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Pathophysiology Exam 3 > Lecture 23 > Flashcards

Lecture 23 Flashcards

1
Q

Acute Gastroenteritis

A

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

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2
Q

Chronic Gastroenteritis

A

Results from another GI disorder (ex: ulcerative colitis)

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3
Q

Irritable Bowel Syndrome

A
  • 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
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4
Q

What is the difference between Irritable Bowel Syndrome and Inflammatory Bowel Disease?

A

Inflammatory Bowel Disease has an identifiable pathological process and Irritable Bowel Syndrome does not

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5
Q

What are the similarities between Ulcerative Colitis and Crohn’s Disease?

A
  • 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)
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6
Q

Crohn’s Disease

A

Transmural inflammation that predominantly affects the terminal ileum and the right side of the colon

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7
Q

Ulcerative Colitis

A
  • 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)
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8
Q

Inflammatory sequelae of Ulcerative colitis

A

Continuous epithelial erosion and functional disruption (ex: decreased production of defensins (Paneth cells), lead to uninhibited exposure to gut microbiota)

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9
Q

Inflammatory Bowel Disease and Crohn’s Disease

A
  • 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
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10
Q

Explain the process of the intestinal immune system in a healthy state.

A
  1. The goblet cells secrete a layer of mucus that limits exposure of the intestinal epithelial cells to bacteria
  2. 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
  3. 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
  4. 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
  5. These activated CD4+ T cells then circulate to the intestinal lamina propria where they carry out effector functions
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11
Q

Inflammatory Bowel Disease and Ulcerative Colitis

A
  • 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)
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12
Q

Symptoms of Ulcerative Colitis

A

Abdominal pain and diarrhea

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13
Q

Treatment of Ulcerative Colitis

A

Corticosteroids, salicylate analogs, immunomodulating agents (azathioprine, mercaptopurine)

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14
Q

Celiac Disease

A
  • 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
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15
Q

What are the primary effects of Celiac Disease?

A

Gluten -> villus injury -> decreased surface area -> decreased absorption of nutrients/ osmotic diarrhea -> malnutrition

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16
Q

What are the secondary effects of Celiac Disease?

A

Gluten -> Mucosal damage -> decreased intestinal hormones -> decreased pancreatic function -> malnutrition

17
Q

What happens when gliadin is taken out of the diet in Celiac Disease?

A

Mucosa returns to normal

18
Q

Tropical Sprue

A
  • Unknown etiology (bacterial?)
  • Prevalent in equatorial countries
  • Main lesion is atrophy of SI mucosa
19
Q

Explain the difference between gluten and gliadin.

A
  • Gluten: major storage protein of wheat and similar grains
  • Gliadin: alcohol-soluble fraction of gluten; contains most of the disease producing components
20
Q

Explain the pathogenesis of Celiac Disease.

A
  1. 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)
  2. 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)
  3. CD8+ lymphocytes become cytotoxic and kill enterocytes that express MIC-A (NKG2D is the receptor for MIC-A)
  4. Resulting epithelium damage may contribute to the process by which other gliadin peptides cross the epithelium to be deamidated by tissue transglutaminase (tTG)
  5. Deamidated gliadin peptides able to interact with antigen-presenting cells (APC) and be presented to CD4+ T-cells
  6. 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
21
Q

Why doesn’t everyone develop Celiac Disease?

A

Host factors determine whether the disease develops

22
Q

Explain the morphology of Celiac Disease.

A
  • 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
23
Q

Explain the histopathology of Celiac Disease.

A

Increased numbers of intraepithelial CD8+ T-lymphocytes (intraepithelial lymphocytosis), crypt hyperplasia, villous atrophy

24
Q

Colorectal Carcinoma

A
  • 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
25
Q

What are predisposing factors of Colorectal Carcinoma?

A

Hereditary syndromes:
1. Familial adenomatous polyposis coli: mutation of APC tumor suppressor gene
2. Hereditary nonpolyposis colon cancer: mutation of DNA repair genes (MMR: mismatch repair gene)

26
Q

How are Colorectal Carcinomas tested?

A
  • Test for occult blood in feces
  • Colonoscopy
  • Colorectal cancers produce carcinoembryonic antigen (CEA) -> tumor marker -> cannot be used for screening (produced in other carcinomas) -> monitored following resections
27
Q

What are the symptoms of Colorectal Carcinoma?

A

Symptoms depend on location of the tumor
- Pencil-like stools: narrowed lumen
- Hematochezia: blood stools (test for occult blood in feces, stool DNA test)

28
Q

Adenomatous Polyposis Coli (APC)

A
  • Tumor suppressor protein
  • Germ-line mutations of APC cause a spectrum of diseases under the broad category of familial adenomatous polyposis
  • Both APC copies are mutated in 80% of sporadic colorectal tumors
  • APC gene product indirectly regulates transcription of a number of critical cell proliferation genes (interactions with the transcription factor, B-catenin)
29
Q

Beta- catenin

A
  • Dual function protein involved in regulation and coordination of cell-cell adhesion and gene transcription
  • APC binding to B-catenin leads to ubiquitin-mediated B- catenin destruction
30
Q

Cadherins

A
  • Transmembrane proteins that establish cell-to-cell contacts, link to F-actin, and participate in cell signaling
  • Intracellular domain associated with a large protein complex that includes B-catenin -> several signaling pathways determine the dissociation of B-catenin from the cell adhesion complex and regulate nuclear transcription
31
Q

What phosphorylates APC-bound B-catenin?

A

Kinase GSK3beta (targets its destruction by the 26S proteasome)

32
Q

Explain the normal APC pathway.

A
  1. B-catenin is phosphorylated by glycogen synthase kinase 3beta (GSK3B) co assembled with APC and axin
  2. Degradation of B-catenin
  3. Ubiquitin-ligase complex: polyubiquitin chain is attached to phosphorylated B-catenin by a ubiquitin-ligase complex
  4. Polyubiquitin-phosphorylated B-catenin complexes are degraded by the 26S proteasome
33
Q

Explain an abnormal APC pathway.

A
  1. B-catenin does not bind to defective APC (or defective B-catenin does not bind to APC) -> no degradation of B-catenin
  2. Unphosphorylated B-catenin accumulates in the cell
  3. Excess of free B-catenin binds to Tcf3-Lef transcription factor complex (translocates to the cell nucleus)
  4. Colorectal tumorigenesis
34
Q

APC binding to B-catenin leads to what?

A

Ubiquitin-mediated B-catenin destruction

35
Q

A loss of APC or B-catenin function leads to what?

A

Increases transcription of B-catenin targets

Pathophysiology Exam 3 (10 decks)

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