Chapter 17 part 6--Small Intestine counted Flashcards
1
Q
Celiac disease
A
- also called gluten-sensitive enteropathy or celiac sure
- immune-mediated diarrheal disorder triggered by ingestion of gluten-containing foods (e.g., derived from wheat, oat, rye, or barley) in genetically predisposed individuals
- worldwide incidence=0.6% to 1%
2
Q
Pathogenesis of Celiac Disease
A
-results from gluten-mediated delayed-type hypersensitivity–specifically to a 33 amino acid a-gliadin polypeptide resistant to digestive enzymes
3
Q
What does gliadin do?
A
- induces epithelial IL-15 expression with local activation and proliferation of CD8+ cytotoxic cells that can drive enterocyte apoptosis
- Gliadin access to underlying tissue permits increased deamination by transglutaminase
4
Q
Morphologic alterations in celiac disease
A
- villous atrophy
- increased numbers of intraepithelial lymphocytes (IELs), and epithelial proliferations with crypt elongation
5
Q
Pathogenesis of celiac disease
A
-Both innate (CD8+ intraepithelial T cells activated by IL-15) and adaptive (CD4+ T cells and B cells sensitization to gliadin) immune mechanisms are involved in the tissue responses to gliadin
6
Q
NKG2D
A
-natural killer cell marker and receptor for MIC-A
7
Q
Pathogenesis of Celiac disease–what happens after gliadin permits increased deamination by transglutaminase?
A
- Deaminated peptide binds to specific MHC on Ag-presenting cells in susceptible individuals (expressing human leukocyte antigen [HLA}-DQ2 or HLA-DQ8)
- leads to CD4+ T cell activation and cytokine mediated epithelial damage
8
Q
Additional factors that influence Celiac disease susceptibility
A
-polymorphisms of genes that affect immune regulation and epithelial polarity
9
Q
Morphology of celiac disease
A
- Diffusely flattened (atrophic) villi and elongated regenerative crypts are associated with intraepithelial CD8+ T cells and exuberant lamina propria chronic inflammation
- severity is greatest in the more proximal intestine
10
Q
Clinical features of celiac disease
A
- occurs in infants to middle age
- S/S: diarrhea, flatulence, weight loss, effects of anemia
- most sensitive tests look for presence of IgA Abs to tissue transglutaminase or IgA or IgG to dominated gliadin
11
Q
Celiac disease associations with other diseases
A
- associated with pruritic, blistering skin disorder dermatitis hepetiformis
- Lymphocytic gastritis or colitis also more common
12
Q
Celiac disease increases the risk for
A
- iron and vitamin deficiencies
- ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA and small intestine adenocarcinoma
13
Q
Celiac disease usually responds to?
A
-gluten withdrawl
14
Q
Environmental Enteropathy
A
- Also called tropical enteropathy or tropical sprue
- malabsorption and malnutrition syndrome that occurs in areas with poor sanitation–affects 150 million children worldwide
- histology similar to celiac disease
15
Q
Etiology of Environmental Enteropathy
A
-Infectious etiology implicated with defective intestinal barrier function
16
Q
Consequences of Environmental Enteropathy
A
- in developing children there may be associated irreversible losses in physical development and cognition
- Even with oral antibiotics and nutritional supplementation, the deficits may not be corrected
17
Q
Autoimmune Enteropathy
A
- X-linked disorder of children characterized by a persistent auto-immune driven diarrhea
- A severe familial form (IPEX, immune dysregulation, polyendocrinopathy, enteropathy and X-linked) is due to gremlin mutations in the FOXP3 gene–TF responsible for differentiation of CD4+ regulatory T cells
- AutoAbs to a variety of GI epithelial cell types may be present
18
Q
Lactase (Disaccharide) Deficiency–what is lactase?
A
-an apical membrane disacchridase of surface absorptive cells
19
Q
Lactase deficiency–what happens?
