymphoma in small bowel, adenocarcinoma in small bowel or colon). 
  • for patients with extensive Crohn’s colitis the strategy of colorectal cancer surveillance is similar to ulcerative colitis.

15

Extraintestinal Manifestations of Inflammatory Bowel Disease:
Arthritis (p.40+46-47)

  • Peripheral arthritis
    • frequency
    • UC vs. CD
    • usually parallels/
    • usually/
  • Central (axial) arthritis 
    • consists of/
    • UC vs. CD
    • may be associated with/
    • correlation with bowel disease activity
    • relation to the diagnosis of bowel disease
    • may progress despite/

  • Peripheral arthritis
    • The most common extraintestinal manifestation of IBD
    • occurring equally in ulcerative colitis and Crohn’s disease.
    • usually parallels the activity of underlying bowel disease,
      • i.e. when a patient is “flaring” from their IBD the peripheral arthritis will also “flare.”
    • usually monoarticular, asymmetrical, involves large>small joints (knee most common), has no synovial destruction, no subcutaneous nodules, and is rheumatoid factor negative.
  • Central (axial) arthritis
    • consists of ankylosing spondylitis and sacro-iliitis
    • occurs equally in ulcerative colitis and Crohn’s disease
    • may be associated with HLA haplotype B27.
    • activity often does not correlate with bowel disease activity
    • may precede the diagnosis of bowel disease;
    • may progress despite a total colectomy in ulcerative colitis.

16

Extraintestinal Manifestations of Inflammatory Bowel Disease (p.40+43-44+48-49)

  • Eye Inflammation:
    • CD vs. UC
    • Uveitis
    • Episcleritis
    • Episcleritis and iritis
  • Oral Lesions:

  • Eye Inflammation:
    • Occurs in both Crohn’s disease and ulcerative colitis.
    • Uveitis
      • often painful
      • presents with synechiae and opacity in the anterior chamber of the eye and follows a course that is independent of the bowel activity.
      • clusters with ankylosing spondylitis and sacro-iliitis
      • usulaly associated with HLA-B27.
      • an ophthomologic emergency that may lead to blindness if untreated.
    • Episcleritis presents with injection of deep ciliary’s vessels and tends to parallel bowel disease activity.
    • Episcleritis and iritis often respond to IBD medications and does not lead to visual changes.
  • Oral Lesions:
    • Aphthous ulceration/stomatitis is more common in Crohn’s disease but can occur in ulcerative colitis.
    • These lesions usually parallel bowel disease activity.

17

Extraintestinal Manifestations of Inflammatory Bowel Disease (p.40+43-44+48-49)

  • Skin Lesions:
    • CD vs. UC
    • Erythema nodosum
    • Pyoderma gangrenosum
    • Both erythema nodosum and pyoderma gangrenosum
  • Vascular Complications:
    • Autoimmune hemolytic anemia and thrombotic disease
    • IBD is now recognized as an important/

  • Skin Lesions:
    • Occurs in both Crohn’s disease and ulcerative colitis.
    • Erythema nodosum presents as red, raised lesions that occur most commonly over the lower extremities.
    • Pyoderma gangrenosum is a blistering skin lesion that presents as large, punched out ulcers on the skin (usually lower extremities) that can be particularly disfiguring and complicated by infection.
    • Both erythema nodosum and pyoderma gangrenosum parallel bowel disease activity.
  • Vascular Complications:
    • Autoimmune hemolytic anemia and thrombotic disease (specifically, deep venous thrombosis) are more common in ulcerative colitis than Crohn’s disease.
    • IBD is now recognized as an important hypercoagulable risk factor, and patients admitted to the hospital warrant prophylactic anticoagulation (both medical and surgical admissions).

18

Extraintestinal Manifestations of Inflammatory Bowel Disease:
Primary Sclerosing Cholangitis (p.50)

  • characterized by/
    • how many patients with UC have sclerosing cholangitis
    • how many patients with sclerosing cholangitis have IBD
    • gender and genetics
    • Onset of primary sclerosing cholangitis/
  • colectomy 
  • Patients with primary sclerosing cholangitis have an even greater risk of developing

