Cholera Vignette Flashcards
Signs of very advanced dehydration
Sunken eyes Skin turgor Blindness & loss of consciousness may result due to lack of perfusion
What causes cholera?
Infection of the small intestine by Vibrio cholerae bacteria Produces an enterotoxin that mediates disease
Symptoms and treatment of cholera
Diarrhea and vomiting Most cases mild/moderate, but 20% potentially fatal with profuse watery diarrhea (rice water diarrhea) and vomit Can kill within hours if untreated Treatment is relatively easy, ~80% can be treated with oral rehydration salts.
How to Na, Cl, and H2O cross from the lumen into the ECF & plasma?
The apical surface of epithelial cells is very permeable to Na+. The Na+/K+ pumps on the basilateral surface pump 3Na+ out for 2K+ in. ECF accumulates Na+ and draws Cl- and H2O directly from the lumen via electrical gradient and osmolality.
What does the A/B cholera toxin consist of and what are the first stages of its mechanism?
Cholera toxin is produced as an alpha subunit (active toxin) and a beta subunit (transport molecule). 1) Beta subunit binds to GM1 ganglioside receptor on apical surface 2) alpha subunit enters the cell and binds to G protein Adenylate cyclase and produces cAMP.
What are the last steps in the A/B cholera pathway?
3) cAMP activates the CFTR (cystic fibrosis) Cl- channel on the apical face, allowing outflow of Cl- ion down their electrochemical gradient
4) H2O follows outflow of Cl- ions into the lumen, causing a “secretory diarrhea”.
What is the mechanism of action for the ZOT cholera pathway?
The Zonula Occludens Toxin is a protein from the Vibrio cholerae cell wall that binds to the ZOT receptor on the apical surface.
It activates a complex intracellular cascade of events the results in loosening of tight junctions between cells, causing a “leaky gut”.
Three general steps of oral rehydration treatment for cholera.
1) Rehydrate - Oral hydration salts, small sips can be absorbed even while vomiting.
2) Maintain hydration - ORS, replace vomit and stool losses.
3) Early feedings - nutritional rehabilitation. Poor nutritional status will inhibit recovery from disease.
Why does the WHO encourage the use of Reduced Osmolarity Solution in place of previous ORS?
The original formula of the ORS provided a higher osmolarity than the body, resulting in increased H2O and Na+ diffusion into the lumen. Reduced Osmolarity Solution reverses the osmolar pressure, driving more hydration into the body.
What advantages to rice based ORS have over glucose ORS?
Complex polysaccharides are broken down to glucose at the brush border.
Additional amino acids present in rice may help activate AA/Na+ cotransporters in the apical membrane.
How can cholera toxins be useful in therapies, and what is a potential pitfall of this technique?
The beta subunit binds with gangliosides on the cell surface and can be linked with drugs to cause their internalization. Utilizing this in an influenza vaccine resulted in many cases of Bell’s palsy in a trial in Switzerland.
How might cholera explain the prevalence of cystic fibrosis?
Mice who are heterozygous for CFTR mutations secrete 1/2 of the fluid when infected with cholera, so CFTR mutations may offer protection against cholera, leading to their relatively high (1:50,000) prevalence. However, CFTR mutations and cholera do not seem to share historical populations, thus the theory is tenuous.
Three potential drug targets for protection again cholera
1) CFTR channels targetted by thiazolidinone (CFTR inhibitor)
2) Inhibitor of the cAMP-activated intestinal chloride secretion
3) Regulation of tight junctions to decrease intestinal permeability
Three cholera vaccinations and the potential uses and drawbacks
Dukoral, Shanchol, nORCVAC
Problems are immunity only lasts for .5-2 years, boosters are needed.
Effective for aid workers, and for general population at the time of an outbreak.
Useful antibiotics, their advantages and drawbacks
Ciprofloxin, azithromycin, doxycycline
Decreases purging rate and illness length by 50%, duration of excretion of Vibrio cholerae in stool is shortened from 5 days to 1-2
Potentially lead to the development of resistant strains of Vibrio cholerae
