Chapter 17 part 6--Small Intestine counted Flashcards
Celiac disease
- 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%
Pathogenesis of Celiac Disease
-results from gluten-mediated delayed-type hypersensitivity–specifically to a 33 amino acid a-gliadin polypeptide resistant to digestive enzymes
What does gliadin do?
- 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
Morphologic alterations in celiac disease
- villous atrophy
- increased numbers of intraepithelial lymphocytes (IELs), and epithelial proliferations with crypt elongation
Pathogenesis of celiac disease
-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
NKG2D
-natural killer cell marker and receptor for MIC-A
Pathogenesis of Celiac disease–what happens after gliadin permits increased deamination by transglutaminase?
- 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
Additional factors that influence Celiac disease susceptibility
-polymorphisms of genes that affect immune regulation and epithelial polarity
Morphology of celiac disease
- 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
Clinical features of celiac disease
- 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
Celiac disease associations with other diseases
- associated with pruritic, blistering skin disorder dermatitis hepetiformis
- Lymphocytic gastritis or colitis also more common
Celiac disease increases the risk for
- iron and vitamin deficiencies
- ENTEROPATHY-ASSOCIATED T-CELL LYMPHOMA and small intestine adenocarcinoma
Celiac disease usually responds to?
-gluten withdrawl
Environmental Enteropathy
- 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
Etiology of Environmental Enteropathy
-Infectious etiology implicated with defective intestinal barrier function
Consequences of Environmental Enteropathy
- 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
Autoimmune Enteropathy
- 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
Lactase (Disaccharide) Deficiency–what is lactase?
-an apical membrane disacchridase of surface absorptive cells
Lactase deficiency–what happens?
- 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
Rare congenital autosomal recessive form of lactase deficiency is due to
-mutations in lactase gene
Acquired form of lactase deficiency is caused by
- downregulation of lactase gene expression
- common in Native American, African-American and Chinese populations
Abetalipoproteinemia
- 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
Symptoms of Abetalipoproteinemia in infants
- 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
Consequences of Abetalipoproteinemia
- Increased enterocyte triglyceride stores manifest as lipid vacuolation
- Altered erythrocyte lipid membranes manifest as acanthocytes (burr cells)
Symptoms of infectious enterocolitis
-range from urgency to diarrhea to incontinence and perianal discomfort to abdominal pain
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
Pediatric infectious diarrhea is usually caused by
-Enteric viruses
Cholera is caused by
- Vibrio cholera, gram-negative bacteria typically transmitted by drinking contaminated water
- humans, shellfish and plankton are the only reservoirs
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
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
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
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
Pathogenesis of Campylobacter Enterocolitis
-major virulence factors=flagellar motility, adherence molecules to facilitate colonization, cytotoxins and a cholera toxin-like enterotoxin
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
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
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
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
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
Morphology of shigellosis
-Mucosa is hemorrhagic and ulcerated, often with pseudomembranes
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
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
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
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
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
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
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
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)
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