  • characterized by progressive inflammation, fibrosis, and destruction of intra- and extra- hepatic bile ducts, which results in cirrhosis and portal hypertension.
    • Approximately 5% of patients with ulcerative colitis have sclerosing cholangitis and it is less common in Crohn’s disease.
    • Conversely, 75% of patients with sclerosing cholangitis have inflammatory bowel disease (approx. 85% with ulcerative colitis and 15% with Crohn’s disease).
    • Sclerosing cholangitis is more common in men (2:1 ratio) and is associated with HLA-DRw52a and HLA-B8 and perinuclear antineutorphil cytoplasmic antibodies (p-ANCA).
    • Onset of primary sclerosing cholangitis may precede the onset of clinical colitis by years and its course does NOT parallel bowel disease activity.
  • Similar to ankylosing spondylitis and uveitis, colectomy does not alter the clinical course of primary sclerosing cholangitis.
  • Patients with primary sclerosing cholangitis have an even greater risk of developing cholangiocarcinoma (bile duct cancer) and colon cancer than do patients with ulcerative colitis alone.

19

Extraintestinal Manifestations of Inflammatory Bowel Disease:
Diseases Associated with Small Bowel Crohn's Disease

  • Vitamin deficiencies
  • Vitamin B12 deficiency
  • Bile salts
    • Bile salt malabsorption results in /
    • Bile salt malabsorption predisposes the formation of /
  • Zinc deficiency 

  • Vitamin deficiencies are common with small bowel Crohn’s disease.
  • Vitamin B12 deficiency is very common in Crohn’s disease due to the fact that it is absorbed in the distal 60cm of terminal ileum (which is the most common location for Crohn’s disease).
  • Bile salts are absorbed in the distal 100cm of the terminal ileum and may be affected by Crohn’s disease or surgical resection of this area.
    • Bile salt malabsorption results in
      • cholerhetic diarrhea, which is characterized by significant abdominal cramping and pain,
      • burning diarrhea, which is poorly responsive to anti-diarrheal medicines which slow motility, but will respond well to bile acid binding resins.
    • Bile salt malabsorption predisposes the formation of
      • gallstones (usually cholesterol rich stones)
      • kidney stones (usually calcium oxalate stones).
  • Zinc deficiency
    • common
    • related to diarrhea,
    • repletion with zinc may play a role in the active treatment of Crohn’s disease.

20

Pathogenesis of Inflammatory Bowel Disease:
Genetic Factors

  • inflammatory bowel disease is a heritable disorder. 
    • racial and ethnic aggregations 
    • family history
  • specific genes associated with inflammatory bowel disease
  • certain environmental factors/

  • inflammatory bowel disease is a heritable disorder.
    • racial and ethnic aggregations
      • IBD is most common in Caucasians with the highest incidence and prevalence in the Ashkenazi Jewish population
    • 10-20% of patients with inflammatory bowel disease have a positive family history.
      • The risk for IBD in first-degree relatives of Crohn’s disease is 10-20 times the risk
      • stronger familial aggregation for Crohn’s disease than for ulcerative colitis.
      • There is a higher concordance for IBD among monozygotic twins than dizygotic twins.
      • There is a higher monozygotic twin pair concordance for Crohn’s disease than ulcerative colitis.
  • specific genes associated with inflammatory bowel disease.
    • over 100 SNP’s or pieces of genetic material are associated with IBD.
    • genes probably only explain one-quarter of all inflammatory bowel disease.
  • certain environmental factors are central in the pathogenesis of IBD. 

21

Pathogenesis of Inflammatory Bowel Disease:
Genetic Factors

  • There have been several modest HLA associations with IBD:
    • HLA-B5 (or HLA-B5 subtype, HLA-B52)
    • HLA-DR2 (particularly HLA-DRB1*01502)
      • HLA-DRB1*0103
    • HLA- B44
    • HLA-DR4
  • Based on inflammatory bowel disease genetic linkage mapping studies, several linkages have been confirmed with certain chromosomes:
    • IBD1 locus
    • IBD2 locus
    • IBD3 locus
    • IBD4 locus

  • There have been several modest HLA associations with IBD:
    • HLA-B5 (or HLA-B5 subtype, HLA-B52) in ulcerative colitis in the Japanese population.
    • HLA-DR2 (particularly HLA-DRB1*01502) in ulcerative colitis in Japanese and Jewish populations.
      • HLA-DRB1*0103 has been associated with particularly extensive ulcerative colitis.
    • HLA- B44 and Crohn’s disease
    • HLA-DR4 and Crohn’s disease in a Japanese population.
  • Based on inflammatory bowel disease genetic linkage mapping studies, several linkages have been confirmed with certain chromosomes:
    • Crohn’s disease and a locus on chromosome 16 (the IBD1 locus)
    • Inflammatory bowel disease (mainly ulcerative colitis) and a locus on chromosome 12q (the IBD2 locus).
    • Inflammatory bowel disease (mainly Crohn’s disease) and a locus on chromosome 6p (the IBD3 locus).
    • Inflammatory bowel disease (mainly Crohn’s disease) and a locus on chromosome 14q (the IBD4 locus).