A
- undigested and unabsorbed lactose exerts an osmotic pull, causing diarrhea and malabsorption
- bacterial fermentation of lactose can cause abdominal distention and flatus
- histo: mucosa is unremarkable
20
Q
Rare congenital autosomal recessive form of lactase deficiency is due to
A
-mutations in lactase gene
21
Q
Acquired form of lactase deficiency is caused by
A
- downregulation of lactase gene expression
- common in Native American, African-American and Chinese populations
22
Q
Abetalipoproteinemia
A
- rare autosomal recessive disease caused by inability of lipids to egress absorptive epithelial cells
- underlying defect is a mutation in microsomal triglyceride transfer protein (MTP) responsible for transferring lipids to apolipoprotein B within the rough ER so the MTP impacts lipoprotein and fatty acid export from mucosal cells
23
Q
Symptoms of Abetalipoproteinemia in infants
A
- failure to thrive
- diarrhea
- steatorrhea
- absence of all lipoproteins containing apolipoprotein B (although apolipoprotein B gene is unaffected)
- Failure to absorb essential fatty acids leads to deficiencies of fat-soluble vitamins as well as lipid membrane defects
24
Q
Consequences of Abetalipoproteinemia
A
- Increased enterocyte triglyceride stores manifest as lipid vacuolation
- Altered erythrocyte lipid membranes manifest as acanthocytes (burr cells)
25
Symptoms of infectious enterocolitis
-range from urgency to diarrhea to incontinence and perianal discomfort to abdominal pain
26
Outcomes of infectious enterocolitis
- dehydration, malabsorption, or hemorrhage
- half of all deaths worldwide before age 5 is due to infectious enterocolitis!!
- In developing countries, 2000 children die daily from it--bacterial infections usually responsible but most common pathogen differ based on geography, age, nutrition and host immune status
27
Pediatric infectious diarrhea is usually caused by
-Enteric viruses
28
Cholera is caused by
- Vibrio cholera, gram-negative bacteria typically transmitted by drinking contaminated water
- humans, shellfish and plankton are the only reservoirs
29
Cholera pathogenesis
- Vibrio organisms are noninvasive, although flagellar proteins are important for epithelial attachment and efficient bacterial colonization
- mucosal biopsies show normal histology
- causes diarrhea by production of a cholera toxin that is internalized after binding enterocyte surface GM1 gangliosides
30
Steps of Vibrio cholera toxin
- Toxin A subunit processed in ER to a fragment and enters cytosol
- Toxin A fragment interacts with (ADP) ribosylation factors to activate the G protein Gsa
- Activated Gsa stimulates adenylate cyclase (AC)
- Resulting surge cAMP opens cystic fibrosis conductance regulator, CFTR and releases chloride ions into lumen
- Luminal chloride causes secretion of bicarb and sodium, with obligate water, leading to massive diarrhea
31
Clinical features of cholera
- Only minority develop severe diarrhea; in those that get it, unto 1L/hr of "rice-water"-like stool can be produced
- Without Tx, the mortality is 50% due to dehydration, hypotension, and shock but most can be saved with timely rehydration
32
Campylobacter Enterocolitis--Campylobacter jejuni
- gram negative
- most common bacterial enteric pathogen in developed countries and important cause of traveler's diarrhea
- Transmission is often though ingestion of poorly cooked chicken but water or milk contamination can also occur
33
Pathogenesis of Campylobacter Enterocolitis
-major virulence factors=flagellar motility, adherence molecules to facilitate colonization, cytotoxins and a cholera toxin-like enterotoxin
34
Campylobacter enterocolitis infection can also result in
- extraintestinal complications like reactive arthritis, and erythema nodosum
- 40% of Guillain-Barre syndrome are associated with Campylobacter infection in the preceding 1-2 weeks
35
Clinical features of campylobacter enterocolitis
- Dx is primarily through stool cultures
- Biopsies show only nonspecific neutrophilic colitis with variable epithelial damage
- Diarrhea is typically watery; dysentery, associated with invasive strains occurs in 15% of cases
