SECTION I CELLULAR PHYSIOLOGY Cholera A 32-year-old woman is brought,almost comatose,into a clinic in Bangladesh during the monsoon season.She has severe diarrhea and is producing watery stool at the rate of nearly 1 L/hr.Her skin appears shriveled,and when a fold of skin is pinched,it remains so for several minutes.Microscopic examination of the patient's stool reveals the presence of a large number of Vibrio cholerae bacteria.The patient cannot drink.so intravenous isotonic NaCl is administered.When the patient is fully conscious,she is given a rehydratiom solution to drink.This oral rehydration solution contains glucose.NaCl,KCI,and NallCD3.After ahout 5 days the patient had recovered sufficiently to leave the hospftal. 1.What is the pathophysiologic nechanism of the patient's diarrhea? 2.How do intravenous fluids improve the patient's coedition? 3.What is the rationale for administering the oral rehydration solution to the patient? 4.Why does the patient recover in about 5 days? ANSVER 1.The patient has most likely taken in Vibrio cholerae in contaminated drinking water.In tropical countries without well-developed sewer systems,the flooding from monsoon rains frequently results in the contamination of drinking water sources with fecal bacteria such as Vibrio cbolerae.This bacteriun has colonized the patient's small intestine,where it releases a protein knowm as cholera toxin.Cholera toxin has two subunits.One cholera toxin subunit binds to GMI cangliosides on the luninal surface of the brush border plasma nenbrane of the small intestine and thereby
SECTION I CELLULAR PHYSIOLOGY Cholera A 32-year-old woman is brought, almost comatose, into a clinic in Bangladesh during the monsoon season. She has severe diarrhea and is producing watery stool at the rate of nearly 1 L/hr. Her skin appears shriveled, and when a fold of skin is pinched, it remains so for several minutes. Microscopic examination of the patient's stool reveals the presence of a large number of Vibrio cholerae bacteria. The patient cannot drink, so intravenous isotonic NaCl is administered. When the patient is fully conscious, she is given a rehydration solution to drink. This oral rehydration solution contains glucose, NaCl, KCl, and NaHCO3. After about 5 days the patient had recovered sufficiently to leave the hospital. 1. What is the pathophysiologic mechanism of the patient's diarrhea? 2. How do intravenous fluids improve the patient's condition? 3. What is the rationale for administering the oral rehydration solution to the patient? 4. Why does the patient recover in about 5 days? ANSWER 1. The patient has most likely taken in Vibrio cholerae in contaminated drinking water. In tropical countries without well-developed sewer systems, the flooding from monsoon rains frequently results in the contamination of drinking water sources with fecal bacteria such as Vibrio cholerae. This bacterium has colonized the patient's small intestine, where it releases a protein known as cholera toxin. Cholera toxin has two subunits. One cholera toxin subunit binds to GM1 gangliosides on the luminal surface of the brush border plasma membrane of the small intestine and thereby
provides a pathaay for the other subunit of cholera toxin to enter the cell.The cholera toxin subunit that enters the cells is an enzyne that catalyzes the transfer of ADP-ribose to the a subait of Gs,the heterotrimeric G protein that stimulates adenylyl cyelase.The ADP-ribosylated Gs is permanently locked in the active conformation.The activated Gs then irreversibly activates adenylyl cyclase in the brush border plasma membrane of the patient's small intestine.This leads to a prolonged elevation of the level of cyclic AMP in the cytosol of the epithelial cells. The elevated cyelic AMp results in persistent activation of electrogenic Cl- channels in the brush border plasma menbrane.The efflux of cl-from the cytosol into the lumen of the small intestine drives the flow of Nat into the lumen.The ospotic effect of the Cl-and Nat secretion into the lunen of the small intestine causes the secretion of water into the lumen of the small intestine.The anounts of Nat,Cl-.and water that enter the colon exceed by far the ability of the colon to absorb thea,resulting in the marked diarrhea experienced by the patient. 2.The patient's almost comatose condition is caused by severe dehydration. Rehydration of the patient with intravenous isotonic Nacl improves the patient's fluid halance. 3.The oral rehydration solution is designed to both restore the patient's hydration and correct electrolyte imbalances caused by her profound and prolonged diarrbea.The patient has lost significant anounts of bicarbonate and potassiun ions in her voluminous stool.For that reason bicarbonate and potassiun are included in the oral rehydration solution.To help the patient to absorb water froa the rehydration solution,and thus to aid in restoring her lost extracellular fluid volume,glucose and Nacl are ineluded in the oral rehydration solution.The brush border transporter that uses the electrochemical potential difference of Nat to power the active uptake of glucose transports two Na+ioms together with one glucose molecule into the intestinal epithelial cell.Because of this obligatory coupling between the uptake of Nat and glucose,the presence of Nat in the lumen pronotes the uptake of glucose.and the presence of glucose enhances the uptake of Na+(and thus Cl-to preserve electroneutrality).The absorption of these solutes,Na+.CI-