22

Pathogenesis of Inflammatory Bowel Disease:
Genetic Factors

  • NOD2 gene 
    • present in/
    • located/
    • encodes/
  • One of the Crohn’s disease associated NOD2 variants 
    • defective/
    • encodes/
    • associated with/
  • decrease in human defensin 5 production from Paneth cells in the terminal ileum of Crohn’s disease patients with NOD2 3020insC mutations
    • this defect in the NOD2 gene present in many Crohn’s disease patients disrupts/
    • this genetic defect leads to/

  • NOD2 gene
    • present in 20% of Caucasian patients with Crohn’s disease.
    • located precisely within the Crohn’s disease-linked IBD1 locus on chromosome 16.
    • encodes a protein that is expressed in monocytes and Paneth cells which modulates gene intracellular activation signaling pathways in response to bacterial lipopolysaccharides.
  • One of the Crohn’s disease associated NOD2 variants
    • defective (specifically, a cytosine insertion at nucleotide position 3020; 3020insC causing a frame shift)
    • encodes a truncated NOD2 protein.
    • associated with a deficient activation of NF-kB in response to bacterial lipopolysaccharides.
  • decrease in human defensin 5 production from Paneth cells in the terminal ileum of Crohn’s disease patients with NOD2 3020insC mutations.
    • this defect in the NOD2 gene present in many Crohn’s disease patients disrupts the innate immune response to bacteria and leads to an exaggerated response by the adaptive (acquired) immune system, causing the tissue damage associated with Crohn’s disease.
    • this genetic defect leads to an abnormal immune response to the bacteria that are normally present in the gastrointestinal tract, and explains the genetic link in 20% of people with Crohn’s disease. 

23

Pathogenesis of Inflammatory Bowel Disease:
Immunologic Factors (p.67)

  • Inflammatory bowel disease represents/
  • The normal, appropriate response of the mucosal immune system to an invading pathogen is/
  • Normally, this inflammation/
  • In people predisposed to inflammatory bowel disease/

  • Inflammatory bowel disease represents an abnormal immune response in a genetically susceptible individual to what would otherwise be normal environmental stimuli.
  • The normal, appropriate response of the mucosal immune system to an invading pathogen is inflammation, with production of inflammatory cytokines and the recruitment of inflammatory cells necessary to eradicate the infectious pathogen.
  • Normally, this inflammation is rapidly downregulated after successfully “fighting off” the infection (termed controlled inflammation).
  • In people predisposed to inflammatory bowel disease, there is a failure of the immune system to downregulate an inflammatory response that leads to chronic and uncontrolled inflammation.

24

Pathogenesis of Inflammatory Bowel Disease:
Immunologic Factors (p.67)

  • Inflammatory bowel disease is the result of/
    • This dysregulation in T cell mediation leads to/
    • Examples of pro-inflammatory cytokines
    • Examples of anti-inflammatory cytokines that are produced by Th2 helper cells
  • A better understanding of this immune dysregulation and imbalance between pro- and anti-inflammatory cytokines have lead to/

  • Inflammatory bowel disease is the result of an overabundance of inflammatory (Th1) cells and lack of an appropriate T (Th2) regulatory response.
    • This dysregulation in T cell mediation leads to an imbalance between pro-inflammatory and anti-inflammatory cytokines.
    • Examples of pro-inflammatory cytokines include tumor necrosis factor alpha, interferon gamma, and interleukin 12.
    • Examples of anti-inflammatory cytokines that are produced by Th2 helper cells include interleukins 4,5,10, and 13.
  • A better understanding of this immune dysregulation and imbalance between pro- and anti-inflammatory cytokines have lead to
    • newer therapies,
      • e.g. anti-tumor necrosis factor antibody (infliximab),
    • more aggressive treatment with immunomodulator agents,
      • e.g. 6-mercaptopurine, azathioprine, methotrexate, and cyclosporine.