Lecture 23 Flashcards
Acute Gastroenteritis
Result of direct infection of GI tract lining by a virus or ingestion of bacteria (ex: Clostridium perfringes), preformed toxins (ex: Staph aureus, Vibrio cholerae), or imbalance of normal flora
Chronic Gastroenteritis
Results from another GI disorder (ex: ulcerative colitis)
Irritable Bowel Syndrome
- No clear definition or etiology
- Common: 20% of the US population
- Manifestations: alternating diarrhea and constipation with cramping pain in the absence of any identifiable pathologic process
What is the difference between Irritable Bowel Syndrome and Inflammatory Bowel Disease?
Inflammatory Bowel Disease has an identifiable pathological process and Irritable Bowel Syndrome does not
What are the similarities between Ulcerative Colitis and Crohn’s Disease?
- Unknown origin
- 20% of all cases, cannot be told apart
- Multi-factoral
- Familial
- Peak incidence in the 3rd decade
- Same extra-intestinal complications
- Same drugs for treatment (palliative)
Crohn’s Disease
Transmural inflammation that predominantly affects the terminal ileum and the right side of the colon
Ulcerative Colitis
- 2-3 times more common than Crohn’s Disease
- Inflammation confined to mucosa and predominantly involves the left side of the large intestine (descending colon and rectum)
Inflammatory sequelae of Ulcerative colitis
Continuous epithelial erosion and functional disruption (ex: decreased production of defensins (Paneth cells), lead to uninhibited exposure to gut microbiota)
Inflammatory Bowel Disease and Crohn’s Disease
- Chronic granulomatous disease of unknown origin
- Affects multiple portions of the colon with intervening normal areas
- May involve any part of the GI tract (called regional colitis and granulomatous colitis)
- Entends through all layers of intestinal wall (deep linear ulcers in the bowel wall which may extend to adjacent organs)
- Appears to result from blockage of lymphoid and lymphatic structures in GI wall
Explain the process of the intestinal immune system in a healthy state.
- The goblet cells secrete a layer of mucus that limits exposure of the intestinal epithelial cells to bacteria
- Both the secretion of antimicrobial peptides (ex: alpha-defensins) by Paneth cells and the production of immunoglobulin A (IgA) provide additional protection from luminal microbiota
- Innate microbial sensing by epithelial cells, dendritic cells, and macrophages is mediated through pattern-recognition receptors such as toll-like receptors and nucleotide oligomerization domain (NOD) proteins
- Dendritic cells present antigens to naive CD4+ T cells in secondary lymphoid organs (Peyer’s patches and mesenteric lymph nodes), where factors such as the phenotype of the antigen-presenting cells and the cytokine milieu (transforming growth factor B (TGF-B) and interleukin-10) modulate differentiation of CD4+ T-cell subgroups with characteristic cytokine profiles (regulatory T cells (ex: Treg) and helper T cells (ex: Th1, Th2, and Th17), and enterotropic molecules (ex: alpha4beta7) are induced that provide for gut homing of lymphocytes from the systemic circulation
- These activated CD4+ T cells then circulate to the intestinal lamina propria where they carry out effector functions
Inflammatory Bowel Disease and Ulcerative Colitis
- Relapsing inflammatory disease of the mucosa of rectum and colon of unknown etiology
- Accompanies autoimmune diseases
- Changes are more severe in the rectum and extend for a variable extent in colon (begins at the base of crypts, with eventual invasion of WBC and formation of abscesses in the crypts)
- Large areas of ulceration
- Confluent areas of mucosal ulceration occur, leaving protruding islands of inflamed mucosa and submucosa, which stimulate colonic polyps (pseudopolyps)
Symptoms of Ulcerative Colitis
Abdominal pain and diarrhea
Treatment of Ulcerative Colitis
Corticosteroids, salicylate analogs, immunomodulating agents (azathioprine, mercaptopurine)
Celiac Disease
- Nontropical Sprue
- Intolerance to gliadin (component of wheat protein gluten)
- Gluten-sensitive enteropathy
- Immune disorder triggered by exposure to gliadin in genetically predisposed individuals
- Main lesion is villous atrophy
- Risk of developing lymphoma
What are the primary effects of Celiac Disease?
Gluten -> villus injury -> decreased surface area -> decreased absorption of nutrients/ osmotic diarrhea -> malnutrition
What are the secondary effects of Celiac Disease?
Gluten -> Mucosal damage -> decreased intestinal hormones -> decreased pancreatic function -> malnutrition
What happens when gliadin is taken out of the diet in Celiac Disease?
Mucosa returns to normal
Tropical Sprue
- Unknown etiology (bacterial?)
- Prevalent in equatorial countries
- Main lesion is atrophy of SI mucosa
Explain the difference between gluten and gliadin.
- Gluten: major storage protein of wheat and similar grains
- Gliadin: alcohol-soluble fraction of gluten; contains most of the disease producing components
Explain the pathogenesis of Celiac Disease.
- Gluten is digested by luminal and brush-border enzymes into amino acids and peptides (including a 33 amino acid alpha-gliadin peptide that is resistant to degradation by gastric, pancreatic, and small intestinal proteases)
- Some gliadin peptides induce epithelial cells to express IL-15 -> triggers activation and proliferation of CD8+ intraepithelial lymphocytes that are induced to express NKG2D (natural killer cell marker)
- CD8+ lymphocytes become cytotoxic and kill enterocytes that express MIC-A (NKG2D is the receptor for MIC-A)
- Resulting epithelium damage may contribute to the process by which other gliadin peptides cross the epithelium to be deamidated by tissue transglutaminase (tTG)
- Deamidated gliadin peptides able to interact with antigen-presenting cells (APC) and be presented to CD4+ T-cells
- CD4+ T-cells produce cytokines (TH1 reaction) that contribute to tissue damage and the characteristic mucosal pathology and induce B cells to produce antibodies against gliadin, tTG
Why doesn’t everyone develop Celiac Disease?
Host factors determine whether the disease develops
Explain the morphology of Celiac Disease.
- Advanced cases show complete loss of villi or villous atrophy
- Biopsy specimens from the second portion of the duodenum or proximal jejunum (exposed to the highest concentrations of dietary gluten) generally diagnostic
Explain the histopathology of Celiac Disease.
Increased numbers of intraepithelial CD8+ T-lymphocytes (intraepithelial lymphocytosis), crypt hyperplasia, villous atrophy
Colorectal Carcinoma
- Most common cancer of the GI tract (90% occur in > 50-year old)
- Familial history in 25% of patients (may originate in polyps -> all neoplastic polyps should be removed prophylactically)
- Most are initially asymptomatic (early detection essential)
- Even after removing cancerous segments, there is an increase risk of developing other malignancies
- Most cancers develop in proximal or distal large intestines
- Associated features: upper GI tract polyps (melena), desmoid tumors, and extracolonic malignancies