- Abx therapy is usually not required; patients can shed bacteria for a month after symptoms resolve
36
Shigellosis--shigella
- nonencapsulated, gram negative bacilli
- facultative anaerobes and one of the most common causes of bloody diarrhea
- Humans are the only reservoir
- fecal-oral transmission is accomplished with as few as several hundred microbes
- Most infections and deaths occur in children under age 5
- in endemic areas, Shigella causes 10% of pediatric diarrhea, 75% of diarrhea related deaths
37
Pathogenesis of shigellosis
- Organisms are highly resistant to gastric acidity
- taken up by intestinal M cells, escape into lamina propria, and ingested by macrophages which then undergo apoptosis
- Subsequent inflammation and release of Shiga toxin causes epithelial damage that facilitates even greater bacterial access
38
Cholera toxin transport and signaling
- After retrograde toxin transport to the ER, the A subunit is released by the action of protein disulfide isomerase (PDI) and is then able to access the epithelial cell cytoplasm
- In concert with an ADP-ribosylation factor (ARF), the A subunit then APD-ribosylates Gsa which locks it in in the active, GTP-bound state
- leads to AC activation, and the cAMP produced opens CFTR to drive chloride secretion and diarrhea
39
Morphology of shigellosis
-Mucosa is hemorrhagic and ulcerated, often with pseudomembranes
40
Clinical features of Shigella
- typically a self-limited diarrhea of approximately 6 days
- Initially watery diarrhea becomes dysenteric in half of patients
- Fever and abdominal pain persists after diarrhea stops
- Dx requires stool cultures
- Antibiotics can shorten the clinical course and reduce the duration of bacterial shedding
41
Salmonella
- gram-negative bacillus
- Salmonella typhi and Salmonella paratyphi cause typhoid fever whereas non typhoid Salmonella is usually due to S. enteritides
- Transmission is through contaminated food; children and the elderly are most commonly affected
42
Pathogenesis of Salmonella
- Virulence factors include type III secretion system that transfers bacterial proteins into M cells and enterocytes and facilitates bacterial uptake and growth in phagosomes
- some strains also express a virulence factor that prevents TLR4 activation
- Mucosal Th17 responses limit infection to colon but can cause secondary injury
43
Clinical features of Salmonella
- Symptoms and pathologic appearances are similar to other enteric pathogens
- Dx requires stool cultures
- Most infections are self limited (exceptions are immunocompromised hosts) and last approximately a week
- Antibiotics not recommended bc they prolong the carrier state and do not shorten the duration of diarrhea
44
Typhoid fever
- In endemic areas, children and adolescents mostly affected
- infxn associated with travel in India, Mexico and Philippines and less-developed countries
- Humans= only reservoir and transmission= contaminated food and water
- Gallbladder colonization associated with gallstones and chronic carrier state
45
Pathogenesis of Typhoid fever
- Organisms resistant to gastric acid--invade M cells and are subsequently engulfed by mononuclear cells in the mucosal lymphoid tissues
- Bacteria then disseminate widely via lymphatics and blood vessels causing systemic macrophage and lymph node hyperplasia
46
Morphology of Typhoid fever
- marked expansion of Peyer patches and draining nodes
- Acute and chronic inflammatory cell recruitment to lamina propria associated with necrotic debris and overlying mucosal ulceration
- Liver shows focal hepatocyte necrosis with macrophage aggregates called typhoid nodules
47
Clinical features of typhoid fever
-initial dysentery followed by bacteremia (90% of patients), fever and abdominal pain that persists for 2 weeks without antibiotic treatment (typhoid fever)
48
Systemic dissemination of typhoid fever causes
- extraintestinal complications including encephalopathy, meningitis, endocarditis, myocarditis, pneumonia and cholecystitis
- Patients with sickle cell disease are prone to osteomyelitis