provides a pathway for the other subunit of cholera toxin to enter the cell. The cholera toxin subunit that enters the cells is an enzyme that catalyzes the transfer of ADP-ribose to the α submit of Gs, the heterotrimeric G protein that stimulates adenylyl cyclase. The ADP-ribosylated Gs is permanently locked in the active conformation. The activated Gs then irreversibly activates adenylyl cyclase in the brush border plasma membrane of the patient's small intestine. This leads to a prolonged elevation of the level of cyclic AMP in the cytosol of the epithelial cells. The elevated cyclic AMP results in persistent activation of electrogenic Clchannels in the brush border plasma membrane. The efflux of Cl- from the cytosol into the lumen of the small intestine drives the flow of Na+ into the lumen. The osmotic effect of the Cl- and Na+ secretion into the lumen of the small intestine causes the secretion of water into the lumen of the small intestine. The amounts of Na+, Cl-, and water that enter the colon exceed by far the ability of the colon to absorb them, resulting in the marked diarrhea experienced by the patient. 2. The patient's almost comatose condition is caused by severe dehydration. Rehydration of the patient with intravenous isotonic NaCl improves the patient's fluid balance. 3. The oral rehydration solution is designed to both restore the patient's hydration and correct electrolyte imbalances caused by her profound and prolonged diarrhea. The patient has lost significant amounts of bicarbonate and potassium ions in her voluminous stool. For that reason bicarbonate and potassium are included in the oral rehydration solution. To help the patient to absorb water from the rehydration solution, and thus to aid in restoring her lost extracellular fluid volume, glucose and NaCl are included in the oral rehydration solution. The brush border transporter that uses the electrochemical potential difference of Na+ to power the active uptake of glucose transports two Na+ ions together with one glucose molecule into the intestinal epithelial cell. Because of this obligatory coupling between the uptake of Na+ and glucose, the presence of Na+ in the lumen promotes the uptake of glucose, and the presence of glucose enhances the uptake of Na+ (and thus Cl- to preserve electroneutrality). The absorption of these solutes, Na+, Cl-
and glucose.osmotically powers the absorption of water from the lumen of the small intestine into the blood.This belps to restore the patient's extracellular fluid volune. 4.Those intestinal epithelial cells that are affected by the cholera toxin have their adenylyl cyclase molecules irreversibly activated.This persists as long as the cells themselves do.For this reason,giving the patient an antibiotie to kill the Vibrio cholerae in her intestine,without also giving oral rehydration therapy, would not have saved this wonan's life.If this patient with cholera is given no antibiotic.but is kept hydrated and in electrolyte balance with oral rehydration therapy,she will recover.The diarrhea will clear the Vibrio cholerae fron her gastrointestinal tract.As the affected intestinal epithelial cells are exfoliated into the lumen,they will be replaced by new epithelial cells that differentiate from the crypts of Lieberkuhn as they migrate up out of the crypts to repopulate the epithelial surface of the small intestine.These newly differentiated cells are not affected by the cholera toxin.their cyclic Allp levels are normal,and they will not secrete Cl-and thus Na+and water at abnormal rates.It takes approximately 3 to 4 days for the entire epithelium to be replaced in this way.The total recovery time will be a day or two longer than that because of the time required for the patient to restore her extracellular fluid volue and electrolyte composition to near normal levels.If the patient is kept hydrated and in reasonable electrolyte balance,normal physiologie processes will cure her of this disease
and glucose, osmotically powers the absorption of water from the lumen of the small intestine into the blood. This helps to restore the patient's extracellular fluid volume. 4. Those intestinal epithelial cells that are affected by the cholera toxin have their adenylyl cyclase molecules irreversibly activated. This persists as long as the cells themselves do. For this reason, giving the patient an antibiotic to kill the Vibrio cholerae in her intestine, without also giving oral rehydration therapy, would not have saved this woman's life. If this patient with cholera is given no antibiotic, but is kept hydrated and in electrolyte balance with oral rehydration therapy, she will recover. The diarrhea will clear the Vibrio cholerae from her gastrointestinal tract. As the affected intestinal epithelial cells are exfoliated into the lumen, they will be replaced by new epithelial cells that differentiate from the crypts of Lieberkühn as they migrate up out of the crypts to repopulate the epithelial surface of the small intestine. These newly differentiated cells are not affected by the cholera toxin, their cyclic AMP levels are normal, and they will not secrete Cl- and thus Na+ and water at abnormal rates. It takes approximately 3 to 4 days for the entire epithelium to be replaced in this way. The total recovery time will be a day or two longer than that because of the time required for the patient to restore her extracellular fluid volume and electrolyte composition to near normal levels. If the patient is kept hydrated and in reasonable electrolyte balance, normal physiologic processes will cure her of this disease